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REACH

6-Amino-5-chloro-2-cyclopyrimidine-4-carboxylic acid

EC number: 617-769-9 | CAS number: 858956-08-8

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

Subchronic toxicity, oral

NOAEL (rat): 6000 ppm (corresponding to 349 and 448 mg/kg bw/day in males and females, respectively)

NOAEL (mouse): 7000 ppm (corresponding to 1088 and 1623 mg/kg bw/day in males and females, respectively)

NOAEL (dog): 15000 ppm (corresponding to 426 and 388 mg/kg bw/day in males and females, respectively)

Subacute toxicity, dermal:

NOAEL (rat): 1000 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference 1

Endpoint:: sub-chronic toxicity: oral
Type of information:: experimental study
Adequacy of study:: key study
Study period:: 02 February 2007 to 01 July 2008
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Qualifier:: according to guideline
Guideline:: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:: adopted 21 September 1998
Deviations:: no
Remarks:: no hormonal measurements performed
GLP compliance:: yes
Limit test:: no
Species:: rat
Strain:: other: Crl:CD(SD)
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina, USA
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 7 weeks
- Weight at study initiation: 253.0 - 256.4 g (males), 173.7 - 179.4 (females)
- Housing: individually in stainless steel, wire-mesh cages suspended above cage boards
- Diet: PMI® Nutrition International, LLC Certified Rodent LabDiet 5002®, ad libitum
- Water: tap water, ad libitum
- Acclimation period: approximately 9 days

DETAILS OF FOOD AND WATER QUALITY: water samples were ananalyzed for total bacterial counts, and the presence of coliforms, lead, and other contaminants. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 -26
- Humidity (%): 50 ± 20
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:: oral: feed
Vehicle:: unchanged (no vehicle)
Details on oral exposure:: PREPARATION OF DOSING SOLUTIONS: test substance was added directly to the diet to achieve the target concentrations specified by the study design; the test diets were thoroughly mixed to ensure homogeneous distribution of the test substance throughout the diet.

DIET PREPARATION
- Rate of preparation of diet: weekly, except in two instances in which diets were prepared for 10 or 11 days, after stability was confirmed.
- Mixing appropriate amounts with: PMI® Nutrition International, LLC Certified Rodent LabDiet 5002®.
- Storage temperature of food: all diets were refrigerated until used.
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Duplicate samples (concentration verification and homogeneity (from top, middle bottom of the sample) of all dietary concentrations were collected at the initial diet preparation and analyzed to verify the concentration (average of homogeneity samples) and homogeneity of test substance in the diets. Near the middle and end of the study, samples were taken to verify concentration. Duplicate samples were taken from the lowest (300 ppm) and the highest (18,000 ppm) dietary concentration of the initial diet preparation and were analyzed to verify the stability of the test substance in the diets. The 300 ppm concentration was included in the initial diet preparation to establish the stability to cover the dietary concentrations of the present study (600 to 18,000 ppm) as well as the concurrent mouse study (300 to 7000 ppm).

The certificate of analysis (COA) included in the original finalized report listed a purity of 92.2%, which did not fully account for all the inorganic impurities associated with this sample. Due to follow-up analysis of the test substance the COA was revised for the purity 90.5% that accounts for the full impurity profile. This reduction in determined purity of 1.7% had minimal impact on the reported doses determined by chemical analyses and on the values utilized for risk assessments. Therefore, the reported dose values were not adjusted.
Duration of treatment / exposure:: approximately 90 days (94 or 95 days in males and 96 or 97 days in females)
Frequency of treatment:: daily
Dose / conc.:: 600 ppm
Remarks:: Males: corresponding to 35 mg/kg bw/day
Females: corresponding to 45 mg/kg bw/day
Dose / conc.:: 2 000 ppm
Remarks:: Males: corresponding to 114 mg/kg bw/day
Females: corresponding to 146 mg/kg bw/day
Dose / conc.:: 6 000 ppm
Remarks:: Males: corresponding to 349 mg/kg bw/day
Females: corresponding to 448 mg/kg bw/day
Dose / conc.:: 18 000 ppm
Remarks:: Males:corresponding to 1045 mg/kg bw/day
Females:corresponding to 1425 mg/kg bw/day
No. of animals per sex per dose:: 15
Control animals:: yes, plain diet
Details on study design:: - Dose selection rationale: The test substance is a metabolite of methyl 6-amino-5-chloro-2-(cyclopropyl)-4-pyrimidinecarboxylate. A previous 28-day study in rats was conducted with methyl 6-amino-5-chloro-2-(cyclopropyl)-4-pyrimidinecarboxylate at dietary concentrations of 600, 2000, 6000, and 20,000 ppm. No test substance-related effects occurred on ophthalmogical observations, clinical observations, clinical pathology parameters, food consumption, organ weights, gross morphological observations, or survival. A test substance-related decrease in body weight, weight gain, and food efficiency occurred in 20,000 ppm males and females. Males in the 20,000 ppm group had thyroid follicular cell hypertrophy and pancreatic acinar cell apoptosis. Females in the 20,000 ppm group had induction of hepatic ß-oxidation activity. Based on these findings, the dietary concentrations selected for the current 90-day study were 600, 2000, 6000, and 18,000 ppm.

- Rationale for selecting satellite groups: on test day 56, blood was collected from satellite animals for evaluation of test substance and/or metabolite concentration in plasma (separate report was not available).
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
- Cage side observations checked: moribund/dead rats, abnormal behavior/appearance and acute clinical signs of systemic toxicity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Day 0 and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0 and weekly thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest and week 13
- Dose groups that were examined: all dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 14
- Anaesthetic used for blood collection: not specified
- Animals fasted: not specified
- How many animals: all dose groups
- Parameters checked in table No. 1 in the "Any other information and methods incl. tables" section were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 14
- Animals fasted: not specified
- How many animals: all dose groups
- Parameters checked in table No.2 in the "Any other information and methods incl. tables" section were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: week 14
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table No.3 in the "Any other information and methods incl. tables" section were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: pretest and weeks 4, 8, and 13
- Dose groups that were examined: all dose groups
- Battery of functions tested: motor activity / grip strength, rectal body temperature other: please refer to table No 4 in the "Any other information and methods incl. tables" section.

IMMUNOLOGY: No
Sacrifice and pathology:: GROSS PATHOLOGY: Yes (Please refer to table 5 in the "Any other information and methods incl. tables" section.)

HISTOPATHOLOGY: Yes (Please refer to table 6 in the "Any other information and methods incl. tables" section.)
Organ weights determined for organs/tissues listed in table 7 in the "Any other information and methods incl. tables" section.)
Other examinations:: Subchronic Neurotoxicity:
On test days 94 and 95, rats were designated for neuropathology (5 rats/sex/group) analysis. Animals were anesthetized and underwent whole-body in situ perfusion.
(For tissues analysed and further details, please refer to table 8 in the "Any other information and methods incl. tables" section.)

Evaluation of test substance and/or metabolite concentration in plasma (satellite animals)
Approximately 0.5 mL of blood was collected from the satellite animals (5 rats/sex/concentration) on test day 56, for determination of plasma concentration of test substance and/or metabolites.
Statistics:: Significance was judged at p < 0.05. Separate analyses were performed on the data collected for each sex.
For details on statistics please refer to table 9 in the "Any other information and methods incl. tables" section.
Clinical signs:: effects observed, non-treatment-related
Description (incidence and severity):: 600 ppm and 2000 ppm: one female of each dose group had abnormal gait. However, abnormal gait was not observed in these animals during any of the neurobehavioral evaluations. Since no dose response was evident and occurrence was limited to 1 animal/group, these observations were considered to be spurious and not treatment-related.

Other clinical signs observed throughout the study were typical for rats of this age and strain, and included hair loss, eye, ear, or nose discharge hyperactivity, high posture, protrusion in abdomen, absent teeth, clipped teeth, maloccluded teeth, ear twitch, corneal opacity and wound. These clinical signs were observed at low incidence and with no dose response.

(Please refer to table 10 in the "Any other information on results incl. tables" section.)
Mortality:: mortality observed, non-treatment-related
Description (incidence):: control and 6000 ppm: one control male rat and one female rat in the 6000 ppm group were accidentally killed during blood collection just prior to necropsy (non-treatment-related).

(Please refer to table 10 in the "Any other information on results incl. tables" section.)
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: 18,000 ppm: significant decrease in mean body weights and body weight gains were observed in males and females. In males, mean body weight was 9% lower than that of controls on the final test day 91. Overall (test days 0-91) body weight gain in males was 15% lower (statistically significant) than that of controls. In females, mean body weight was 8% lower than that of controls on the final test day 91. Overall (test days 0-91) body weight gain in males was 18% lower (statistically significant) than that of controls.The effects were considered treatment-related and adverse.

6000 ppm: statistically significantly lower body weights and body weight gains compared to controls were observed in males and females over test days 21-28 and 14-21, respectively. (non-treatment-related and non-adverse)

600 ppm: statistically significantly lower body weights and body weight gains compared to controls were observed in females over test days 84-91 (non-treatment-related and non-adverse)..

Changes observed at 6000 and 600 ppm were considered spurious because they occurred only in one time interval and there was no dose response.

(Please refer to table 11 and 12 in the "Any other information on results incl. tables" section.)
Food consumption and compound intake (if feeding study):: effects observed, non-treatment-related
Description (incidence and severity):: 18,000 ppm: mean daily food consumption was statistically significantly lower in males over test day intervals 0-7, 21-28, and 42-49 and in females over test day interval 70-77. These sporadic changes were considered incidental and not treatment-related, because overall mean food consumption was not significantly different from control.
Food efficiency:: effects observed, treatment-related
Description (incidence and severity):: 18,000 ppm: significant decrease in food efficiency was observed in males and females. The overall food efficiency (test days 0-91) in males and females of this dose group was 89% and 83% of control, respectively. In addition, statistically significantly lower mean food efficiency was noted in males over test day intervals 21-28, 70-77, and 77-84 and in females over test day interval 62-70. Since the changes in mean food efficiency were consistent with decreased body weight parameters, they were considered treatment-related and adverse.

6000 ppm: statistically significant reductions in food efficiency were noted in males over test days 21-28 (non-treatment-related and non-adverse).

600 ppm: statistically significant reductions in food efficiency were noted in females over test days 84-91 (non-treatment-related and non-adverse).

Since the findings at 6000 and 600 ppm occurred only over one weekly interval, they were considered spurious, non-treatment-related and non-adverse.

(Please refer to table 13 in the "Any other information on results incl. tables" section.)
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: effects observed, non-treatment-related
Description (incidence and severity):: 600 ppm: one male had a posterior lens opacity and one female had a lens opacity and dislocation, retinal degeneration and iritis. Since effects were observed only in single animals and no dose-response relationship was visible, the observations were not considered treatment-related and non-adverse.
Haematological findings:: no effects observed
Description (incidence and severity):: (Please refer to table 14 in the "Any other information on results incl. tables" section.)
Clinical biochemistry findings:: effects observed, non-treatment-related
Description (incidence and severity):: 6000 ppm: triglyceride (69% of control), total protein and albumin (94% and 93% of control, respectively) and calcium (95% of control) were decreased in female rats. The observed statistically significant changes in group mean clinical chemistry parameters at test days 96-97 in females were considered to be non-treatment-related and non-adverse, because the change did not occur in a dose-related manner.

(Please refer to table 15 in the "Any other information on results incl. tables" section.)
Urinalysis findings:: effects observed, non-treatment-related
Description (incidence and severity):: 18,000 ppm: urine volume was decreased (52% of control) in male rats. However, urine volumes ranging from 2.0 to 14.6 mL in male rats were within the urine volume range of the male control group, 0.7 to 21.0 mL. In addition, there were no correlative clinical pathology or histopathology changes and a similar decrease in urine volume was not observed in females. Therefore, this change was considered non-treatment-related and non-adverse. Furthermore, pH was minimally decreased (91% of control) in female rats dosed. This change was considered non-adverse due to the minimal nature of the change and the lack of associated changes in other urinalysis or clinical chemistry parameters.

(Please refer to table 16 in the "Any other information on results incl. tables" section.)
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: effects observed, non-treatment-related
Description (incidence and severity):: 18,000 ppm: in males, a small (9%) decrease in the mean final body weight, as compared to the control value, was associated with a similar decrease in the mean absolute liver, heart, spleen, and thymus weights. Some of these decreases were statistically significant. Since, there were no gross or microscopic pathology correlates observed and most mean relative (% body weight) organ weights were comparable to control values, the small decreases in mean absolute organ weights were interpreted to be a result of the decreased mean final body weight and not an indication of an organ-specific effect. There was a statistically significant decrease (12%) in the mean relative (% brain weight) liver weight in males, as compared to controls. This difference was also attributed to the decrease in final body weight and secondary to decrease in mean absolute liver weights.

(Please refer to table 17 in the "Any other information on results incl. tables" section.)
Gross pathological findings:: effects observed, non-treatment-related
Description (incidence and severity):: All gross observations were consistent with normal background lesions in rats of this age and strain and thus non-treatment-related and non-adverse.

(Please refer to table 18 in the "Any other information on results incl. tables" section.)
Neuropathological findings:: no effects observed
Description (incidence and severity):: (Please refer to table 23 and 24 in the "Any other information on results incl. tables" section.)
Histopathological findings: non-neoplastic:: effects observed, non-treatment-related
Description (incidence and severity):: All microscopic findings were consistent with normal background lesions in rats of this age and strain and thus non-treatment-related and non-adverse.

(Please refer to table 19 in the "Any other information on results incl. tables" section.)
Histopathological findings: neoplastic:: no effects observed
Other effects:: no effects observed
Description (incidence and severity):: Neurobehavioral evaluation

Functional Observational Battery: There were no treatment-related or statistically significant effects/differences on forelimb or hindlimb grip strength, in footsplay and in the number of rearing movements in the open field arena in males and females of any dose group. (Please refer to table 20, 21 and 22 in the "Any other information on results incl. tables" section.)

600 and 6000 ppm: occasional occurrence of abnormal gait in either the home cage or open field were noted in one 600 ppm male and one 6000 ppm female. Since a dose-response relationship was not evident for either males or females, these incidents were considered to be spurious, non-treatment-related and non-adverse.

Motor acitivity: There were no treatment-related or statistically significant effects on duration of movement or number of movements for males or females of any dose group.
: Key result
Dose descriptor:: LOAEL
Effect level:: 18 000 ppm
Based on:: test mat.
Sex:: male/female
Basis for effect level:: body weight and weight gain; food efficiency
Remarks on result:: other: corresponding to 1045 and 1425 mg/kg bw/day in males and females, respectively.
: Key result
Dose descriptor:: NOAEL
Effect level:: 6 000 ppm
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: no adverse effect observed
Remarks on result:: other: corresponding to 349 and 448 mg/kg bw/day in males and females, respectively.
Critical effects observed:: no

Reference 2

Endpoint:: sub-chronic toxicity: oral
Type of information:: experimental study
Adequacy of study:: key study
Study period:: 28 February - 30 May 2007
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Qualifier:: according to guideline
Guideline:: OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
Version / remarks:: not specified
Deviations:: yes
Remarks:: dosage: the highest dose level did not induce toxicity and no hormonal measurements performed
GLP compliance:: yes
Limit test:: no
Species:: dog
Strain:: Beagle
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Covance Research Products Inc., Kalamazoo, Michigan, USA
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: 9 months
- Weight at study initiation: 8.26 to 12.03 kg (males), 7.59 to 9.81 kg (females),
- Housing: double-housed (single sex) in double-sized stainless steel suspended cages (arrival), two days after arrival dogs were housed individually in single-sized stainless steel suspended cages in an environmentally controlled room.
- Diet: powdered Lab Diet® (Certified Canine Diet #5007, PMI Nutrition International, Inc.), ad libitum. The animals were offered approximately 400 g of meal daily for approximately 2 h.
- Water: tap water, ad libitum
- Acclimation period: 15 days

DETAILS OF FOOD AND WATER QUALITY: Yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 28
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 28 February 2007 To: 30 May 2007
Route of administration:: oral: feed
Vehicle:: unchanged (no vehicle)
Details on oral exposure:: PREPARATION OF DOSING SOLUTIONS: All test diets were prepared on a weight by weight basis with the ground Lab Diet® and were blended for approximately 5 min using a Hobart blender, and approximately 10 min using a twin-shell blender.

DIET PREPARATION
- Rate of preparation of diet: weekly
- Mixing appropriate amounts with: ground Lab Diet® (Certified Canine Diet #5007, PMI Nutrition International, Inc.)
- Storage temperature of food: refrigerated
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: The diet was analysed for homogeneity, stability and concentration of the test substance. For analysis of homogeneity duplicate samples (25.0 g) were collectedfrom the top, middle, and bottom portions of the prepared diets for Week 1 at 250, 1250, 5000, and 15000 ppm and were placed in plastic bags. Samples were stored frozen at approximately -20°C until analysis. For analysis of stability, 8 numbered samples (25.0 g each) were collected from the middle portion of the prepared diets for Week 1 at 250 and 15000 ppm (two sets of duplicate samples at each concentration) and were placed in plastic bags. Samples were stored refrigerated or at room temperature for 7 and 14 days, and then frozen at approximately -20ºC. The Day 7 samples were stored frozen at approximately -20ºC at MPI Research, Inc., for possible future analysis. The Day 14 samples were shipped frozen for analysis. For analysis of the concentration, duplicate samples (25.0 g) were collected from the middle portion of the prepared diets for Weeks 1, 5, 9, and 13 at 250, 1250, 5000, and 15000 ppm and and the respective control sample and placed in plastic bags. Samples were stored frozen at approximately -20°C until shipped frozen for analysis. All analytical work was conducted by the Sponsor. Concentrations of test substance were determined by high-performance liquid chromatography (HPLC) with UV detection. The analytical results demonstrated that the test substance was at the targeted concentrations, was homogeneously mixed in the diet, and was stable in the diet under the study storage conditions for all dietary levels. Test substance was not detected in the control samples.
Duration of treatment / exposure:: 91 days
Frequency of treatment:: daily
Dose / conc.:: 250 ppm
Remarks:: Males: corresponding to 6.46 mg/kg bw/day
Females: corresponding to 7.02 mg/kg bw/day
Dose / conc.:: 1 250 ppm
Remarks:: Males: corresponding to 33.31 mg/kg bw/day
Females: corresponding to 37.94 mg/kg bw/day
Dose / conc.:: 5 000 ppm
Remarks:: Males: corresponding to 126.23 mg/kg bw/day
Females: corresponding to 124.12 mg/kg bw/day
Dose / conc.:: 15 000 ppm
Remarks:: Males: corresponding to 425.71 mg/kg bw/day
Females: corresponding to 387.53 mg/kg bw/day
No. of animals per sex per dose:: 4
Control animals:: yes, plain diet
Details on study design:: - Dose selection rationale: The dose levels were selected on the basis of the results of previous studies conducted with a related chemical.
- Fasting period before blood sampling for clinical biochemistry: yes
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked: morbidity, mortality and injury

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: day after arrival, on day -7, day -1 and weekly during the study

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest and prior to the scheduled terminal necropsy
- Dose groups that were examined: all animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks -2, -1, 4, 8, and 12
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table No.1 in the "Any other information and methods incl. tables" section were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks -2, -1, 4, 8, and 12
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table No.1 in the "Any other information and methods incl. tables" section were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: weeks -2, -1, 4, 8, and 12
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes
- Parameters checked in table No.1 in the "Any other information and methods incl. tables" section were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: once weekly (approximately 4 h after food removal)
- Dose groups that were examined: all animals
- Battery of functions tested: changes in the level of activity, gait, posture, altered strength, and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g., excessive grooming, repetitive circling) or bizarre behavior (e.g., self-mutilation).

IMMUNOLOGY: No
Sacrifice and pathology:: GROSS PATHOLOGY: Yes (Please refer to table 2 in the "Any other information and methods incl. tables" section.)

HISTOPATHOLOGY: Yes (Please refer to table 3 in the "Any other information and methods incl. tables" section.)
Other examinations:: Liver Biochemical Analysis:
Liver samples were snap frozen in liquid nitrogen for analysis of cytochrome P-450 (total and isozyme profile). The microsomal suspensions were analyzed for total cytochrome P-450 levels and quantification of cytochrome P-450 1A1, 1A2, 2B1/2, 2E1, 3A2, and 4A1/2/3. The total microsomal cytochrome P-450 contents were measured by spectral analysis. The spectra were recorded at room temperature with a spectrophotometer. Quantification of cytochrome P-450 isozymes 1A1, 1A2 , 2B1/2, 2E, 3A2 (Chemicon, Temecula, California,USA) and 4A1/2/3 (ABR, Golden, Colorado, USA) were done by Western Blot analysis using commercially available antibodies.

Plasma analysis for determination of test substance and metabolite:
- Time schedule for collection of blood: once during week 9 (approximately 2 h after food removal)
- Animals fasted: No
- How many animals: all animals
Statistics:: Data for each sex within a set were analyzed separately. The raw data were tabulated within each time interval, and the mean and standard deviations were calculated for each endpoint by sex and group. For each endpoint, treatment groups were compared to the control group. Data for some endpoints, as indicated, were transformed by either a log or rank transformation prior to conducting the specified analysis. For details on statistics please refer to table 4 in the "Any other information and methods incl. tables" section.
Clinical signs:: effects observed, non-treatment-related
Description (incidence and severity):: 250, 1250, 5000 and 15,000 ppm: increased incidence of scaling skin on the feet compared to control animals were noted mainly over the last month of dietary exposure in males and females. Incidences per dose were as followed (number of time observed/number of animals affected): 0/0, 182/1, 32/2, 410/2, 1184/4 (males) and 0/0, 43/1, 464/2, 129/2, 444/2 (females) (no strict dose-related pattern was observed). It can not be exluded that this finding is test substance-related, but it was not considered to be an adverse effect as it was not associated with any other clinical or pathological responses.

control, 250, 1250, 5000 and 15,000 ppm: higher incidence of soft and mucoid feces were observed in males and females, but these observations were noted in all dose groups and thus not considerer treatment-related. Incidences per dose were as followed (number of time observed/number of animals affected): feces mucoid: 6/3, 56/4, 56/4, 33/3 and 15/3 (males), 13/1, 9/3, 69/3, 3/3 and 19/3 (females); feces soft: 122/4, 250/4, 352/4, 144/4 and 92/4 (males), 69/4, 122/4, 163/4, 108/4 and 70/4 (females)

Other clinical observations noted are common in this species and not considered related to treatment.
(Please refer to table 5 in the "Any other information on results incl. tables" section.)
Mortality:: no mortality observed
Body weight and weight changes:: effects observed, non-treatment-related
Description (incidence and severity):: control, 250, 1250, 5000 and 15,000 ppm: statistically significant lower mean body weight gain was observed in all male dose groups over the week 1 through 2 interval. These differences were considered spurious as they did not exhibit a dose-response. In addition, mean body weight gain in these groups exceeded that of control in week -1 to 13 (not statistically significant).

(Please refer to table 6, 7 and 8 in the "Any other information on results incl. tables" section.)
Food consumption and compound intake (if feeding study):: effects observed, non-treatment-related
Description (incidence and severity):: There were sporadic statistically significant differences in the mean weekly food consumption in different dose groups and time intervals, but these were not considered treatment-related as they did not exhibit a dose response and there were no treatment-related differences in the mean total food consumption over the entire study period.

(Please refer to table 9 and 10 in the "Any other information on results incl. tables" section.)
Food efficiency:: effects observed, non-treatment-related
Description (incidence and severity):: There were sporadic statistically significant differences in the mean weekly food efficiency in different dose groups and time intervals, but these were not considered treatment-related as they did not exhibit a dose response and there were no treatment-related differences in food efficiency over
the entire study period.

(Please refer to table 11 and 12 in the "Any other information on results incl. tables" section.)
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: effects observed, non-treatment-related
Description (incidence and severity):: 1250 ppm: one female had a detached retina in the right eye noted during the pretest evaluation. This minor abnormality was not noted at the terminal opthalmoscopic examination and was considered to have spontaneously healed without intervention during the study. No test article-related observations were noted in the ophthalmoscopic examinations.
Haematological findings:: effects observed, non-treatment-related
Description (incidence and severity):: 15,000 ppm: erythrocytes and mean activated partial thromboplastin time (APTT) values were statistically significantly decreased in males (week -1).

1250 ppm: lymphocytes (week -1 and -2 ) and large unstained cells (LUC) ( week 8 and 12) were statistically significantly decreased in males.

All observations were considered not meaningful due to the interval involved (pretest) or lack of dose-dependency.

(Please refer to table 13 in the "Any other information on results incl. tables" section.)
Clinical biochemistry findings:: no effects observed
Urinalysis findings:: effects observed, non-treatment-related
Description (incidence and severity):: 250 and 15,000 ppm: statistically significant decreases in urine pH were observed in males (week 12).

5000 ppm: statistically significant decreases in urine pH were observed in females (week 8).

250 and 1250: statistically significant increases in urine pH were observed in females (week 8).

All observations were considered to be not treatment-related due to the lack of dose-dependency, unusually low urine pH in the female controls, and high urine pH in the male controls.

(Please refer to table 14 in the "Any other information on results incl. tables" section.)
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: effects observed, non-treatment-related
Description (incidence and severity):: 1250, 5000, and 15,000 ppm: mean thyroid/parathyroid gland weights were greater in females. Considering the variability among normal dogs, the observation that 2 control female dogs probably had thyroid gland weights at the low end of the range, and no microscopic abnormalities were detected in thyroid glands indicates that the observed differences were not treatment-related.

1250 ppm: absolute brain weight of males and the absolute heart weight of females were statistically significantly different from control animals. Since a dose-response was not visible and these organs were microscopically normal at the highest dose level, it was concluded that these differences were a result of biological variability, rather than treatment-related.

(Please refer to table 15 in the "Any other information on results incl. tables" section.)
Gross pathological findings:: effects observed, non-treatment-related
Description (incidence and severity):: Findings observed were usual and/or incidental in dogs of this type and age. (Please refer to table 16 in the "Any other information on results incl. tables" section.)
Neuropathological findings:: effects observed, non-treatment-related
Description (incidence and severity):: No treatment-related neurobehavioral findings observed. (Please refer to table 18 in the "Any other information on results incl. tables" section.)
Histopathological findings: non-neoplastic:: effects observed, non-treatment-related
Description (incidence and severity):: Findings observed were usual and/or incidental in dogs of this type and age. (Please refer to table 17 in the "Any other information on results incl. tables" section.)
Histopathological findings: neoplastic:: effects observed, non-treatment-related
Description (incidence and severity):: Findings observed were usual and/or incidental in dogs of this type and age. (Please refer to table 17 in the "Any other information on results incl. tables" section.)
Other effects:: effects observed, treatment-related
Description (incidence and severity):: Liver Biochemical Analysis: oral exposure of male and female dogs to the test substance induced several individual hepatic cytochrome P-450 enzymes.

15, 000 ppm: in males a statistically significant decrease in cytochrome P-450 4A1/2/3 was observed (89% of control). This decrease was not considered treatment- related due to the low magnitude of change and sample variability.

5000 and 15,000 ppm: in male dogs enzymes 1A1 (501 and 518% of control, respectively) and 2B1/2 (225 and 191% of control, respectively) were treatment-related increased. At 5000 ppm, the increases in both 1A1 and 2B1/2 were statistically significant whereas increases observed at 15,000 ppm were not statistically significant. However at both doses the increases were considered treatment-related.
In female dogs, cytochrome P-450 isozymes 2B1/2 (193 and 134% of control, respectively) were treatment-related increased. At 5000 ppm, the increases in both 1A1 and 2B1/2 were statistically significant whereas increases observed at 15,000 ppm were not statistically significant. However at both doses the increases were considered treatment-related.

1250, 5000 and 15000 ppm: in female dogs, cytochrome P-450 isozymes 4A1/2/3 (113, 109 and 115% of control, respectively) were treatment-related increased. The increases at 1250 and 15,000 ppm were statistically significant. Although the increase observed at 5000 ppm was not statistically significant, it appears to be treatment-related increased due to the low variability between the samples.

1250 ppm: in female dogs, a statistically significant increase in cytochrome P-450 2E1 (187% of control) was observed .
This increase was not considered treatment-related due to high variability between animals and the lack of increase at the higher levels.

In males, no treatment-related alterations were observed in total cytochrome P-450 content or the cytochrome P-450 1A2, 2E1, 3A2, or 4A1/2/3 content. In females, no treatment-related alterations were observed in total cytochrome P-450 content or the cytochrome P-450 1A1, 1A2, 2E1 or 3A2 content.

(Please refer to table 21 in the "Any other information on results incl. tables" section.)

Plasma analyis for test substance and metabolite:
In both male and female dogs, test substance was by far the most abundant analyte, with the highest concentrations reaching 63,000 and 82,575 ng/mL for 15000 ppm males and females, respectively. In contrast, the plasma levels of the metabolite were significantly lower for this dose group with concentrations of approximately 12 ng/mL for males and females. This value was just above the limit of quantitation. The concentration of test substance in plasma was higher in females than in males at all dose levels, which may suggest greater dietary absorption by female dogs. There was no apparent plateau for the test substance plasma concentrations versus the dietary intake levels.

(Please refer to table 20 in the "Any other information on results incl. tables" section.)
: Key result
Dose descriptor:: NOAEL
Effect level:: 15 000 ppm
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: no adverse effect observed
Remarks on result:: other: corresponding to 426 and 388 mg/kg bw/day in males and females
Critical effects observed:: no

Reference 3

Endpoint:: sub-chronic toxicity: oral
Type of information:: experimental study
Adequacy of study:: key study
Study period:: 08 February 2007- 01 July 2008
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Qualifier:: according to guideline
Guideline:: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:: adopted 21 September 1998
Deviations:: no
Remarks:: no hormonal measurements performed
GLP compliance:: yes
Limit test:: no
Species:: mouse
Strain:: other: Crl:CD1(ICR)
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina, USA
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: 29.0 - 29.5 g (males), 21.7 - 22.0 (females)
- Housing: individually in stainless steel, wire-mesh cages suspended above cage boards.
- Diet: PMI® Nutrition International, LLC Certified Rodent LabDiet 5002®, ad libitum
- Water: tap water, ad libitum
- Acclimation period: approximately 11 days

DETAILS OF FOOD AND WATER QUALITY: Water samples were ananalyzed for total bacterial counts, and the presence of coliforms, lead, and other contaminants. Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations of key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26
- Humidity (%): 50 ± 20
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:: oral: feed
Vehicle:: unchanged (no vehicle)
Details on oral exposure:: PREPARATION OF DOSING SOLUTIONS: Test substance was added directly to the diet to achieve the target concentrations specified by the study design; the test diets were thoroughly mixed to ensure homogeneous distribution of the test substance throughout the diet.

DIET PREPARATION
- Rate of preparation of diet: weekly
- Mixing appropriate amounts with: PMI® Nutrition International, LLC Certified Rodent LabDiet 5002®.
- Storage temperature of food: all diets were refrigerated until used.
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Duplicate samples (concentration verification and homogeneity (from top, middle bottom of the sample) of all dietary concentrations were collected at the initial diet preparation and analyzed to verify the concentration (average of homogeneity samples) and homogeneity of test substance in the diets. The stability of the test substance in the diet were confirmed in the concurrently conducted 90-day rat study. Duplicate samples were taken from the lowest (300 ppm) and the highest (18,000 ppm) dietary concentration of the initial diet preparation and were analyzed to verify the stability of the test substance in the diets. The 300 ppm concentration was included in the initial diet preparation to establish the stability to cover the dietary concentrations of the present study (600 to 18,000 ppm) as well as the concurrent mouse study (300 to 7000 ppm). Near the middle and the end of the study, samples were taken to verify concentration. After study start, the test substance was remilled and sieved to remove clumps. Diet samples prepared using this processed test substance at the concentration of 300 ppm were collected for homogeneity/concentration verification. A control sample was also collected on the same day.

The analytical results show that the test substance was homogeneously mixed in the diet, present at the targeted concentrations, and stable in the diet under the study storage conditions for all dietary levels. Test substance was not detected in the control samples.
Duration of treatment / exposure:: 90 days (95 or 96 days in males and 96 or 97 days in females)
Frequency of treatment:: daily
Dose / conc.:: 300 ppm
Remarks:: Males: corresponding to 47 mg/kg bw/day
Females: corresponding to 61 mg/kg bw/day
Dose / conc.:: 1 000 ppm
Remarks:: Males: corresponding to 154 mg/kg bw/day
Females: corresponding to 230 mg/kg bw/day
Dose / conc.:: 3 000 ppm
Remarks:: Males: corresponding to 459 mg/kg bw/day
Females: corresponding to 649 mg/kg bw/day
Dose / conc.:: 7 000 ppm
Remarks:: Males: corresponding to 1088 mg/kg bw/day
Females: corresponding to 1623 mg/kg bw/day
No. of animals per sex per dose:: 15 (Additional analysis: blood was collected from 5 rats/sex/concentration on test day 56 for additional analysis of test substance and its metabolite)
Control animals:: yes, plain diet
Details on study design:: - Dose selection rationale: The test substance is a metabolite of methyl 6-amino-5-chloro-2-(cyclopropyl)-4-pyrimidinecarboxylate. In a previous 28-day feeding study conducted with methyl 6-amino-5-chloro-2-(cyclopropyl)-4-pyrimidinecarboxylate, mice were dosed with up to 7000 ppm (equivalent to 1149/1429 mg/kg bw/day in males and females, respectively) in the diet. No adverse or treatment-related effects in male or female mice were observed on body weight, nutritional parameters, clinical observations, hematology, clinical chemistry (plasma total protein), gross pathology, or histopathology. No test substance-related effects were noted for beta-oxidation activity, total cytochrome P450 content, or cytochrome P450 isozyme profile. Dietary concentrations of 300, 1000, 3000, or 7000 ppm were selected for the current study, based on the results of the previous study.

- Fasting period before blood sampling for clinical biochemistry:
- Rationale for selecting satellite groups: on test day 60, blood was collected from 5 animals from each group (satellite animals) at necropsy for evaluation of test substance and/or metabolite concentration in plasma.
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
- Cage side observations checked: moribund/dead rats, abnormal behavior/appearance and acute clinical signs of systemic toxicity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Day 0 and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0 and weekly thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest and week 13 (prior to the final sacrifice on test day 92)
- Dose groups that were examined: all dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 14
- Anaesthetic used for blood collection: Yes (carbon dioxide anesthesia)
- Animals fasted: not specified
- How many animals: first ten animals in each group on test days 95-96 and 96-97 for males and females, respectively
- Parameters checked in table No. 1 in the "Any other information and methods incl. tables" section were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 14
- Animals fasted: not specified
- How many animals: first ten animals in each group on test days 95-96 and 96-97 for males and females, respectively
- Parameters checked in table No.2 in the "Any other information and methods incl. tables" section were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

OTHER
Blood collection Plasma Concentration of Test Substance/ Metabolite (Satellite animals only) on day 60
Sacrifice and pathology:: GROSS PATHOLOGY: Yes (Please refer to table 3 in the "Any other information and methods incl. tables" section.)

HISTOPATHOLOGY: Yes (Please refer to table 4 in the "Any other information and methods incl. tables" section.)
(Organ weight determined for organs/tissues listed in table 5 in the "Any other information and methods incl. tables" section.)
Statistics:: Significance was judged at p < 0.05. Separate analyses were performed on the data collected for each sex.
For details on statistics please refer to table 6 in the "Any other information and methods incl. tables" section.
Clinical signs:: effects observed, non-treatment-related
Description (incidence and severity):: Clinical signs observed throughout the study were typical for mice of this age and strain.

(Please refer to table 7 in the "Any other information on results incl. tables" section.)
Mortality:: mortality observed, non-treatment-related
Description (incidence):: 1000 ppm: one male mouse was found dead. The cause of death was malignant lymphoma, apparently originating in the thymus. The occurrence of this neoplasm was interpreted to be incidental and not treatment- related.

(Please refer to table 7 in the "Any other information on results incl. tables" section.)
Body weight and weight changes:: effects observed, non-treatment-related
Description (incidence and severity):: 7000 ppm: in males, statistically significant decreases in weekly mean body weights were noted from test days 49 to 77 except test day 70. The final (test day 91) mean body weight was 7% lower than control. In addition, mean body weight gains were statistically lower over 4 weekly intervals. Overall (test days 0-91) body weight gains were statistically significant (27%) lower than control. In females, statistically significant decreases in weekly mean body weights were noted from test days 63 to 84. The final (test day 91) mean body weight was 8% lower than control. In addition, mean body weight gains were statistically lower over the weekly intervals of 35-42 and statistically significant increases were seen over the weekly intervals of 28-35 and 84-91. Overall (test days 0-91) body weight gains were (28%) lower than control.

3000 ppm: in males, statistically significant decreases in weekly mean body weights were noted at test day 21. The final (test day 91) mean body weight was 4% lower than control. In addition, mean body weight gains were statistically lower over 3 weekly intervals and statistically significant higher body in the weekly interval of 84-91. Overall (test days 0-91) body weight gains were (12%) lower than control. In females, statistically significant decreases in weekly mean body weights were noted at test day 70. The final (test day 91) mean body weight was 3% lower than control. Statistically significant increases of body weight gainswere seen over the weekly interval 84-91. Overall (test days 0-91) body weight gains were (10%) lower than control.

1000 ppm: in males, statistically significant decreases in weekly mean body weights were noted from test days 42 to 91 except test days 70 and 84. The final (test day 91) mean body weight was 8% statistically significant lower than control. In addition, mean body weight gains were statistically lower over 1 weekly interval and statistically significant higher body in the weekly interval of 77-84. Overall (test days 0-91) body weight gains were statistically significant (25%) lower than control. In females, statistically significant decreases in weekly mean body weights were noted from test days 42 to 77 except test day 49. The final (test day 91) mean body weight was 9% lower than control. Overall (test days 0-91) body weight gains were (31%) lower than control.

300 ppm: The final (test day 91) mean body weight was 5% lower than control. In addition, mean body weight gains were statistically lower over 1 weekly interval. Overall (test days 0-91) body weight gains were (16%) lower than control. The final (test day 91) mean body weight was 4% lower than control. Overall (test days 0-91) body weight gains were (14%) lower than control.

The magnitude of overall (test days 0-91) decreases in body weight parameters observed in the 7000 ppm group was similar to 1000 ppm group and the values of 3000 ppm were generally higher than 1000 and 7000 ppm groups. Also, the body weight parameters were statistically significantly higher in some intervals of treated groups than control. Since there was no clear dose-response and changes were inconsistent, the changes in body weight parameters were considered incidental and not treatment-related.

(Please refer to table 8 and 9 in the "Any other information on results incl. tables" section.)
Food consumption and compound intake (if feeding study):: effects observed, non-treatment-related
Description (incidence and severity):: 7000 ppm: in females statistically significant increases in food consumption over 3 weekly intervals were observed, but considered spurious and not treatment-related.
Food efficiency:: effects observed, non-treatment-related
Description (incidence and severity):: 7000 ppm: in males, statistically significant decreases in food efficiency were noted over 4 weekly intervals. Overall (test days 0-91) food efficiency was statistically (24%) lower than control. In females, statistically significant decreases of food efficiency were noted over weekly intervals of 35-42 and 0-91. In addition, statistically significant increases were observed over the weekly interval of 28-35. Overall (test days 0-91) food efficiency was statistically significant (29%) lower than control.

3000 ppm: in males, statistically significant decreases in food efficiency were noted over 3 weekly intervals. Statistically significant increases were observed over the weekly interval of 84-91. Overall (test days 0-91) food efficiency was statistically lower (10%) lower than control. In females, statistically significant decreases of food efficiency were noted over weekly intervals of 49-56 and 0-91. In addition, statistically significant increases were observed over the weekly interval of 84-91. Overall (test days 0-91) food efficiency was (7%) lower than control.

1000 ppm: in males, statistically significant decreases in food efficiency were noted over 1 weekly intervals. Statistically significant increases were observed over the weekly interval of 77-84. Overall (test days 0-91) food efficiency was statistically significant (19%) lower than control in males. In females, overall (test days 0-91) food efficiency was statistically significant (36%) lower than control.

300 ppm: in males, statistically significant decreases in food efficiency were noted over 1 weekly intervals. Overall (test days 0-91) food efficiency was statistically lower (14%) lower than control. Overall (test days 0-91) food efficiency was (14%) lower than control.

Since the changes seen in food efficiency did not show a clear dose response, these changes were not considered to be treatment-related.

(Please refer to table 10 in the "Any other information on results incl. tables" section.)
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: no effects observed
Haematological findings:: effects observed, non-treatment-related
Description (incidence and severity):: 7000 ppm: reticulocyte count was minimally decreased in female mice (85% of control). This change was not considered treatment-related as there were no associated statistically significant changes in red blood cell mass parameters (red blood cell, haemoglobin and haematocrit).

100 and 3000 ppm: red cell distribution width was statistically significant, but minimally increased in female mice at test days 96-97 (109% and 106% of control, respectively). Observed changes were considered treatment-unrelated and non-adverse, because the change did not occur in a dose-related pattern.

300 ppm: haematocrit was statistically significant, but minimally increased in male mice at test days 95-96 (110% of control). The observed change was considered treatment-unrelated and non-adverse, because the change did not occur in a dose-related pattern.

(Please refer to table 11 in the "Any other information on results incl. tables" section.)
Clinical biochemistry findings:: no effects observed
Description (incidence and severity):: (Please refer to table 12 in the "Any other information on results incl. tables" section.)
Urinalysis findings:: not examined
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: effects observed, non-treatment-related
Description (incidence and severity):: 7000 ppm: a small, statistically significant, decrease in mean absolute heart weight in females, as compared to the controls, was not interpreted to be treatment-related since the decrease corresponded to a lower mean body weight in this group, the mean relative (% body weight) heart weight was not statistically different from the control value and there were no gross or microscopic findings that correlated with the lower mean heart weight.

Other occasional statistical differences were considered spurious and not test substance related.

(Please refer to table 13 in the "Any other information on results incl. tables" section.)
Gross pathological findings:: effects observed, non-treatment-related
Description (incidence and severity):: All gross observations were consistent with normal background lesions in mice of this age and strain.

(Please refer to table 14 in the "Any other information on results incl. tables" section.)
Neuropathological findings:: not examined
Histopathological findings: non-neoplastic:: effects observed, non-treatment-related
Description (incidence and severity):: All microscopic findings were consistent with normal background lesions in mice of this age and strain.

(Please refer to table 15 in the "Any other information on results incl. tables" section.)
Histopathological findings: neoplastic:: effects observed, non-treatment-related
Description (incidence and severity):: All microscopic findings were consistent with normal background lesions in mice of this age and strain.

(Please refer to table 15 in the "Any other information on results incl. tables" section.)
Other effects:: not examined
Details on results:: Blood collection (study reprot M-538332-01-1) - plasma concentration of test substance/ metabolite in satellite animals on day 60:
Plasma samples were analyzed for the test substance and one metabolite. None of the mouse plasma samples had metabolite concentrations above the limit of quantitation (10 ng/mL). The average concentration of the test substance in plasma was slightly higher in males than in females at all dose levels, with the highest concentrations reaching 2484 and 2313 ng/mL for 7000 ppm males and females, respectively. There was no apparent plateau for the test substance plasma concentrations versus the dietary intake levels.
: Key result
Dose descriptor:: NOAEL
Effect level:: 7 000 ppm
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: no adverse effect observed
Remarks on result:: other: corresponding to 1088 and 1623 mg/kg bw/day in males and females, respectively.
Critical effects observed:: no

Endpoint conclusion

Endpoint conclusion:: adverse effect observed
Dose descriptor:: NOAEL
: 349 mg/kg bw/day
Study duration:: subchronic
Experimental exposure time per week (hours/week):: 168
Species:: rat
Quality of whole database:: The available information comprises adequate, reliable (Klimisch score 1) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006. The selected study describes effects in the most vulnerable species with the lowest dose descriptor.
System:: other:
Organ:: other: reduced body weight, weight gain and food efficiency

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:: no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:: no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:: short-term repeated dose toxicity: dermal
Type of information:: experimental study
Adequacy of study:: key study
Study period:: 13 June - 12 July 2007
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Qualifier:: according to guideline
Guideline:: OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Version / remarks:: adopted 12 May 1981
Deviations:: no
GLP compliance:: yes
Limit test:: no
Species:: rat
Strain:: Sprague-Dawley
Remarks:: Hsd:Sprague Dawley®
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Harlan, Indianapolis, IN, USA
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 8 - 9 weeks
- Weight at study initiation: 243-267 g (males), 175-199 g (females)
- Housing: individually in suspended stainless steel cages (conform with the Guide for the Care and Use of Laboratory Animals, DHEW (NIH).
- Diet: Purina Certified Rodent Meal #5002, ad libitum
- Water: filtered tap water, ad libitum
- Acclimation period: 8 days

DETAILS OF FOOD AND WATER QUALITY: Yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23
- Humidity (%): 57 - 67
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:: not specified
Vehicle:: unchanged (no vehicle)
Remarks:: moistened with distilled water
Details on exposure:: TEST SITE
- Area of exposure: control: 2 x 3 inch (males and females), 150 mg/kg bw/day: 1 x 2 inch (males) and 1 x 1 inch (females), 400 mg/kg bw/day: 2 x 2 inch (males) and 1 x 2 inch (females), 1000 mg/kg bw/day: 2 x 3 inch (males and females). (For the range of dermal doses in g, please refer to table 14 in the"Any other information on results incl. tables" section.)
- % coverage: approximately 10
- Type of wrap if used: non-irritating tape (3 inch 3M Micropore™)
- Time intervals for shavings: as needed throughout the study

REMOVAL OF TEST SUBSTANCE
- Washing: wiped with water using clean towels to remove any residual test substance and then gently patted dry with a clean pad
- Time after start of exposure: following the 6 h exposure period

TEST MATERIAL
- Amounts applied: test substance (150, 400 or 1000 mg/kg bw/day) moistened with water
- Constant volume or concentration used: no
- For solids, paste formed: yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes/no
Analytical verification of doses or concentrations:: no
Duration of treatment / exposure:: 6 h per day / 7 days per week for 28 days
Frequency of treatment:: daily
Dose / conc.:: 150 mg/kg bw/day
Dose / conc.:: 400 mg/kg bw/day
Dose / conc.:: 1 000 mg/kg bw/day
No. of animals per sex per dose:: 10
Control animals:: yes, concurrent no treatment
Details on study design:: - Dose selection rationale: The highest dose (1000 mg/kg bw/day) is the regulatory limit dose. The high level was expected to potentially exhibit some evidence of toxicity and the NOAEL was expected at the low or intermediate exposure level in both male and female rats.
- Fasting period before blood sampling for clinical biochemistry: yes
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (mortality), once daily (general inspection)
- - Cage side observations checked in table No.1 (in the "Any other information and methods incl. tables" section) were examined.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily before test substance application and weekly thereafter

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: after patch removal for signs of erythema and edema on Day 3, each Friday and on the day of the final application
- Scoring system: "Primary Skin Irritation Scoring System" developed by Draize et al.

BODY WEIGHT: Yes
- Time schedule for examinations: prior to the first patch application (days 1 and 2 for males and females, respectively) and weekly thereafter (intervals were 7 days ± 1 day)

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to study initiation and Day 24
- Dose groups that were examined: all dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 29 (males) or Day 30 (females), prior to sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane anesthesia)
- Animals fasted: Yes (except for blood samples used for analysis of coagulation parameters)
- How many animals: all animals
- Parameters listed in table No.2 (in the "Any other information and methods incl. tables" section) were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Day 29 (males) or
Day 30 (females), prior to sacrifice
- Animals fasted: Yes
- How many animals: all animals
- Parameters listed in table No.2 (in the "Any other information and methods incl. tables" section) were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:: GROSS PATHOLOGY: Yes (Please refer to table 3 in the "Any other information and methods incl. tables" section.)

HISTOPATHOLOGY: Yes (Please refer to table 3 in the "Any other information and methods incl. tables" section.)
Statistics:: Group means and standard deviations were calculated for body weight, daily body weight gain, daily food consumption, daily food efficiency, organ weight, and organ-to-body/brain weight ratio data. Data within groups were evaluated for homogeneity of variances and normality by Bartlett’s test. Where Bartlett’s test indicated homogeneous variances, treated and control groups were compared using a One-Way Analysis of Variance (ANOVA), followed by comparison of the treated groups to control by Dunnett’s t-test for multiple comparisons. Where variances were considered significantly different by Bartlett’s test, groups were compared using a non-parametric method (Kruskal-Wallis non parametric analysis of variance followed by Dunn’s test) (INSTAT Biostatistics, Graph Pad
Software, San Diego, CA). Differences among groups were judged to be significant at a probability value of p 0.05. Male and female rats were evaluated separately.
Clinical signs:: no effects observed
Description (incidence and severity):: There were no test substance-related clinical signs in any test group that were considered to be of toxicological significance.
Dermal irritation:: effects observed, treatment-related
Description (incidence and severity):: 400 and 1000 mg/kg bw/day: very slight erythema graded with a score of 1 were noted for the dose sites in single animals (400 mg/kg bw/day: 1/10 males on Day 28; 1000 mg/kg bw/day: 2/10 males on Day 3 and 28, respectively).

(Please refer to table 4 in the "Any other information on results incl. tables" section.)
Mortality:: no mortality observed
Body weight and weight changes:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: Mean body weight and daily body weight gain and overall (Days 2-29) body weight gain were statistically significantly increased in females during Week 4 and/or overall. Since during the same period, control group values for these parameters were notably lower than historical control values for rats of the same age, these findings were not considered treatment-related or adverse and considered not to be of toxicological importance.

(Please refer to table 5 and 6 in the "Any other information on results incl. tables" section.)
Food consumption and compound intake (if feeding study):: effects observed, non-treatment-related
Description (incidence and severity):: 150 and 400 mg/kg bw/day: Statistically significant decreases in mean daily food consumption were observed in female rats for the test period overall (Days 2-29) and during week 3, respectively. These findings were not dose-related and thus not considered treatment-related.

(Please refer to table 7 in the "Any other information on results incl. tables" section.)
Food efficiency:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: an increase in mean food efficiency for the overall test period (Days 2-29) was seen in females and correlated with increased body weight gain for the same test period. Since week 4 control group values for food efficiency were notably lower than historical control values for rats of the same age, these findings were not considered treatment-related or adverse and considered not to be of toxicological importance.

(Please refer to table 8 in the "Any other information on results incl. tables" section.)
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: no effects observed
Haematological findings:: effects observed, non-treatment-related
Description (incidence and severity):: 150 mg/kg bw/day: Red cell distribution width was slightly increased in females compared to control. Since there were no corresponding red cell mass findings, the statistically significant change in mean haematology results was not considered to be adverse or treatment-related.

(Please refer to table 9 in the "Any other information on results incl. tables" section.)
Clinical biochemistry findings:: effects observed, non-treatment-related
Description (incidence and severity):: 150 and 1000 mg/kg bw/day: creatinine was statistically significantly decreased in males compared to control. Due to the absence of a dose-response relationship and the small magnitude of the change it is not considered treatment-related or adverse.

(Please refer to table 10 in the "Any other information on results incl. tables" section.)
Urinalysis findings:: not examined
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: absolute adrenal weights were significantly increased in females compared to controls.

150 mg/kg bw/day: both absolute and relative ovarian weights and kidney-to-brain weight ratios were significantly decreased in females compared to controls.

Since there were no microscopic correlates observed for these findings, they were determined to be toxicologically insignificant.

(Please refer to table 11, 12 and 13 in the "Any other information on results incl. tables" section.)
Gross pathological findings:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: a lung adhesion in 1 female had no corresponding microscopic finding.

400 mg/kg bw/day: an epididymal mass (2.0 x 2.0 mm) from 1 male was histologically confirmed as a small sperm granuloma.

Control: 1 male exhibited a small appearing right testis and epididymis which were confirmed microscopically as mild unilateral tubular atrophy and intratubular cellular debris, respectively.

All these incidental findings were considered unrelated to treatment and, as such, toxicologically insignificant. All other macroscopic changes were observed at comparable incidences in the control and treated groups, and/or commonly observed in untreated rats.
Neuropathological findings:: not examined
Histopathological findings: non-neoplastic:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: minimal focal lobular atrophy in the pancreas of 1/10 males. Slight focal fibrosis in the salivary glands in 1/10 females These observations were considered
unrelated to treatment due to their isolated occurrences, focal distribution and their common occurrence in untreated rats.

All other microscopic changes were of comparable incidence and severity in the test substance-treated and control animals, and are commonly observed in untreated laboratory rats.
Histopathological findings: neoplastic:: no effects observed
Other effects:: not examined
: Key result
Dose descriptor:: NOAEL
Effect level:: 1 000 mg/kg bw/day
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: no adverse effects observed
: Key result
Critical effects observed:: no

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 1 000 mg/kg bw/day
Study duration:: subacute
Experimental exposure time per week (hours/week):: 42
Species:: rat
Quality of whole database:: The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:: short-term repeated dose toxicity: dermal
Type of information:: experimental study
Adequacy of study:: key study
Study period:: 13 June - 12 July 2007
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Qualifier:: according to guideline
Guideline:: OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Version / remarks:: adopted 12 May 1981
Deviations:: no
GLP compliance:: yes
Limit test:: no
Species:: rat
Strain:: Sprague-Dawley
Remarks:: Hsd:Sprague Dawley®
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Harlan, Indianapolis, IN, USA
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: 8 - 9 weeks
- Weight at study initiation: 243-267 g (males), 175-199 g (females)
- Housing: individually in suspended stainless steel cages (conform with the Guide for the Care and Use of Laboratory Animals, DHEW (NIH).
- Diet: Purina Certified Rodent Meal #5002, ad libitum
- Water: filtered tap water, ad libitum
- Acclimation period: 8 days

DETAILS OF FOOD AND WATER QUALITY: Yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23
- Humidity (%): 57 - 67
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:: not specified
Vehicle:: unchanged (no vehicle)
Remarks:: moistened with distilled water
Details on exposure:: TEST SITE
- Area of exposure: control: 2 x 3 inch (males and females), 150 mg/kg bw/day: 1 x 2 inch (males) and 1 x 1 inch (females), 400 mg/kg bw/day: 2 x 2 inch (males) and 1 x 2 inch (females), 1000 mg/kg bw/day: 2 x 3 inch (males and females). (For the range of dermal doses in g, please refer to table 14 in the"Any other information on results incl. tables" section.)
- % coverage: approximately 10
- Type of wrap if used: non-irritating tape (3 inch 3M Micropore™)
- Time intervals for shavings: as needed throughout the study

REMOVAL OF TEST SUBSTANCE
- Washing: wiped with water using clean towels to remove any residual test substance and then gently patted dry with a clean pad
- Time after start of exposure: following the 6 h exposure period

TEST MATERIAL
- Amounts applied: test substance (150, 400 or 1000 mg/kg bw/day) moistened with water
- Constant volume or concentration used: no
- For solids, paste formed: yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes/no
Analytical verification of doses or concentrations:: no
Duration of treatment / exposure:: 6 h per day / 7 days per week for 28 days
Frequency of treatment:: daily
Dose / conc.:: 150 mg/kg bw/day
Dose / conc.:: 400 mg/kg bw/day
Dose / conc.:: 1 000 mg/kg bw/day
No. of animals per sex per dose:: 10
Control animals:: yes, concurrent no treatment
Details on study design:: - Dose selection rationale: The highest dose (1000 mg/kg bw/day) is the regulatory limit dose. The high level was expected to potentially exhibit some evidence of toxicity and the NOAEL was expected at the low or intermediate exposure level in both male and female rats.
- Fasting period before blood sampling for clinical biochemistry: yes
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (mortality), once daily (general inspection)
- - Cage side observations checked in table No.1 (in the "Any other information and methods incl. tables" section) were examined.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily before test substance application and weekly thereafter

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: after patch removal for signs of erythema and edema on Day 3, each Friday and on the day of the final application
- Scoring system: "Primary Skin Irritation Scoring System" developed by Draize et al.

BODY WEIGHT: Yes
- Time schedule for examinations: prior to the first patch application (days 1 and 2 for males and females, respectively) and weekly thereafter (intervals were 7 days ± 1 day)

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to study initiation and Day 24
- Dose groups that were examined: all dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 29 (males) or Day 30 (females), prior to sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane anesthesia)
- Animals fasted: Yes (except for blood samples used for analysis of coagulation parameters)
- How many animals: all animals
- Parameters listed in table No.2 (in the "Any other information and methods incl. tables" section) were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Day 29 (males) or
Day 30 (females), prior to sacrifice
- Animals fasted: Yes
- How many animals: all animals
- Parameters listed in table No.2 (in the "Any other information and methods incl. tables" section) were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:: GROSS PATHOLOGY: Yes (Please refer to table 3 in the "Any other information and methods incl. tables" section.)

HISTOPATHOLOGY: Yes (Please refer to table 3 in the "Any other information and methods incl. tables" section.)
Statistics:: Group means and standard deviations were calculated for body weight, daily body weight gain, daily food consumption, daily food efficiency, organ weight, and organ-to-body/brain weight ratio data. Data within groups were evaluated for homogeneity of variances and normality by Bartlett’s test. Where Bartlett’s test indicated homogeneous variances, treated and control groups were compared using a One-Way Analysis of Variance (ANOVA), followed by comparison of the treated groups to control by Dunnett’s t-test for multiple comparisons. Where variances were considered significantly different by Bartlett’s test, groups were compared using a non-parametric method (Kruskal-Wallis non parametric analysis of variance followed by Dunn’s test) (INSTAT Biostatistics, Graph Pad
Software, San Diego, CA). Differences among groups were judged to be significant at a probability value of p 0.05. Male and female rats were evaluated separately.
Clinical signs:: no effects observed
Description (incidence and severity):: There were no test substance-related clinical signs in any test group that were considered to be of toxicological significance.
Dermal irritation:: effects observed, treatment-related
Description (incidence and severity):: 400 and 1000 mg/kg bw/day: very slight erythema graded with a score of 1 were noted for the dose sites in single animals (400 mg/kg bw/day: 1/10 males on Day 28; 1000 mg/kg bw/day: 2/10 males on Day 3 and 28, respectively).

(Please refer to table 4 in the "Any other information on results incl. tables" section.)
Mortality:: no mortality observed
Body weight and weight changes:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: Mean body weight and daily body weight gain and overall (Days 2-29) body weight gain were statistically significantly increased in females during Week 4 and/or overall. Since during the same period, control group values for these parameters were notably lower than historical control values for rats of the same age, these findings were not considered treatment-related or adverse and considered not to be of toxicological importance.

(Please refer to table 5 and 6 in the "Any other information on results incl. tables" section.)
Food consumption and compound intake (if feeding study):: effects observed, non-treatment-related
Description (incidence and severity):: 150 and 400 mg/kg bw/day: Statistically significant decreases in mean daily food consumption were observed in female rats for the test period overall (Days 2-29) and during week 3, respectively. These findings were not dose-related and thus not considered treatment-related.

(Please refer to table 7 in the "Any other information on results incl. tables" section.)
Food efficiency:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: an increase in mean food efficiency for the overall test period (Days 2-29) was seen in females and correlated with increased body weight gain for the same test period. Since week 4 control group values for food efficiency were notably lower than historical control values for rats of the same age, these findings were not considered treatment-related or adverse and considered not to be of toxicological importance.

(Please refer to table 8 in the "Any other information on results incl. tables" section.)
Water consumption and compound intake (if drinking water study):: not examined
Ophthalmological findings:: no effects observed
Haematological findings:: effects observed, non-treatment-related
Description (incidence and severity):: 150 mg/kg bw/day: Red cell distribution width was slightly increased in females compared to control. Since there were no corresponding red cell mass findings, the statistically significant change in mean haematology results was not considered to be adverse or treatment-related.

(Please refer to table 9 in the "Any other information on results incl. tables" section.)
Clinical biochemistry findings:: effects observed, non-treatment-related
Description (incidence and severity):: 150 and 1000 mg/kg bw/day: creatinine was statistically significantly decreased in males compared to control. Due to the absence of a dose-response relationship and the small magnitude of the change it is not considered treatment-related or adverse.

(Please refer to table 10 in the "Any other information on results incl. tables" section.)
Urinalysis findings:: not examined
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: absolute adrenal weights were significantly increased in females compared to controls.

150 mg/kg bw/day: both absolute and relative ovarian weights and kidney-to-brain weight ratios were significantly decreased in females compared to controls.

Since there were no microscopic correlates observed for these findings, they were determined to be toxicologically insignificant.

(Please refer to table 11, 12 and 13 in the "Any other information on results incl. tables" section.)
Gross pathological findings:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: a lung adhesion in 1 female had no corresponding microscopic finding.

400 mg/kg bw/day: an epididymal mass (2.0 x 2.0 mm) from 1 male was histologically confirmed as a small sperm granuloma.

Control: 1 male exhibited a small appearing right testis and epididymis which were confirmed microscopically as mild unilateral tubular atrophy and intratubular cellular debris, respectively.

All these incidental findings were considered unrelated to treatment and, as such, toxicologically insignificant. All other macroscopic changes were observed at comparable incidences in the control and treated groups, and/or commonly observed in untreated rats.
Neuropathological findings:: not examined
Histopathological findings: non-neoplastic:: effects observed, non-treatment-related
Description (incidence and severity):: 1000 mg/kg bw/day: minimal focal lobular atrophy in the pancreas of 1/10 males. Slight focal fibrosis in the salivary glands in 1/10 females These observations were considered
unrelated to treatment due to their isolated occurrences, focal distribution and their common occurrence in untreated rats.

All other microscopic changes were of comparable incidence and severity in the test substance-treated and control animals, and are commonly observed in untreated laboratory rats.
Histopathological findings: neoplastic:: no effects observed
Other effects:: not examined
: Key result
Dose descriptor:: NOAEL
Effect level:: 1 000 mg/kg bw/day
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: no adverse effects observed
: Key result
Critical effects observed:: no

Endpoint conclusion

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 6.97 mg/cm²
Study duration:: subacute
Species:: rat
Quality of whole database:: The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, of Regulation (EC) No 1907/2006.

Additional information

Repeated dose toxicity: oral

Repeated dose toxicity following the oral route was tested in a GLP-compliant 90-Day feedingstudy in rats (Crl:CD(SD)) according to OECD 408 (2011 g). In this study, 15 rats per sex and dose level were fed with a diet containing 600, 2000, 6000 and 18000 ppm test substance (corresponding to 35, 114, 349, and 1045 mg/kg bw/day in males and 45, 146, 448, and 1425 mg/kg bw/day in females, respectively). Control animals received standard diet (Rodent Lab Diet^®5002). Analysis of the diets proved that the test substance was homogeneously mixed in the diet, at the targeted concentrations, and stable in the diet under the study storage conditions for all dietary levels. Due to follow-up analysis of the test substance the certificate of analysis was revised and the purity was changed from 92.2% to 90.5% that accounts for the full impurity profile. This reduction in determined purity of 1.7% was considered to have a minimal impact on the reported doses determined by chemical analyses, thus the reported dose values were not adjusted, retrospectively. Examinations included clinical observations, body weight, food consumption and efficiency, test substance uptake, opthalmoscopic analysis, urinalysis, haematology and biochemical parameters. Furthermore, neurobehavioral evaluations, consisting of functional observational battery and motor activity, were conducted prior to study start and during weeks 4, 8, and 13 of exposure. After approximately 90 days (94 or 95 days in males and 96 or 97 days in females) rats were subjected to gross pathology and histopathology analysis. In addition, selected animals (5 rats/sex/group) were perfused and analysed for neuropathology findings.

Most clinical signs observed throughout the study were typical for rats of this age and strain, and included hair loss, eye, ear, or nose discharge, hyperactivity, high posture, protrusion in abdomen, absent clipped or maloccluded teeth, ear twitch, corneal opacity and wound. Since these clinical signs were observed at low incidence and with no dose response, they were not considered treatment-related. At 600 and 2000 ppm abnormal gait was observed in on female of each group. Since this finding was not visible in these animals during any of the neurobehavioral evaluations, no dose-response was evident and occurrence was limited to 1 animal/group, these observations were considered to be incidental and not treatment-related. Beside the death of two accidentally killed animals (1/15 males of the control and 1/15 females of the 6000 ppm dose group) no further treatment-related mortality was observed in any dose group.

Treatment-related and adverse decreases in body weight, body weight gain and food efficiency, were noted in males and females of the highest dose group (18.000 ppm). Since the changes in mean food efficiency were consistent with decreased body weight parameters at this dose level, they were considered treatment-related and adverse. Statistically significant effects observed on these parameters at 6000 ppm were not considered treatment-related or adverse due to the occurrence at isolated time intervals (body weight was only reduced at test days 21-28 and 14-21 in males and females and food efficiency was reduced at test days 21-28 in males). In both sexes of the high dose group, food consumption was reduced at single time intervals. Because the overall mean food consumption did not differ significantly and due to the sporadic occurrence, these observations were not considered treatment-related.

Ophthalmoscopic analyses revealed that one male of the 600 ppm dose group had a posterior lens opacity and one female had a lens opacity and dislocation, retinal degeneration and iritis. Since these effects were observed only in single animals and no dose-response relationship was visible, the observations were not considered treatment-related or adverse.

No adverse effects were observed on neurobehavioral, haematology, clinical biochemistry or urinalysis parameters. The observed decrease in triglyceride (69% of control), total protein and albumin (94% and 93% of control, respectively) and calcium (95% of control) levels in female rats of the 6000 ppm were not considered treatment-related due to a missing dose-response relationship.

The decreased urine volume and minimally increased urine pH in male high dose rats were also not considered treatment-related, due to missing correlative clinical pathology or histopathology changes or their minimal nature and lack of associated changes in other urinalysis or clinical chemistry parameters.

Analysis of organ weight findings and ratios revealed a decrease in the mean absolute liver, heart, spleen and thymus weights in males of the high dose group. Some of these decreases were statistically significant. As these changes were accompanied by a decrease of the mean final body weights, there were no gross or microscopic pathology correlates observed and most mean relative (% body weight) organ weights were comparable to control values, the small decreases in mean absolute organ weights were interpreted to be a result of the decreased mean final body weight and not an indication of an organ-specific effect. In addition, there was a statistically significant decrease (12%) in the mean relative (% brain weight) liver weight in males, as compared to controls. This difference was also attributed to the decrease in final body weight and secondary to a decrease in mean absolute liver weights.

All observed gross and microscopic findings were consistent with normal background lesions in rats of this age and strain and thus not considered treatment-related or adverse. Neuropathology examinations performed in selected animals did not reveal any adverse effects.

Based on effects observed on body weight and weight gain and food efficiency at 18,000 ppm the LOAEL/NOAEL for male and female rats was determined at 6000 ppm and 18,000 ppm, respectively, corresponding to 349 and 448 mg/kg bw/day (NOAEL) and 1045 and 1425 mg/kg bw/day (LOAEL) in males and females, respectively.

A further 90-Day oral toxicity study was performed in Crl:CD1(ICR) mice in compliance with GLP and according to OECD guideline 408 (2011 h). 15 animals per sex and dose group were fed with diets containing 300, 1000, 3000 or 7000 ppm test substance (corresponding to 47, 154, 459, and 1088 mg/kg bw/day in males and 61, 230, 649, and 1623 mg/kg bw/day in females, respectively). Control animals were fed plain Rodent LabDiet 5002^®.

The analytical analysis of the diet revealed that the test substance was homogeneously mixed, present at the targeted concentrations and stable under the study storage conditions for all dietary levels. Also for this study the analytical purity was revised form 92.2% to 90.5% to account for the full impurity profile. This reduction in determined purity of 1.7% was considered to have a minimal impact on the reported doses determined by chemical analyses, thus the reported dose values were not adjusted, retrospectively.

Examinations in mice included clinical observations, determination of body weight, food consumption and food efficiency, test substance uptake and analysis of ophthalmology, haematology and biochemical parameters. In addition, blood of selected animals (5/sex/dose level) was collected for determination of plasma concentrations of the test substance and one of its metabolites on Day 60. After 95 or 96 days in males and 96 or 97 days in females, mice were sacrificed and subjected to gross pathology and histopathology analysis, including organ weight values and ratios.

All observed clinical signs were typical for mice of this age and strain and thus not considered to be treatment-related. One male dosed at 1000 ppm was found dead. The cause of death was a malignant lymphoma, apparently originating in the thymus, which was interpreted to be incidental and not treatment- related due to the isolated occurrence in one single animal. No further deaths were observed in any dose group.

Decreased body weight and weight gain were observed at 300, 1000, 3000 and 7000 ppm. Although these findings were partially statistically significant, they were considered incidental, because there was no clear dose-response, changes were restricted to certain time intervals and changes were inconsistent (The magnitude of overall (test days 0-91) decreases in body weight parameters observed in the 7000 ppm group was similar to the decrease observed at 1000 ppm and the values of 3000 ppm were generally higher than in the 1000 and 7000 ppm groups.) Furthermore, for certain time intervals treated animals revealed a statistically significantly higher body weight than controls.

Thus overall, the observed effects on body weight in all dose groups were inconsistent and not dose-related and are thus considered unrelated to treatment and not adverse. Food consumption was significantly increased in females over 3 weekly intervals, but this finding was considered incidental and not treatment-related. Significant decreases in food efficiency were observed at 300, 1000, 3000 and 7000 ppm, but since a dose response-relationship was not obvious, these effects were not considered treatment-related. No effects on ophthalmology and biochemical parameters were observed in any dose group. Haematology analysis revealed a minimally decreased reticulocyte count in female mice of the 7000 ppm group (85% of control). But since there were no associated statistically significant changes in red blood cell mass parameters (red blood cell, haemoglobin and haematocrit), this finding was not considered of toxicological significance. In addition, there was a statistically significant, but minimally increase in red cell distribution width in female mice at test days 96-97 (109% and 106% of control, respectively). Because the change did not occur in a dose-related pattern, it was not considered treatment-related.

All gross and microscopic findings were consistent with normal background lesions in mice of this age and strain and thus not treatment-related. In females of the 7000 ppm dose group, a small, statistically significant, decrease in mean absolute heart weight, as compared to the controls, was not interpreted to be treatment-related since the decrease corresponded to a lower mean body weight in this group, the mean relative (% body weight) heart weight was not statistically different from the control value and there were no gross or microscopic findings that correlated with the lower mean heart weight.

Analysis of plasma samples for the concentration of test substance and metabolite, revealed that the average concentration of the test substance in plasma was slightly higher in males than in females at all dose levels, with the highest concentrations reaching 2484 and 2313 ng/mL for 7000 ppm males and females, respectively. There was no apparent plateau for the test substance plasma concentrations versus the dietary intake levels.

The metabolite was below the limit of quantitation (10 ng/mL) in all examined mouse plasma samples.

In the absence of any treatment-related findings, a NOAEL for male and female mice was defined at 7000 ppm (1088 and 1623 mg/kg/day, respectively), the highest dose-tested.

Oral toxicity after repeated administration was also tested in a GLP compliant 90 Day feeding study in dogs according to OECD guideline 409 (2011 i). In this study, 4 Beagle dogs per dose and sex were fed diet containing test substance concentrations of 250, 1250, 5000 and 15,000 ppm (corresponding to 6.46, 33.31, 126.23 and 425.71 mg/kg bw/day in males and 7.02, 37.94, 124.12, and 387.53 mg/kg bw/day in females, respectively). Control animals received plain diet (Certified Canine Diet #5007). The test substance was available once daily (for approximately 2 hours) for 91 consecutive days. Analysis of diet samples demonstrated that the test substance was present at the targeted concentrations, homogeneously mixed and stable under the study storage conditions for all dietary levels. Due to follow-up analysis of the test substance the certificate of analysis was revised and the purity was changed from 92.2% to 90.5% that accounts for the full impurity profile. This reduction in determined purity of 1.7% was considered to have a minimal impact on the reported doses determined by chemical analyses, thus the reported dose values were not adjusted, retrospectively.

Dogs were examined twice daily for mortality, morbidity and clinical observation before and 4 h after removal of food. Neurobehavioral parameters were checked weekly. Ophthalmoscopic analyses were conducted before test substance administration and at study end prior to necropsy. In addition, body weight and weight gain, food consumption and food efficiency were determined. Blood (haematology/coagulation and clinical chemistry parameters) and urine were analysed in weeks -2, - 1, 4, 8, and 12. For analysis of test substance and metabolite in the plasma, blood samples were additionally collected in week 9.

At study termination, necropsy examinations were performed, organ weights were recorded, and selected tissues were microscopically examined. Furthermore, liver samples were snap frozen in liquid nitrogen for analysis of cytochrome P-450 (total and isozyme profile). The microsomal suspensions were analysed for total cytochrome P-450 levels and quantification of cytochrome P-450 1A1, 1A2, 2B1/2, 2E1, 3A2, and 4A1/2/3.

All dogs survived until study termination. There was an increased incidence of skin scaling in treated animals with the highest incidence noted in the 15,000 ppm group (number of time observed/number of animals affected in control, 250, 1250, 5000 and 15,000 ppm dose groups, respectively): 0/0, 182/1, 32/2, 410/2 and 1184/4 (males) and 0/0 43/1, 464/2, 129/2 and 444/2 (females). Since the incidence did not exhibit a strict dose-response and there were no other correlative clinical or pathological responses, this effect was not considered to be adverse. In addition, mucoid and soft feces was observed in all treatment groups including control animals and thus, this effect is considered non-treatment-related. Other clinical observations noted are common in this species and were therefore not considered related to treatment. Statistically significant lower mean body weight gain was observed in all male dose groups over the week 1 through 2 time intervals, since a dose response was not visible, this finding was considered to be incidental and not treatment-related. Sporadic incidences of statistically significant differences in the mean weekly food consumption and food efficiency were observed in different dose groups and time intervals. However, since a dose-response relationship was not visible, these findings were not considered treatment-related.

Ophthalmoscopic analyses revealed that one female of the 1250 ppm dose group had a detached retina this incidental isolated finding was only visible at the pretest evaluation and thus not considered treatment-related. No effects were observed on clinical biochemistry and neurobehavioral parameters.

Erythrocytes and mean activated partial thromboplastin time (APTT) values were statistical significantly decreased in males (week -1) of the highest dose group. Furthermore, lymphocytes (week -1 and -2) and large unstained cells (LUC) (week 8 and 12) were statistically significantly decreased in males of the 1250 ppm group. All findings were considered not toxicologically relevant due to the interval involved (pretest) or lack of dose-dependency.

Urinalysis revealed statistical significant decreases in urine pH in males dosed at 250 and 15,000 ppm (week 12) and in females dosed at 5000 ppm (week 8). Statistical significant increases in urine pH were observed in females dosed at 250 and 1250 ppm (week 8). All findings were considered unrelated to treatment due to the lack of dose-dependency, unusually low urine pH in the female controls, and high urine pH in the male controls.

All gross and microscopic findings were usual and/or incidental in dogs of this type and age and thus not considered treatment-related.

At 1250, 5000, and 15,000 ppm mean thyroid/parathyroid gland weights were greater in females, but considered to be within normal variability among dogs, taking into account the observation that 2 control female dogs probably had thyroid gland weights at the low end of the range. Furthermore, there were no microscopic abnormalities detected in thyroid glands indicating that these findings are not linked to adversity. In the 1250 ppm dose group, absolute brain weight of males and the absolute heart weight of females were statistically significantly different from control animals. Since a dose-response was not visible and there were no microscopically visible correlates at the highest dose level, it was concluded that these differences were a result of biological variability, rather than treatment-related.

Liver biochemical analysis revealed that the test substance induced several hepatic cytochrome P-450 enzymes. In males dogs of the 5000 and 15,000 ppm dose group, enzymes 1A1 (501 and 518% of control, respectively) and 2B1/2 (225 and 191% of control, respectively) were treatment-related increased. Only at 5000 ppm, the increases in both 1A1 and 2B1/2 were statistically significant whereas increases observed at 15,000 ppm were not. However at both doses the increases were considered treatment-related.

In female dogs, cytochrome P-450 isozymes 2B1/2 (193 and 134% of control, respectively) were treatment-related increased. At 5000 ppm, the increases in both 1A1 and 2B1/2 were statistically significant whereas increases observed at 15,000 ppm were not statistically significant. However at both doses the increases were considered treatment-related.

At 1250, 5000 and 15,000 ppm cytochrome P-450 isozymes 4A1/2/3 (113, 109 and 115% of control, respectively) were treatment-related increased in females. The increases at 1250 and 15,000 ppm were statistically significant. Although the increase observed at 5000 ppm was not statistically significant, it appears to be treatment-related increased due to the low variability between the samples.

In males of the highest dose group, a statistically significant decrease in cytochrome P-450 4A1/2/3 was observed (89% of control). In female dogs dosed at 1250 ppm, a statistically significant increase in cytochrome P-450 2E1 (187% of control) was observed. Findings in both sexes were not considered treatment-related due to high variability between animals and/or the lack of increase at the higher levels.

There were no treatment-related alterations observed in total cytochrome P-450 content or the cytochrome P-450 1A2, 2E1, 3A2, or 4A1/2/3 content in males and no treatment-related alterations were observed in total cytochrome P-450 content or the cytochrome P-450 1A1, 1A2, 2E1 or 3A2 content in females.

Determination of plasma concentrations of test substance and metabolite revealed that in both male and female dogs, the test substance was the most abundant analyte, with the highest concentrations reaching 63,000 and 82,575 ng/mL for 15,000 ppm males and females, respectively. In contrast, the plasma levels of the metabolite were significantly lower for this dose group with concentrations of approximately 12 ng/mL for males and females. This value was just above the limit of quantitation. The concentration of test substance in plasma was higher in females than in males at all dose levels, which may suggest greater dietary absorption by female dogs. There was no apparent plateau for the test substance plasma concentrations versus the dietary intake levels.

The NOAEL was determined at 15,000 ppm in male and female dogs, due to the absence of adverse effects at the highest dose tested. This level is equivalent to 426 and 388 mg/kg bw/day in males and females, respectively.

Repeated dose toxicity: dermal

The toxicity of the test substance after repeated dermal administration was tested in rats (Hsd:Sprague Dawley^®) in a GLP compliant 28-Day study according to OECD guideline 410 (2008 a). In this study, 10 rats per sex and dose were administered the test substance for 6 h per day /7 days per week for a total of 28 days at 150, 400 and 1000 mg/kg bw/day. The test substance was administered without vehicle, but was moistened with distilled water to form a paste. Control animals were similarly exposed to distilled water. The area of exposure was shaved as needed throughout the study and covered approximately 10% of the body surface. In detail, the areas were as follows in the respective treatment groups: control: 2 x 3 inch (males and females), 150 mg/kg bw/day: 1 x 2 inch (males) and 1 x 1 inch (females), 400 mg/kg bw/day: 2 x 2 inch (males) and 1 x 2 inch females), 1000 mg/kg bw/day: 2 x 3 inch (males and females). The entire trunk of each animal was wrapped with non-irritating tape (3 inch 3M Micropore™) to avoid ingestion of the test substance or dislocation of the patch. Following exposure to the test substance, the wrappings were removed and the entire application site of all test and control animals was wiped with water to remove any residual test substance.

Animals were daily checked for clinical observations, mortality, clinical signs of toxicity and changes in behaviour. Body weight and weight gain was determined prior to test substance administration and weekly thereafter. Exposure sites of each animal were evaluated for dermal irritation on Day 3 of the study and thereafter at the end of each week. Food consumption, food efficiency, haematology and clinical chemistry parameters were determined. In addition, opthalmoscopic analyses were performed prior to study initiation and at Day 24. At Day 28, gross necropsy was performed on all rats. Tissues were collected for gross and microscopic evaluation from all rats (males on Day 29 and females on Day 30). Selected tissues from the control and high dose groups (10 per sex) and gross lesions from all test groups were analysed.

There were no mortalities observed and no test substance-related clinical signs in any dose group. At 400 and 1000 mg/kg bw/day very slight erythema were noted for the dose sites in one male of the mid and another one in the high dose group on Day 28. In addition, one high dose male showed very slight erythema on Day 3.

In females, mean body weight, daily body weight gain and overall (Days 2-29) body weight gain were statistically significantly increased during Week 4 and/or overall. In addition, an increase in mean food efficiency for the overall test period (Days 2-29) was observed. Both observations were not considered to be treatment-related or adverse since during the same period, control group values for these parameters were notably lower than historical control values for rats of the same age. In the low and mid dose group statistically significant decreases in mean daily food consumption were observed in female rats for the overall test period (Days 2-29) and during week 3, respectively. Without any dose response relationship, these findings were not considered treatment-related.

Single statistically significant differences in haematology and clinical chemistry data were observed, but not considered treatment-related. In the low dose group, red cell distribution width was slightly increased in females compared to control, but there were no corresponding red cell mass findings. In males of the low and high dose group creatinine levels were statistically significantly decreased compared to control, however the magnitude of the change was very small and a dose-response relationship could not be determined.

Gross pathology and histopathology analyses did not reveal any treatment-related findings, due to their isolated occurrences and/or focal distribution and/or their common occurrence in untreated rats.

In the high dose group, one female had a lung adhesion, but no corresponding microscopic finding. A male of the high dose group had a minimal focal lobular atrophy in the pancreas. Slight focal fibrosis in the salivary glands was observed in 1/10 females. In the mid dose group one male had a small sperm granuloma, visible as increased epididymal mass and a male of the control group exhibited a small appearing right testis and epididymis which were confirmed microscopically as mild unilateral tubular atrophy and intratubular cellular debris, respectively.

Analysis of organ weights, revealed a statistically significant increase in absolute adrenal weights in females of the high dose group. In addition, both absolute and relative ovarian weights and kidney-to-brain weight ratios were significantly decreased in females of the low dose group. Since there were no microscopic correlates observed for these findings, they were considered not to be of toxicological relevance.

Due to the absence of any adverse effect up to the highest dose level, the NOAEL for dermal repeated administration of the test substance was determined to be 1000 mg/kg bw/day in both male and female rats.

Justification for classification or non-classification

Adverse effects, in form of reduced body weight gain and food efficiency were observed in the sub-chronic rat study with oral test substance administration at18,000 ppm, corresponding to 1045 and 1425 mg/kg bw/day in males and females, respectively. The NOAEL of 6000 ppm (corresponding to 348 and 448 mg/kg bw/day in males and females, respectively) does exceed the current valide cut-off level for classification in category 2 of ≤ 100 mg/kg bw/day (oral route) and thus, the data requirements for classification are not met according to Regulation (EC) No. 1272/2008 (CLP).

Although the effects on body weight parameters and food efficiency did not lead to a classification, they were considered treatment-related and adverse. Since these effects were also evident in the reproductive and developmental toxicity studies resulting in maternal toxicity and consequently to secondary non-specific maternal developmental toxicity, a DNEL for workers was derived for longterm exposure, systemic effects (For further details, please refer to the endpoint summary on toxicity to reproduction section 7.8.1).

Based on the available data on repeated dose toxicity, after oral or dermal administration, the target substance is not considered to meet the classification criteria for a specific target organ toxicity according to Regulation (EC) No. 1272/2008 (CLP).

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Males
Group Concentration (ppm)	Control	600	2000	6000	18000
Number	15	15	15	15	15
Discharge - black – eye(s)/ear(s)
Number of Observations	2			7	4
Number of Animals	1			2	1
Days from - to	49 - 56			7 - 62	28 – 49
Discharge - brown - nose
Number of Observations				3
Number of Animals				1
Days from - to				7 – 21
Hair loss
Number of Observations	13		40		11
Number of Animals	1		4		2
Days from - to	7 - 91		7 - 91		21 - 91
Hyperreactive
Number of Observations			7
Number of Animals			1
Days from - to			49 - 91
Posture - high
Number of Observations			7
Number of Animals			1
Days from - to			49 - 91
Protrusion - abdomen				13
Number of Observations				1
Number of Animals				7 - 91
Days from - to
Teeth absent
Number of Observations	7			12
Number of Animals	1			1
Days from - to	49 - 91			14 – 91
Teeth clipped
Number of Observations				12	8
Number of Animals				1	1
Days from - to				14 – 91	42 – 91
Teeth maloccluded
Number of Observations				23	10
Number of Animals				2	1
Days from - to				7 - 91	28 - 91
Accidentally Killed
Number of Observations	1
Number of Animals	1
Days from - to	95 - 95
Neuropathology sacrifice
Number of Observations	5	5	5	5	5
Number of Animals	5	5	5	5	5
Days from - to	94 - 95	94 - 95	94 - 95	94 - 95	94 - 95
Scheduled sacrifice
Number of Observations	9	10	10	10	10
Number of Animals	9	10	10	10	10
Days from - to	94 - 95	94 - 95	94 - 95	94 - 95	94 - 95
Females
Number	15	15	15	15	15
Abnormal gait
Number of Observations		1	4
Number of Animals		1	1
Days from - to		91 - 91	70 – 91
Ear twitch
Number of Observations	1			1
Number of Animals	1			1
Days from - to	7 -7			70 -70
Eye corneal opacity
Number of Observations		9
Number of Animals		1
Days from - to		35 - 91
Hair loss
Number of Observations		18	7	6	16
Number of Animals		2	1	1	2
Days from - to		7 - 91	49 - 91	56 - 91	14 – 91
Wound - superficial - neck
Number of Observations					3
Number of Animals					1
Days from - to					14 -28
Accidentally Killed				1
Number of Observations				1
Number of Animals				96 – 96
Days from - to
Neuropathology sacrifice
Number of Observations	5	5	5	5	5
Number of Animals	5	5	5	5	5
Days from - to	94 - 95	94 - 95	94 - 95	94 - 95	94 - 95
Scheduled sacrifice
Number of Observations	10	10	10	10	10
Number of Animals	10	10	10	10	10
Days from - to	96 - 97	96 - 97	96 - 97	96 - 97	96 - 97

Males
Group Concentration (ppm)	Control	600	2000	6000	18000
BW:DAY0	256.4	254.7	253.7	255.3	253.0
	11.3(15)	13.3(15)	13.7(15)	13.0(15)	10.7(15)
BW:DAY7	311.7	310.4	308.9	309.4	300.6
	15.8(15)	15.3(15)	17.6(15)	19.8(15)	11.8(15)
BW:DAY14	358.2	357.1	356.9	354.6	345.7
	21.1(15)	17.6(15)	22.9(15)	36.2(15)	15.3(15)
BW:DAY21	390.4	390.3	390.2	384.3	371.9
	27.3(15)	20.4(15)	27.8(15)	35.5(15)	17.7(15)
BW:DAY28	429.4	424.7	424.0	416.1	401.7*
	31.9(15)	24.9(15)	30.6(15)	36.2(15)	17.2(15)
BW:DAY35	459.7	451.9	455.3	450.3	427.2*
	36.0(15)	26.2(15)	35.6(15)	39.6(15)	19.7(15)
BW:DAY42	486.3	480.3	482.3	479.9	452.1*
	38.7(15)	29.6(15)	39.0(15)	41.6(15)	23.8(15)
BW:DAY49	506.3	497.7	504.1	498.9	470.1*
	41.9(15)	31.8(15)	42.8(15)	46.1(15)	25.3(15)
BW:DAY56	520.8	512.8	517.5	513.1	483.3
	47.5(15)	36.5(15)	41.9(15)	49.7(15)	26.0(15)
BW:DAY62	538.7	531.2	534.6	533.7	500.2*
	46.0(15)	36.2(15)	44.0(15)	50.2(15)	27.1(15)
BW:DAY70	551.6	543.6	551.7	549.5	514.2
	46.4(15)	38.9(15)	46.7(15)	45.1(15)	26.4(15)
BW:DAY77	571.0	560.6	566.7	566.4	524.5*
	48.1(15)	39.7(15)	50.2(15)	47.9(15)	30.4(15)
BW:DAY84	578.7	568.5	575.1	575.3	526.5*
	48.1(15)	42.6(15)	51.2(15)	50.9(15)	31.9(15)
BW:DAY91	580.7	572.9	580.3	578.9	529.4*
	50.4(15)	43.6(15)	51.4(15)	53.0(15)	34.9(15)
Females
Group Concentration (ppm)	Control	600	2000	6000	18000
BW:DAY0	179.4	176.7	180.2	173.7	174.6
	10.2(15)	8.8(15)	9.8(15)	10.1(14)	9.8(15)
BW:DAY7	196.5	193.9	200.3	189.1	188.7
	13.0(15)	9.6(15)	16.3(15)	11.1(15)	11.7(15)
BW:DAY14	214.9	216.5	221.7	209.9	206.2
	15.5(15)	14.8(15)	20.2(15)	12.6(15)	16.5(15)
BW:DAY21	226.9	228.0	236.3	214.5	213.9
	17.2(15)	14.9(15)	21.8(15)	11.6(15)	16.5(15)
BW:DAY28	244.6	242.9	247.5	234.3	229.7
	22.1(15)	18.2(15)	23.8(15)	14.6(15)	18.2(15)
BW:DAY35	254.0	251.7	261.1	243.5	239.3
	22.9(15)	18.8(15)	28.5(15)	13.8(15)	22.4(14)
BW:DAY42	261.5	262.6	268.9	251.5	248.3
	22.6(15)	20.2(15)	31.3(15)	13.7(15)	23.1(15)
BW:DAY49	267.1	268.3	273.5	254.6	250.0
	22.5(15)	25.0(15)	29.5(15)	16.2(15)	19.3(15)
BW:DAY56	276.8	273.8	279.4	262.7	254.0*
	24.1(15)	22.4(15)	27.9(15)	18.3(15)	22.4(15)
BW:DAY62	280.9	280.1	288.2	269.3	262.0
	23.3(15)	20.0(15)	29.7(15)	20.9(15)	21.5(15)
BW:DAY70	287.4	289.6	293.6	276.1	261.7*
	24.9(15)	24.1(15)	30.3(15)	23.2(15)	23.1(15)
BW:DAY77	293.7	292.2	302.9	279.9	264.7*
	24.3(15)	26.1(15)	31.7(15)	25.9(15)	24.1(15)
BW:DAY84	293.4	294.9	301.9	282.9	269.6
	29.8(15)	24.2(15)	32.9(15)	23.0(15)	21.2(15)
BW:DAY91	294.6	288.6	304.9	284.1	270.6
	30.5(15)	24.6(15)	34.5(15)	23.4(15)	22.6(15)

Males
Group Concentration (ppm)	Control	600	2000	6000	18000
BWG:DAY0-DAY7	55.3	55.7	55.2	54.1	47.6*
	8.1(15)	4.6(15)	6.0(15)	10.3(15)	5.4(15)
BWG:DAY7-DAY14	46.5	46.7	48.1	45.2	45.1
	6.6(15)	5.9(15)	7.3(15)	21.0(15)	7.2(15)
BWG:DAY14-DAY21	32.2	33.2	33.3	29.7	26.2
	9.1(15)	6.5(15)	9.1(15)	8.7(15)	6.0(15)
BWG:DAY21-DAY28	39.0	34.4	33.8	31.7*	29.7*
	7.1(15)	6.6(15)	8.5(15)	5.5(15)	6.3(15)
BWG:DAY28-DAY35	30.3	27.3	31.3	34.2	25.5
	6.0(15)	4.4(15)	6.4(15)	7.2(15)	6.5(15)
BWG:DAY35-DAY42	26.6	28.3	27.0	29.7	24.9
	5.6(15)	5.8(15)	6.8(15)	4.9(15)	7.3(15)
BWG:DAY42-DAY49	19.9	17.5	21.8	18.9	17.9
	6.8(15)	5.7(15)	6.5(15)	6.7(15)	8.2(15)
BWG:DAY49-DAY56	14.6	15.0	13.4	14.2	13.2
	8.2(15)	8.9(15)	7.3(15)	7.9(15)	7.1(15)
BWG:DAY56-DAY62	17.9	18.5	17.0	20.6	16.9
	4.2(15)	7.0(15)	4.5(15)	5.6(15)	6.8(15)
BWG:DAY62-DAY70	12.9	12.4	17.1	15.9	14.0
	5.4(15)	6.8(15)	6.0(15)	9.0(15)	3.4(15)
BWG:DAY70-DAY77	19.4	17.0	15.1	16.9	10.3*
	6.2(15)	5.8(15)	6.5(15)	4.5(15)	8.0(15)
BWG:DAY77-DAY84	7.6	7.9	8.4	8.9	1.9*
	4.6(15)	5.5(15)	5.2(15)	7.6(15)	4.8(15)
BWG:DAY84-DAY91	2.0	4.3	5.2	3.7	2.9
	6.4(15)	6.5(15)	6.3(15)	6.8(15)	7.2(15)
BWG:DAY0-DAY91	324.3	318.1	326.7	323.6	276.4*
	45.0(15)	36.5(15)	41.5(15)	42.7(15)	30.0(15)
Females
Goup Concentration (ppm)	Control	600	2000	6000	18000
BWG:DAY0-DAY7	17.1	17.3	20.1	16.0	14.1
	8.6(15)	6.7(15)	7.6(15)	4.4(14)	7.0(15)
BWG:DAY7-DAY14	18.3	22.6	21.4	20.9	17.5
	9.1(15)	9.2(15)	9.4(15)	5.2(15)	7.3(15)
BWG:DAY14-DAY21	12.0	11.5	14.6	4.6*	7.7
	10.8(15)	6.4(15)	6.5(15)	5.8(15)	8.0(15)
BWG:DAY21-DAY28	17.7	14.9	11.2	19.8	15.7
	9.6(15)	9.9(15)	8.1(15)	8.8(15)	6.5(15)
BWG:DAY28-DAY35	9.4	8.8	13.5	9.2	10.0
	7.6(15)	7.2(15)	6.9(15)	5.9(15)	7.3(14)
BWG:DAY35-DAY42	7.5	10.9	7.9	8.0	8.9
	9.6(15)	9.5(15)	6.1(15)	4.9(15)	4.8(14)
BWG:DAY42-DAY49	5.6	5.7	4.5	3.1	1.7
	5.2(15)	7.9(15)	5.5(15)	6.5(15)	6.6(15)
BWG:DAY49-DAY56	9.7	5.5	6.0	8.1	4.0
	8.7(15)	7.5(15)	8.7(15)	6.6(15)	9.8(15)
BWG:DAY56-DAY62	4.1	6.3	8.8	6.6	8.0
	9.6(15)	6.5(15)	9.0(15)	10.1(15)	8.8(15)
BWG:DAY62-DAY70	6.5	9.5	5.4	6.8	-0.2@
	4.5(15)	8.5(15)	5.4(15)	4.0(15)	5.6(15)
BWG:DAY70-DAY77	6.3	2.6	9.2	3.8	2.9
	5.6(15)	8.3(15)	5.2(15)	9.0(15)	6.9(15)
BWG:DAY77-DAY84	-0.3	2.7	-1.0	3.0	4.9
	8.0(15)	9.1(15)	6.4(15)	6.7(15)	7.9(15)
BWG:DAY84-DAY91	1.2	-6.3*	3.1	1.3	1.0
	8.8(15)	7.1(15)	9.4(15)	6.5(15)	6.3(15)
BWG:DAY0-DAY91	115.2	111.9	124.7	112.5	94.9*
	26.9(15)	19.3(15)	26.1(15)	17.5(14)	16.9(14)

Males
Group Concentration (ppm)	Control	600	2000	6000	18000
FE:DAY0-DAY7	0.305	0.310	0.307	0.295	0.286
	0.037(15)	0.021(15)	0.016(15)	0.045(15)	0.032(15)
FE:DAY7-DAY14	0.256	0.252	0.262	0.228	0.247
	0.030(15)	0.029(15)	0.025(15)	0.151(15)	0.030(15)
FE:DAY14-DAY21	0.179	0.181	0.186	0.170	0.151
	0.046(15)	0.032(15)	0.039(15)	0.052(15)	0.031(15)
FE:DAY21-DAY28	0.204	0.180	0.182	0.173*	0.168*
	0.032(15)	0.026(15)	0.039(15)	0.029(15)	0.037(15)
FE:DAY28-DAY35	0.158	0.143	0.165	0.175	0.142
	0.026(15)	0.023(15)	0.022(15)	0.028(15)	0.031(15)
FE:DAY35-DAY42	0.134	0.147	0.140	0.152	0.135
	0.026(15)	0.026(15)	0.029(15)	0.020(15)	0.037(15)
FE:DAY42-DAY49	0.102	0.091	0.114	0.096	0.097
	0.033(15)	0.028(15)	0.029(15)	0.028(15)	0.040(15)
FE:DAY49-DAY56	0.077	0.081	0.074	0.076	0.073
	0.040(15)	0.043(15)	0.039(15)	0.036(15)	0.039(15)
FE:DAY56-DAY62	0.109	0.111	0.103	0.124	0.106
	0.027(15)	0.041(15)	0.022(15)	0.033(15)	0.041(15)
FE:DAY62-DAY70	0.060	0.056	0.078	0.072	0.068
	0.024(15)	0.030(15)	0.025(15)	0.039(15)	0.018(15)
FE:DAY70-DAY77	0.101	0.090	0.076	0.086	0.056*
	0.027(15)	0.031(15)	0.028(15)	0.018(15)	0.042(15)
FE:DAY77-DAY84	0.041	0.042	0.046	0.045	0.011*
	0.024(15)	0.026(15)	0.027(15)	0.035(15)	0.027(15)
FE:DAY84-DAY91	0.010	0.023	0.027	0.018	0.014
	0.036(15)	0.036(15)	0.034(15)	0.033(15)	0.043(15)
FE:DAY0-DAY91	0.133	0.131	0.135	0.132	0.119*
	0.015(15)	0.012(15)	0.007(15)	0.008(15)	0.009(15)
Females
Goup Concentration (ppm)	Control	600	2000	6000	18000
FE:DAY0-DAY7	0.131	0.142	0.150	0.138	0.107
	0.063(15)	0.052(15)	0.049(15)	0.040(14)	0.048(15)
FE:DAY7-DAY14	0.139	0.164	0.160	0.161	0.127
	0.073(15)	0.059(15)	0.066(15)	0.043(15)	0.051(15)
FE:DAY14-DAY21	0.088	0.087	0.109	0.038	0.055
	0.073(15)	0.052(15)	0.044(15)	0.048(15)	0.057(15)
FE:DAY21-DAY28	0.128	0.105	0.079	0.147	0.118
	0.068(15)	0.068(15)	0.053(15)	0.065(15)	0.054(15)
FE:DAY28-DAY35	0.070	0.065	0.095	0.068	0.070
	0.055(15)	0.058(15)	0.046(15)	0.041(15)	0.055(14)
FE:DAY35-DAY42	0.052	0.080	0.055	0.062	0.068
	0.068(15)	0.069(15)	0.043(15)	0.038(15)	0.035(14)
FE:DAY42-DAY49	0.040	0.034	0.034	0.024	0.014
	0.039(15)	0.049(15)	0.040(15)	0.049(15)	0.054(15)
FE:DAY49-DAY56	0.077	0.046	0.045	0.064	0.027
	0.066(15)	0.063(15)	0.068(15)	0.052(15)	0.075(15)
FE:DAY56-DAY62	0.030	0.057	0.072	0.055	0.073
	0.079(15)	0.060(15)	0.069(15)	0.084(15)	0.080(15)
FE:DAY62-DAY70	0.042	0.058	0.034	0.042	-0.005*
	0.029(15)	0.047(15)	0.036(15)	0.021(15)	0.040(15)
FE:DAY70-DAY77	0.047	0.016	0.066	0.028	0.023
	0.040(15)	0.059(15)	0.037(15)	0.070(15)	0.057(15)
FE:DAY77-DAY84	-0.008	0.020	-0.009	0.023	0.038
	0.063(15)	0.067(15)	0.052(15)	0.054(15)	0.062(15)
FE:DAY84-DAY91	0.000	-0.050@	0.020	0.009	0.007
	0.080(15)	0.065(15)	0.068(15)	0.050(15)	0.050(15)
FE:DAY0-DAY91	0.066	0.064	0.071	0.067	0.055*
	0.010(15)	0.009(15)	0.012(15)	0.012(14)	0.010(14)

Male
Groups Concentration (ppm)	Control	600	2000	6000	18000
RBC (x106/µL)
DAY 94-95	8.80	8.82	8.91	8.60	8.88
	0.34(10)	0.25(10)	0.23(10)	0.29(9)	0.51(10)
HGB (g/dL)
DAY 94-95	15.7	15.4	15.6	15.5	15.6
	0.6(10)	0.7(10)	0.4(10)	0.5(9)	0.7(10)
HCT (%)
DAY 94-95	47.8	47.0	47.8	46.8	47.6
	2.0(10)	2.0(10)	1.7(10)	1.6(9)	2.2(10)
MCV (fL)
DAY 94-95	54.3	53.4	53.7	54.5	53.7
	1.7(10)	1.7(10)	1.6(10)	2.5(9)	1.2(10)
MCH (pg)
DAY 94-95	17.8	17.5	17.6	18.0	17.5
	0.6(10)	0.5(10)	0.4(10)	0.6(9)	0.5(10)
MCHC (g/dL)
DAY 94-95	32.7	32.7	32.7	33.0	32.7
	0.6(10)	0.5(10)	0.6(10)	0.5(9)	0.7(10)
RDW (%)
DAY 94-95	12.6	12.6	12.6	12.8	12.7
	0.6(10)	0.6(10)	0.5(10)	0.5(9)	0.6(10)
ARET (x10³/µL)
DAY 94-95	153.0	142.8	159.8	169.2	148.4
	32.0(10)	30.4(10)	23.6(10)	16.8(9)	36.0(10)
PLT (x10³/µL)
DAY 94-95	965	1030	1012	1074	1030
	147(7)	149(10)	131(5)	96(6)	93(8)
WBC (x10³/µL)
DAY 94-95	10.18	10.55	11.66	12.05	9.11
	2.00(10)	3.02(10)	3.70(10)	3.96(9)	2.78(10)
ANEU (x10³/µL)
DAY 94-95	1.71	1.50	1.80	1.64	1.64
	0.39(10)	0.50(10)	0.76(10)	0.49(9)	0.87(10)
ALYM (x10³/µL)
DAY 94-95	7.96	8.54	9.26	9.81	7.03
	1.91(10)	2.78(10)	3.36(10)	3.45(9)	2.47(10)
AMON (x10³/µL)
DAY 94-95	0.23	0.24	0.27	0.24	0.20
	0.07(10)	0.10(10)	0.11(10)	0.10(9)	0.07(10)
AEOS (x10³/µL)
DAY 94-95	0.11	0.12	0.15	0.16	0.09
	0.03(10)	0.06(10)	0.05(10)	0.08(9)	0.03(10)
ABAS (x10³/µL)
DAY 94-95	0.03	0.04	0.05	0.04	0.03
	0.02(10)	0.01(10)	0.02(10)	0.02(9)	0.02(10)
ALUC (x10³/µL)
	0.14	0.12	0.14	0.16	0.12
	0.02(10)	0.06(10)	0.06(10)	0.07(9)	0.07(10)
Summary of coagulation values
DAY 94-95 PT (sec)	14.9	14.7	14.7	14.5	15.4
0.4(9)	0.8(10)	0.9(10)	0.6(10)	0.9(10)
APTT (sec)
DAY 94-95	16.3	15.6	15.5	15.0	16.0
1.8(9)	1.4(10)	1.4(10)	1.0(10)	1.8(10)
Female
Groups Concentration (ppm)	Control	600	2000	6000	18000
RBC (x106/µL)
DAY 96-97	8.42	8.37	8.43	8.53	8.34
	0.30(10)	0.25(10)	0.41(10)	0.29(10)	0.23(10)
HGB (g/dL)
DAY 96-97	15.6	15.4	15.5	15.7	15.4
	0.6(10)	0.6(10)	0.7(10)	0.5(10)	0.5(10)
HCT (%)
DAY 96-97	47.9	46.8	47.0	47.6	46.6
	1.8(10)	1.6(10)	2.2(10)	1.9(10)	1.5(10)
MCV (fL)
DAY 96-97	56.9	55.8	55.8	55.8	55.9
	1.6(10)	1.5(10)	1.0(10)	1.9(10)	1.2(10)
MCH (pg)
DAY 96-97	18.6	18.3	18.4	18.5	18.5
	0.6(10)	0.5(10)	0.4(10)	0.6(10)	0.5(10)
MCHC (g/dL)
DAY 96-97	32.7	32.8	33.0	33.1	33.1
	0.3(10)	0.4(10)	0.5(10)	0.4(10)	0.3(10)
RDW (%)
DAY 96-97	11.9	11.8	11.8	11.4	11.8
	0.5(10)	0.5(10)	0.4(10)	0.5(10)	0.4(10)
ARET (x10³/µL)
DAY 96-97	162.5	133.9	142.6	136.7	145.3
	34.1(10)	37.1(10)	22.3(10)	20.1(10)	31.0(10)
PLT (x10³/µL)
DAY 96-97	1012	1081	940	1032	1012
	63(9)	113(9)	92(9)	125(10)	62(8)
WBC (x10³/µL)
DAY 96-97	9.09	10.03	8.63	9.86	9.30
	2.13(10)	2.39(10)	2.22(10)	1.74(10)	2.80(10)
ANEU (x10³/µL)
DAY 96-97	0.92	1.10	1.10	1.25	1.04
	0.56(10)	0.90(10)	0.50(10)	0.78(10)	0.35(10)
ALYM (x10³/µL)
DAY 96-97	7.76	8.43	7.11	8.11	7.83
	1.88(10)	2.33(10)	2.23(10)	1.19(10)	2.48(10)
AMON (x10³/µL)
DAY 96-97	0.17	0.20	0.18	0.19	0.19
	0.05(10)	0.12(10)	0.10(10)	0.06(10)	0.07(10)
AEOS (x10³/µL)
DAY 96-97	0.10	0.10	0.10	0.12	0.09
	0.05(10)	0.03(10)	0.03(10)	0.06(10)	0.03(10)
ABAS (x10³/µL)
DAY 96-97	0.04	0.06	0.05	0.04	0.05
	0.03(10)	0.04(10)	0.03(10)	0.02(10)	0.03(10)
ALUC (x10³/µL)
DAY 96-97	0.10	0.13	0.09	0.15	0.11
	0.05(10)	0.08(10)	0.03(10)	0.09(10)	0.05(10)
Summary of coagulation values
PT (sec)
DAY 96-97	13.5	13.6	13.3	13.8	13.3
0.5(9)	0.5(10)	1.0(10)	0.5(9)	0.7(10)
APTT (sec)
DAY 96-97	13.8	14.2	14.0	13.4	13.3
0.7(9)	2.1(10)	1.5(10)	1.4(9)	1.6(10)

MALES
Groups Concentration (ppm)	0	600	2000	6000	18000
Mean final body weight and absolute organ weights (g)
Final body weight	565	556	567	568	509*
	55(9)	42(10)	35(10)	62(10)	35(10)
Adrenal glands	0.060	0.060	0.063	0.064	0.060
	0.009(9)	0.012(10)	0.013(10)	0.012(10)	0.010(10)
Brain	2.164	2.164	2.185	2.173	2.125
	0.067(9)	0.121(10)	0.075(10)	0.085(10)	0.073(10)
Epididymides	1.633	1.569	1.654	1.600	1.623
	0.116(9)	0.187(10)	0.215(10)	0.133(10)	0.150(10)
Heart	1.792	1.753	1.744	1.787	1.601*
	0.148(9)	0.147(10)	0.178(10)	0.201(10)	0.113(10)
Kidneys	4.218	4.109	4.186	4.146	4.012
	0.555(9)	0.415(10)	0.349(10)	0.405(10)	0.193(10)
Liver	14.992	14.991	15.100	15.226	12.865*
	1.433(9)	1.839(10)	1.376(10)	1.802(10)	0.839(10)
Spleen	0.896	0.854	0.871	0.880	0.780
	0.163(9)	0.149(10)	0.074(10)	0.099(10)	0.096(10)
Testes	3.735	3.484	3.552	3.553	3.512
	0.330(9)	0.302(10)	0.240(10)	0.361(10)	0.243(10)
Thymus	0.299	0.359	0.346	0.370	0.270
	0.058(9)	0.133(10)	0.081(10)	0.094(10)	0.072(10)
Mean relative organ weight (% of brain weight)
Adrenal glands/ brain * 100	2.780	2.765	2.891	2.950	2.802
	0.414(9)	0.587(10)	0.623(10)	0.528(10)	0.447(10)
Epididymides/ brain * 100	75.601	72.377	75.794	73.708	76.498
	6.756(9)	6.128(10)	10.315(10)	6.211(10)	7.671(10)
Heart/ brain * 100	82.835	81.166	79.826	82.347	75.480
	6.639(9)	7.342(10)	8.029(10)	9.590(10)	6.747(10)
Kidneys/ brain * 100	194.760	189.998	191.839	190.738	188.992
	23.783(9)	16.345(10)	18.312(10)	16.191(10)	10.279(10)
Liver/ brain * 100	691.668	693.084	691.514	701.519	606.506*
	50.435(9)	77.623(10)	63.465(10)	85.394(10)	49.654(10)
Spleen/ brain * 100	41.318	39.697	39.874	40.504	36.810
	6.825(9)	7.907(10)	3.292(10)	4.386(10)	5.222(10)
Testes/ brain * 100	172.749	161.169	162.633	163.641	165.368
	16.499(9)	12.615(10)	11.079(10)	16.434(10)	10.550(10)
Thymus/ brain * 100	13.784	16.519	15.862	17.036	12.727
	2.566(9)	5.800(10)	3.787(10)	4.467(10)	3.572(10)
Mean relative organ weight (% of body weight)
Adrenal glands/ final body * 100	0.011	0.011	0.011	0.011	0.012
	0.002(9)	0.002(10)	0.002(10)	0.002(10)	0.002(10)
Brain/ Final body * 100	0.386	0.391	0.387	0.386	0.419
	0.032(9)	0.033(10)	0.024(10)	0.037(10)	0.035(10)
Epididymides/ final body * 100	0.292	0.283	0.292	0.284	0.321
	0.038(9)	0.034(10)	0.037(10)	0.038(10)	0.042(10)
Heart/ final body * 100 Final body * 100	0.318	0.316	0.307	0.316	0.315
	0.020(9)	0.020(10)	0.021(10)	0.035(10)	0.018(10)
Kidneys/ final body * 100 Final body * 100	0.746	0.741	0.739	0.732	0.791
	0.056(9)	0.065(10)	0.059(10)	0.051(10)	0.054(10)
Liver/ final body * 100 Final body * 100	2.657	2.694	2.664	2.682	2.529
	0.152(9)	0.195(10)	0.175(10)	0.177(10)	0.084(10)
Spleen/ final body * 100 Final body * 100	0.159	0.153	0.154	0.156	0.153
	0.024(9)	0.021(10)	0.009(10)	0.019(10)	0.017(10)
Testes/ final body * 100 Final body * 100	0.664	0.629	0.628	0.631	0.693
	0.065(9)	0.061(10)	0.045(10)	0.081(10)	0.065(10)
Thymus/ final body * 100 Final body * 100	0.053	0.065	0.061	0.066	0.053
	0.007(9)	0.024(10)	0.013(10)	0.018(10)	0.012(10)
Feales
Groups Concentration (ppm)	0	600	2000	6000	18000
Mean final body weight and absolute organ weights (g)
Final body weight	285	283	291	269	262
	30(10)	22(10)	38(10)	22(9)	19(10)
Adrenal glands	0.066	0.069	0.071	0.062	0.068
	0.010(10)	0.010(10)	0.014(10)	0.015(9)	0.013(10)
Brain	1.971	1.956	1.961	1.957	1.907
	0.086(10)	0.052(10)	0.099(10)	0.087(9)	0.075(10)
Heart	1.097	1.118	1.101	0.994	1.026
	0.167(10)	0.154(10)	0.129(10)	0.068(9)	0.080(10)
Kidneys	2.104	2.053	2.053	1.980	2.056
	0.279(10)	0.157(10)	0.232(10)	0.237(9)	0.186(10)
Liver	8.006	7.784	7.857	7.306	7.459
	0.837(10)	0.672(10)	0.899(10)	0.590(9)	0.779(10)
Ovaries	0.124	0.127	0.137	0.118	0.142
	0.028(10)	0.029(10)	0.022(10)	0.022(9)	0.056(10)
Spleen	0.520	0.571	0.566	0.548	0.531
	0.042(10)	0.093(10)	0.081(10)	0.039(9)	0.078(10)
Thymus	0.268	0.298	0.257	0.271	0.261
	0.059(10)	0.068(10)	0.067(10)	0.066(9)	0.057(10)
Uterus	0.720	0.697	0.666	0.709	0.698
	0.186(10)	0.233(10)	0.219(10)	0.196(9)	0.182(10)
Mean relative organ weight (% of brain weight)
Adrenal glands/ brain * 100	3.366	3.542	3.633	3.197	3.551
	0.514(10)	0.533(10)	0.746(10)	0.825(9)	0.658(10)
Heart/ brain * 100	55.717	57.198	56.201	50.900	53.898
	8.439(10)	8.008(10)	6.274(10)	4.226(9)	4.775(10)
Kidneys/ brain * 100	106.548	105.078	104.856	101.386	107.740
	11.471(10)	9.205(10)	11.605(10)	12.737(9)	7.858(10)
Liver/ brain * 100	405.992	398.564	402.451	373.319	391.640
	36.623(10)	39.299(10)	55.286(10)	23.693(9)	43.691(10)
Ovaries/ brain * 100	6.272	6.476	6.982	6.008	7.453
	1.377(10)	1.520(10)	1.145(10)	0.963(9)	3.074(10)
Spleen/ brain * 100	26.404	29.161	28.966	28.071	27.851
	2.479(10)	4.486(10)	4.650(10)	2.381(9)	4.180(10)
Thymus/ brain * 100	13.618	15.240	13.138	13.822	13.673
	2.948(10)	3.387(10)	3.327(10)	3.091(9)	2.684(10)
Uterus/ brain * 100	36.604	35.559	34.009	36.328	36.585
	9.742(10)	11.690(10)	11.128(10)	10.018(9)	9.381(10)
Mean relative organ weight (% of body weight)
Adrenal glands/ final body * 100	0.024	0.025	0.024	0.024	0.026
	0.005(10)	0.004(10)	0.004(10)	0.007(9)	0.005(10)
Brain/ final body * 100 Final body * 100	0.698	0.694	0.686	0.732	0.731
	0.063(10)	0.055(10)	0.120(10)	0.062(9)	0.054(10)
Heart/ final body * 100 Final body * 100	0.386	0.395	0.380	0.371	0.392
	0.043(10)	0.045(10)	0.036(10)	0.023(9)	0.020(10)
Kidneys/ final body * 100 Final body * 100	0.741	0.726	0.709	0.740	0.786
	0.088(10)	0.044(10)	0.062(10)	0.092(9)	0.050(10)
Liver/ final body * 100 Final body * 100	2.815	2.755	2.705	2.738	2.852
	0.182(10)	0.234(10)	0.125(10)	0.343(9)	0.261(10)
Ovaries/ final body * 100 Final body * 100	0.043	0.045	0.048	0.044	0.054
	0.009(10)	0.011(10)	0.010(10)	0.008(9)	0.020(10)
Spleen/ final body * 100 Final body * 100	0.184	0.202	0.196	0.205	0.202
	0.020(10)	0.028(10)	0.025(10)	0.022(9)	0.025(10)
Thymus/ final body * 100 Final body * 100	0.094	0.105	0.088	0.102	0.099
	0.016(10)	0.022(10)	0.016(10)	0.029(9)	0.016(10)
Uterus/ final body * 100 Final body * 100	0.255	0.245	0.232	0.266	0.270
	0.076(10)	0.075(10)	0.083(10)	0.080(9)	0.086(10)

Groups Concentration (ppm)	Sex	0	600	2000	6000	18000
Pancreas	m
no visible lesion		10	10	10	10	9
discoloration		0	0	0	0	1
Eye(s)	f
no visible lesion		9	9	10	10	10
discoloration		0	1	0	0	0
rupture		1	0	0	0	0
Kidneys	f
no visible lesion		10	10	10	9	10
dilatation		0	0	0	1	0
No further visible lesions observed in males and females at any concentrations

Males
Group	Concentration (ppm)	Number	Forelimb grip strength (kg)	Hindlimb grip strength (kg)	Footsplay (cm)	Body temperature (ºC)	Rearing (number)
Baseline
1	0	10	0.81 (0.18)	0.34 (0.06)	6.0 (1.4)	36.4 (0.8)	5
2	600	10	0.81 (0.11)	0.33 (0.03)	6.9 (1.6)	36.2(0.6)	4
3	2000	10	0.86 (0.15)	0.38 (0.06)	6.9 (1.7)	36.2 (0.6)	5
4	6000	10	0.78 (0.13)	0.37 (0.07)	6.9 (18)	36.1(0.5)	5
5	18,000	10	0.85 (0.12)	0.34 (0.06)	6.4 (1.8)	35.9 (0.7)	3
Week 4
1	0	10	1.26 (0.27)	0.35 (0.05)	7.3 (2.6)	35.5 (1.0)	4
2	600	10	1.17 (0.15)	0.39(0.09)	8.4 (2.0)	35.6 (1.1)	4
3	2000	10	1.17(0.23)	0.38 (0.07)	7.1 (2.3)	35.8 (0.9)	3
4	6000	10	1.18 (0.12)	0.37 (0.05)	8.0 (1.8	36.0 (1.0)	3
5	18,000	10	1.18 (0.08)	0.40 (0.09)	6.9 (1.6)	35.4 (1.0)	4
Week 8 1	0	10	1.10 (0.21)	0.45 (0.06)	7.3 (2.8)	34.8 (0.6)	4
2	600	10	1.12 (0.14)	0.41 (0.10)	8.0 (1.3)	35.1 (0.8)	6
3	2000	10	1.19 (0.23)	0.40 (0.10)	7.1 (2.2)	35.0 (0.5)	4
4	6000	10	1.20 (0.13)	0.46 (0.14)	8.6 (1.5)	34.8 (0.4)	4
5	18,000	10	1.22 (0.16)	0.42 (0.07)	7.0 (2.1)	34.9 (0.5)	3
WEEK 13
1	0	10	0.93 (0.23)	0.40 (0.06)	7.4 (2.4)	35.9 (0.9)	4
2	600	10	1.06 (0.19)	0.45 (0.06)	7.9 (2.1)	35.5 (0.6)	4
3	2000	10	1.06 (0.24)	0.50 (0.07)	7.7 (1.9)	36.0 (0.9)	3
4	6000	10	1.15 (0.17)	0.45 (0.10)	8.3 (2.4)	35.7 (0.8)	3
5	18,000	10	1.05 (0.15)	0.41 (0.06)	7.9 (2.1)	35.8 (0.9)	3
Females
Baseline
1	0	10	0.74 (0.18)	0.36 (0.08)	5.4 (1.8)	36.6 (1.0)	6
2	600	10	0.74 (0.17)	0.34 (0.07)	5.2 (2.1)	36.2(1.0)	5
3	2000	10	0.77 (0.14)	0.34 (0.10)	6.4 (2.1)	36.7 (0.5)	6
4	6000	10	0.74 (0.21)	0.32 (0.06)	5.5 (1.5)	36.4(1.0)	6
5	18,000	10	0.72(0.11)	0.30 (0.04)	6.3 (1.4)	36.3 (0.4)	6
Week 4
1	0	10	1.02 (0.18)	0.36 (0.08)	5.6 (1.7)	36.2 (0.4)	8
2	600	10	0.93 (0.20)	0.34(0.04)	6.1 (2.1)	35.7 (0.5)	7
3	2000	10	0.94 (0.16)	0.35 (0.08)	6.4 (2.3)	35.8 (1.1)	6
4	6000	10	0.99 (0.16)	0.39 (0.09)	5.6 (1.4)	36.2 (0.8)	7
5	18,000	10	0.93 (0.18)	0.37 (0.08)	5.8 (2.2)	36.1(1.0)	7
WEEK 8
1	0	10	0.96 (0.26)	0.34 (0.08)	5.3 (1.8)	35.7 (0.4)	10
2	600	10	0.92 (0.20)	0.39 (0.08)	5.2 (1.5)	35.8 (0.4)	8
3	2000	10	0.93 (0.18)	0.38 (0.08)	6.5 (2.7)	36.0 (0.6)	8
4	6000	10	0.94 (0.11)	0.40 (0.07)	5.6 (1.3)	35.8 (0.4)	9
5	18,000	10	0.96 (0.19)	0.37 (0.10)	6.0 (2.3)	35.7 (0.4)	8
Week 13
1	0	10	0.72 (0.21)	0.37 (0.11)	5.8 (1.7)	37.3 (1.0)	10
2	600	10	0.70 (0.16)	0.36 (0.07)	6.0 (1.8)	37.3 (1.0)	8
3	2000	10	0.84 (0.26)	0.39 (0.08)	6.4 (2.4)	36.9 (1.1)	7
4	6000	10	0.80 (0.22)	0.37 (0.09)	5.8 (1.2)	36.5 (1.4)	9
5	18,000	10	0.82 (0.25)	0.39 (0.08)	6.9 (1.8)	36.5 (0.9)#	8

Male
Group	Concentration		Successive 10 minute intervals
	ppm	N	1		2		3		4		5		6		Total
Baseline
1	0	10	136	(18)	137	(17)	110	(28)	72	(44)	45	(64)	29	(40)	529	(150)
2	600	10	122	(18)	117	(43)	8 8	(43)	40	(51)	13	(17)	17	(33)	396	(108)
3	2000	10	123	(20)	126	(25)	120	(23)	88	(51)	45	(54)	23	(47)	525	(148
4	6000	10	131	(19)	133	(25)	104	(42)	55	(37)	8	(6)	10	(8)	441	(86)
5	18,000	10	143	(11)	142	(17)	107	(49)	71	(50)	41	(60)	22	(45)	526	(175)
Week 4
1	0	10	130	(12)	133	(17)	117	(23)	112	(28)	102	(41)	96	(47)	689	(93)
2	600	10	118	(17)	127	(8)	119	(28)	113	(31)	114	(42)	86	(50)	676	(106
3	2000	10	124	(15)	128	(14)	121	(19)	126	(25)	121	(46)	107	(48)	725	(134)
4	6000	10	43	(15)	137	(17)	137	(21)	130	(8)	107	(45)	86	(48)	740	(110)
5	18,000	10	146	(18)	133	(25)	119	(34)	98	(61)	63	(65)	68	63)	627	(224)
Week 8
1	0	10	132	(14)	131	(25)	121	35)	114	(25)	106	(20)	99	(36)	702	(87)
2	600	10	131	(19)	138	(18)	132	27)	126	(31)	110	(41)	105	(37)	742	(142)
3	2000	10	135	(20)	139	(22)	133	13)	128	(15)	119	(37)	118	(43)	771	(117)
4	6000	0	3	(19)	115	(28)	115	32)	101	(45)	86	(51)	71	(51)	622	(158)
5	18,000	10	149	(15)	146	(17)	117	37)	118	(33)	87	(58)	94	(55)	711	(161)
Week 13
1	0	10	133	(18)	127	(22)	110	(32)	99	(26)	91	(43)	79	(44)	638	(75)
2	600	10	132	(21)	134	(18)	113	(27)	107	(30)	96(	(42)	95	(40)	676	(132)
3	2000	10	131	(12)	129	(16)	116	(29)	96	(36)	93	(34)	97	(46)	662	(126)
4	6000	10	137	(14)	129	(20)	102	(37)	102	(29)	94	(38)	79	(37)	642	(113)
5	18,000	10	149	(14)	138	(21)	93	(37)	116	(23)	79	(51)	75	(42)	649	(104)
Female
Group	Concentration	Successive 10 minute intervals
	ppm	N	1		2		3		4		5		6		Total
Baseline
1	0	10	138	(15)	117	(43)	108	(42)	80	(34)	50	(51)	52	(49)	545	(138)
2	600	10	134	(12)	109	(42)	72	(41)	74	(64)	36	(46)	26	(49)	452	(162)
3	2000	10	134	(13)	119	(29)	82	(53)	80	(55)	65	(52)	65	(32)	505	(150)
4	6000	10	132	(11)	125	(25)	99	(42)	89	(44)	49	(47)	49	(36)	528	(111)
5	18,000	10	130	(19)	134	(21)	103	(38)	87	(45)	47	(44)	32	(36)	533	(112)
Week 4
1	0	10	137	(22)	124	(38)	124	(23)	101	(39)	90	(56)	89	(53)	664	(133)
2	600	10	132	(19)	120	(28)	105	(44)	106	(54)	92	(51)	95	(60)	650	(154)
3	2000	10	134	(10)	133	(21)	118	(41)	95	(49)	82	(48)	84	(62)	626	(168)
4	6000	10	127	(16)	122	(46)	108	(34)	90	(58)	95	(64)	126	(35)	679	(190)
5	18,000	10	129	(20)	133	(16)	105	(33)	90	(47)	96	(43)	76	(42)	630	(107)
Week 8
1	0	10	137	(16)	133	(18)	110	(28)	124	(22)	105	(45)	89	(41)	698	(120)
2	600	10	142	(20)	137	(22)	118	(43)	119	(35)	120	(46)	101	(62)	736	(168)
3	2000	10	135	(14)	148	(17)	96	(49)	113	(33)	103	(45)	83	(55)	679	(142)
4	6000	0	137	(18)	123	(41)	112	(50)	118	(47)	86	(45)	81	(63)	657	(144)
5	18,000	10	127	(24)	141	(17)	106	(39)	109	(29)	101	(45)	107	(47)	691	(92)
Week 13
1	0	10	142	(15)	129	(14)	93	(38)	118	(23)	104	(42)	97	(50)	682	(117)
2	600	10	143	(23)	124	(11)	97	(32)	98	(26)	109	(47)	103	(52)	674	(119)
3	2000	10	131	(12)	119	(27)	108	(48)	95	(45)	93	(45)	101	(45)	647	(183)
4	6000	10	131	(18)	127	(12)	113	(44)	110	(23)	106	(35)	83	(53)	670	(96)
5	18,000	10	140	(15)	132	(28)	107	(29)	78	(51)	101	(46)	63	(43)	620	(128)

Dose group (ppm)	Control	250	1250	5000	15,000
Males
Number of Animals Alive at Start of Interval	4	4	4	4	4
Observations	Number of times observed/Total number of animals affected
Behavior/Activity
lnappetence	0/0	1/1	0/0	0/0	0/0
Salivation	1/1	1/1	0/0	1/1	1/1
Excretion
Emesis	3/1	4/2	5/4	7/3	3/2
Feces discolored, Red	0/0	2/1	0/0	2/1	0/0
Feces discolored, Yellow	2/2	1/1	6/3	2/2	0/0
Feces few/absent	0/0	2/1	2/1	5/2	3/2
Feces mucoid	6/3	56/4	56/4	33/3	15/3
Feces soft	122/4	250/4	352/4	144/4	92/4
Feces watery	12/4	52/4	64/4	19/3	7/3
Material in pan/bedding, Red	0/0	2/2	0/0	0/0	0/0
Material in pan/bedding, Yellow	0/0	1/1	0/0	0/0	0/0
External Appearance					0/0
Gums discolored, Pale	0/0	0/0	1/1	0/0	0/0
Lacrimation	100/3	0/0	354/2	138/3	103/2
Thin	33/2	11/2	0/0	127/1	15/2
Tooth/teeth retained	0/0	0/0	0/0	1/1	0/0
Eye/Ocular
Sciera injected	10/1	0/0	2/1	0/0	1/1
Pelage/Skin
Abrasion(s)	8/2	0/0	16/2	0/0	20/2
Hair sparse	192/2	54/1	21/3	94/3	127/2
lnterdigital cyst	0/0	7/1	0/0	6/2	1/1
Scabbed area	44/2	3/1	0/0	38/1	2/1
Scaling	0/0	182/1	32/2	410/2	1184/4
Skin discolored, Gray	0/0	0/0	0/0	1/1	0/0
Skin discolored, Red	95/2	2/1	68/2	146/2	33/2
Females
Number of Animals Alive at Start of Interval	4	4	4	4	4
Observations	Number of times observed/Total number of animals affected
Behavior/Activity	0/0	1/1	3/1	1/1
Salivation					1/1
Excretion
Emesis	4/2	2/2	4/3	5/2	1/1
Feces discolored, Orange	0/0	1/1	0/0	0/0	0/0
Feces discolored, Red	0/0	0/0	3/1	0/0	0/0
Feces discolored, Yellow	0/0	2/2	2/2	0/0	0/0
Feces few/absent	2/1	1/1	1/1	2/2	0/0
Feces hard	0/0	0/0	1/1	0/0	0/0
Feces mucoid	13/1	9/3	69/3	3/3	19/3
Feces soft	69/4	122/4	163/4	108/4	70/4
Feces watery	17/4	15/4	21/4	13/4	7/2
Material in pan/bedding, Red	53/3	14/1	1072	29/3	54/3
External Apperance External Appearance
Discharge, brown	0/0	0/0	0/0	0/0	1/1
Discharge, red	104/4	19/3	41/2	40/3	52/3
Discharge, yellow	0/0	0/0	0/0	4/1	0/0
Lacrimation	23/2	38/1	454/2	222/3	0/0
Limf function lost	0/0	0/0	2/1	0/0	0/0
Swelling	0/0	0/0	0/0	0/0	15/1
Thin	0/0	77/2	7/1	0/0	71/1
Tooth/teeth retained	4/1	2/1	0/0	0/0	0/0
Vulva enlarged	167/4	52/3	51/2	86/3	55/3
Eye/Ocular
Eye discoloured, Red	0/0	0/0	6/1	0/0	0/0
Sclera injected Pelage/Skin	0/0	0/0	3/1	0/0	0/0
Pelge/Skin
Abrasion(s)	5/1	0/0	0/0	0/0	7/1
Hair sparse	0/0	52/2	72/2	151/1	103/1
lnterdigital cyst	9/1	0/0	6/1	0/0	81/2
Nodule, 1-5mm	48/2	0/0	0/0	28/1	0/0
Scabbed area	0/0	8/1	0/0	0/0	0/0
Scaling	0/0	43/1	464/2	129/2	444/2
Skin discolored, Gray	0/0	0/0	41/3	18/1	21/3
Skin discolored, Red	0/0	0/0	0/0	0/0	3/1

	Interval of Study (week)	Control			250			1250			5000			15000
	Interval of Study (week)	Mean	SD	N	Mean	SD	N	Mean	SD	N	Mean	SD	N	Mean	SD	N
Males
Leukocytes 103/µL	-2	9.88	2.119	4	9.50	1 .230	4	10.28	2.660	4	7.73	0.419	4	8.90	0.920	4
	-1	8.43	1 .810	4	8.65	1 .396	4	10.58	3.059	4	7.95	0.443	4	8.80	1 .881	4
	4	10.75	5.026	4	9.28	1 .875	4	10.48	0.988	4	8.98	1 .253	4	9.85	1 .182	4
	8	8.53	1 .482	4	9.03	1 .561	4	9.78	0.618	4	9.28	1 .676	4	8.45	0.342	4
	12	8.18	2.232	4	9.00	2.143	4	10.20	0.432	4	8.78	1 .372	4	9.98	3.670	4
Erythro- cytes 10 6 / µL	-2	7.320	0.5870	4	7.575	0.5043	4	7.705	0.2822	4	7.158	0.3719	4	6.723	0.4066	4
	-1	7.415	0.5125	4	7.475	0.3064	4	7.948	0.2330	4	7.463	0.2492	4	6.703 a	0.3923	4
	4	6.368	0.6939	4	6.568	0.4224	4	7.013	0.5102	4	6.205	0.2588	4	6 .160	0.3623	4
	8	6.483	0.7957	4	6.383	0.4029	4	7.173	0.3598	4	6.385	0.2124	4	6.220	0.4295	4
	12	6.380	0.8176	4	6.420	0.3362	4	6.975	0.3029	4	6.333	0.2474	4	6.095	0.4799	4
Haemoglobin g/dL	-2	16.58	1 .245	4	16.80	0.990	4	17.18	0.881	4	16.35	1 .455	4	15.83	0.746	4
	-1	17.10	0.849	4	16.85	0.947	4	17.70	0.698	4	16.93	0.793	4	15.68	0.854	4
	4	14.40	1 .499	4	14.70	1 .163	4	15.50	1 .405	4	13.78	0.665	4	14.28	0.741	4
	8	14.80	1 .476	4	14.53	0.435	4	15.90	0.658	4	14.13	0.403	4	14.60	0.976	4
	12	14.40	1 .435	4	14.50	0.572	4	15.30	0.956	4	14.03	0.789	4	14.13	0.806	4
Haematocrit %	-2	45.60	2.918	4	46.50	2.897	4	46.33	1 .866	4	43.98	3.090	4	42.60	2.404	4
	-1	46.30	2.965	4	46.65	1 .827	4	49.08	1 .846	4	46.70	2.165	4	43.13	2.034	4
	4	40.68	3.838	4	41 .60	2.889	4	44.03	3.173	4	39.35	2.074	4	40.28	1 .957	4
	8	41 .10	4.436	4	40.18	1 .801	4	44.78	1 .247	4	39.58	0.634	4	39.85	1 .974	4
	12	40.58	4.192	4	40.85	1 .928	4	43.73	2.380	4	39.93	2.630	4	39.80	2.102	4
MCV fl	-2	62.35	1 .491	4	61 .43	1 .455	4	60.15	1 .103	4	61 .40	2.020	4	63.40	2.404	4
	-1	62.50	1 .402	4	62.45	1 .848	4	61 .75	1 .287	4	62.50	1 .417	4	64.43	2.900	4
	4	64.00	1 .334	4	63.33	1 .323	4	62.83	1 .565	4	63.45	2.225	4	65.43	1 .692	4
	8	63.50	1 .538	4	63.03	1 .567	4	62.48	1.725	4	62.03	1 .539	4	64.18	1.711	4
	12	63.75	2.133	4	63.65	1 .936	4	62.65	1 .279	4	63.05	2.844	4	65.38	1.797	4
MCH pg	-2	22.63	0.443	4	22.23	0.981	4	22.28	0.450	4	22.78	0.936	4	23.60	0.808	4
	-1	23.08	0.512	4	22.53	1 .109	4	22.25	0.451	4	22.68	0.834	4	23.35	0.661	4
	4	22.63	0.222	4	22.38	0.556	4	22.08	0.618	4	22.20	0.739	4	23.20	0.374	4
	8	22.90	0.535	4	22.83	1 .124	4	22.18	0.591	4	22.13	0.907	4	23.50	0.622	4
	12	22.65	0.904	4	22.55	0.700	4	21 .93	0.538	4	22.13	0.862	4	23.20	0.688	4
MCHC g/dl	-2	36.30	0.698	4	36.15	0.896	4	37.10	0.548	4	37.13	0.655	4	37.18	0.591	4
	-1	36.90	0.688	4	36.10	0.757	4	36.03	0.206	4	36.28	0.741	4	36.30	0.668	4
	4	35.35	0.465	4	35.35	0.420	4	35.15	0.719	4	34.98	0.126	4	35.45	0.412	4
	8	36.03	0.655	4	36.25	1 .097	4	35.55	0.545	4	35.63	0.746	4	36.58	0.665	4
	12	35.48	0.395	4	35.45	0.451	4	35.03	0.263	4	35.10	0.622	4	35.45	0.289	4
Platelets 103/µL	-2	303.5	93.82	4	290.0	39.09	4	276.3	36.30	4	327.8	55.42	4	254.3	74.55	4
	-1	275.8	92.49	4	283.0	40.73	4	271 .8	54.33	4	313.5	77.88	4	255.0	92.36	4
	4	282.8	75.71	4	276.5	56.13	4	281 .3	50.59	4	321 .5	58.45	4	265.5	39.84	4
	8	306.0	68.48	4	285.3	74.73	4	268.8	35.98	4	302.0	10.30	4	250.8	57.85	4
	12	314.8	58.14	4	313.5	35.60	4	288.5	25.17	4	330.5	36.32	4	261 .8	52.68	4
RDW %	-2	13.15	0.265	4	13.28	0.377	4	13.25	0.465	4	13.35	0.592	4	12.95	0.289	4
	-1	12.53	0.403	4	12.78	0.369	4	13.18	0.222	4	12.88	0.519	4	12.63	0.340	4
	4	12.78	0.550	4	13.00	0.497	4	12.98	0.377	4	12.45	0.420	4	12.65	0.451	4
	8	12.40	0.432	4	12.65	0.645	4	12.78	0.550	4	12.25	0.289	4	12.08	0.340	4
	12	12.30	0.408	4	12.53	0.512	4	12.58	0.250	4	12.63	0.340	4	12.15	0.129	4
Absolute Reticu- locytes 103/µL	-2	26.95	10.744	4	31.90	14.080	4	39.65	21.137	4	28.78	18.075	4	23.38	2.940	4
	-1	31.68	16.792	4	30.08	11.140	4	57.65	28.886	4	37.95	19.503	4	30.38	5.629	4
	4	29.83	4.464	4	35.30	15.306	4	47.63	20.938	4	27.43	11.700	4	35.20	4.997	4
	8	44.00	32.901	4	35.13	13.322	4	54.25	36.076	4	28.83	14.076	4	29.23	4.323	4
	12	42.63	31.070	4	41.00	12.580	4	47.85	29.070	4	41 .88	12.908	4	40.28	9.241	4
Percent Reticu- locytes %	-2	0.35	0.129	4	0.40	0.141	4	0.50	0.258	4	0.38	0.222	4	0.35	0.058	4
	-1	0.43	0.222	4	0.38	0.150	4	0.73	0.377	4	0.50	0.245	4	0.45	0.100	4
	4	0.45	0.129	4	0.53	0.206	4	0.68	0.275	4	0.45	0.173	4	0.55	0.100	4
	8	0.68	0.492	4	0.55	0.173	4	0.78	0.492	4	0.45	0.208	4	0.48	0.096	4
	12	0.63	0.386	4	0.65	0.238	4	0.70	0.408	4	0.65	0.191	4	0.68	0.126	4
Neutrophils 103/µL	-2	7.280	1.5502	4	5.880	1.2234	4	6.393	2.3232	4	4.948	0.4135	4	5.523	0.3344	4
	-1	5.595	1.5532	4	5.123	1.0679	4	6.723	2.7198	4	5.070	0.4662	4	5.495	0.9580	4
	4	7.335	4.1076	4	5.510	1.6918	4	6.453	0.8771	4	5.510	1.2780	4	6.200	0.8581	4
	8	5.583	0.9419	4	5.593	1.5127	4	6.095	0.5606	4	6.013	1.2700	4	5.133	0.5311	4
	12	5.398	1.6236	4	5.770	1.7758	4	6.468	0.2103	4	5.760	1.1587	4	6.635	2.9940	4
Lymphocytes 103/µL	-2	1.618	0.8681	4	2.758	0.5415	4	2.968 a	0.6496	4	2.080	0.2573	4	2.528	0.4957	4
	-1	2.128	0.2123	4	2.718	0.3820	4	2.985 a	0.3574	4	2.213	0.2542	4	2.498	0.6390	4
	4	2.288	0.5117	4	2.848	0.2900	4	3.003	0.3812	4	2.673	0.3716	4	2.800	0.4667	4
	8	2.235	0.3582	4	2.758	0.2208	4	2.795	0.3415	4	2.545	0.4584	4	2.610	0.5073	4
	12	2.135	0.5082	4	2.460	0.3014	4	2.890	0.3114	4	2.358	0.1228	4	2.503	0.5558	4
Monocytes 103/µL	-2	0.728	0.2606	4	0.565	0.0493	4	0.618	0.1144	4	0.480	0.1575	4	0.533	0.1173	4
	-1	0.433	0.1320	4	0.530	0.1233	4	0.570	0.0408	4	0.443	0.0655	4	0.445	0.1112	4
	4	0.688	0.2529	4	0.565	0.1363	4	0.633	0.1005	4	0.423	0.0950	4	0.473	0.0858	4
	8	0.375	0.0695	4	0.450	0.0997	4	0.538	0.1571	4	0.480	0.0535	4	0.340	0.0606	4
	12	0.328	0.0499	4	0.465	0.0854	4	0.585	0.1448	4	0.418	0.0842	4	0.478	0.3596	4
Eosinophils 103/µL	-2	0.183	0.1682	4	0.203	0.0645	4	0.163	0.0250	4	0.155	0.0342	4	0.268	0.2100	4
	-1	0.205	0.1300	4	0.230	0.0942	4	0.160	0.0416	4	0.153	0.0457	4	0.290	0.2417	4
	4	0.370	0.2997	4	0.245	0.0507	4	0.268	0.1130	4	0.335	0.1229	4	0.313	0.1569	4
	8	0.273	0.1903	4	0.158	0.0299	4	0.210	0.0589	4	0.165	0.0332	4	0.315	0.1455	4
	12	0.260	0.2002	4	0.250	0.0271	4	0.178	0.0275	4	0.185	0.0592	4	0.315	0.1628	4
Basophils 103/µL	-2	0.048	0.0457	4	0.055	0.0507	4	0.098	0.0556	4	0.033	0.0126	4	0.043	0.0189	4
	-1	0.048	0.0126	4	0.038	0.0126	4	0.060	0.0271	4	0.035	0.0208	4	0.040	0.0183	4
	4	0.028	0.0050	4	0.038	0.0236	4	0.040	0.0163	4	0.023	0.0206	4	0.030	0.0000	4
	8	0.038	0.0171	4	0.030	0.0141	4	0.053	0.0126	4	0.038	0.0050	4	0.043	0.0096	4
	12	0.028	0.0096	4	0.025	0.0173	4	0.043	0.0150	4	0.030	0.0082	4	0.033	0.0050	4
Large Unstained Cells 103/µL	-2	0.015	0.0129	4	0.028	0.0287	4	0.043	0.0263	4	0.020	0.0082	4	0.028	0.0126	4
	-1	0.028	0.0050	4	0.023	0.0096	4	0.050	0.0183	4	0.025	0.0100	4	0.035	0.0129	4
	4	0.025	0.0058	4	0.028	0.0171	4	0.043	0.0222	4	0.028	0.0189	4	0.025	0.0100	4
	8	0.018	0.0050	4	0.025	0.0129	4	0.040 a	0.0115	4	0.030	0.0115	4	0.030	0.0082	4
	12	0.018	0.0050	4	0.025	0.0100	4	0.040 a	0.0082	4	0.030	0.0082	4	0.033	0.0250	4
APTT sec	-2	10.55	0.493	4	11.20	0.927	4	10.93	0.330	4	10.63	0.330	4	11 .93 a	1 .072	4
	-1	10.80	0.392	4	11.18	0.846	4	11 .15	0.342	4	10.88	0.538	4	11 .95	1 .008	4
	4	11.20	0.744	4	11.60	1 .030	4	11 .13	0.704	4	11 .15	0.473	4	11 .85	0.597	4
	8	10.58	0.427	4	11.55	1 .429	4	10.88	0.525	4	10.73	0.450	4	11 .40	0.744	4
	12	10.30	0.271	4	11.03	0.830	4	10.95	0.370	4	10.73	0.427	4	11 .15	0.759	4
Prothrombin Time sec	-2	6.98	0.222	4	6.83	0.275	4	7.03	0.435	4	6.80	0.283	4	6.93	0.250	4
	-1	6.90	0.245	4	6.98	0.222	4	7.10	0.374	4	6.90	0.392	4	6.93	0.050	4
	4	6.93	0.222	4	7.00	0.258	4	7.08	0.574	4	6.98	0.263	4	7.15	0.173	4
	8	6.90	0.216	4	7.00	0.216	4	7.15	0.500	4	6.93	0.126	4	7.13	0.320	4
	12	6.95	0.208	4	7.10	0.216	4	7.13	0.450	4	7.10	0.163	4	7.00	0.082	4
Females
Leukocytes 103/µL	-2	9.18	1 .090	4	9.60	2.578	4	11 .38	1 .658	4	11 .15	2.706	4	9.75	2.266	4
	-1	8.55	1 .950	4	9.95	2.390	4	10.70	1 .364	4	10.10	2.317	4	9.18	1 .318	4
	4	9.70	2.258	4	8.68	2.425	4	10.15	1 .245	4	9.78	1 .445	4	8.98	1 .028	4
	8	8.13	2.710	4	9.23	2.767	4	9.28	0.929	4	9.45	1 .008	4	8.85	1 .555	4
	12	8.35	1 .308	4	9.35	2.504	4	10.85	1 .372	4	9.83	2.053	4	8.30	1 .438	4
Erythro- cytes 10 6 / µL	-2	7.300	0.3766	4	7.533	0.7338	4	7.793	0.7216	4	7.353	0.4279	4	6.833	0.7894	4
	-1	7.328	0.2640	4	7.470	0.6619	4	7.213	0.3040	4	7.338	0.5226	4	6.593	0.4583	4
	4	6.560	0.2121	4	6.608	0.4056	4	6.453	0.1889	4	6.548	0.4167	4	6.083	0.8693	4
	8	6.435	0.1443	4	6.600	0.2371	4	6.685	0.2841	4	6.518	0.3692	4	5.850	0.6270	4
	12	6.188	0.3544	4	6.605	0.2704	4	6.448	0.3102	4	6.233	0.5823	4	5.780	0.4588	4
Haemoglobin g/dL	-2	16.65	0.785	4	17.45	1 .382	4	17.18	1 .135	4	16.53	0.785	4	15.85	1 .399	4
	-1	16.80	0.374	4	17.28	1 .590	4	16.23	0.709	4	16.63	1 .429	4	15.40	0.779	4
	4	14.83	0.340	4	14.95	0.443	4	14.48	0.386	4	14.73	1 .187	4	13.95	1 .471	4
	8	14.75	0.370	4	15.03	0.967	4	14.95	0.238	4	14.83	0.665	4	13.70	1 .030	4
	12	14.10	0.688	4	15.10	0.294	4	14.28	0.519	4	14.08	1 .087	4	13.25	0.465	4
Haematocrit %	-2	45.30	2.709	4	46.98	3.568	4	47.95	3.699	4	44.83	2.055	4	43.70	3.387	4
	-1	46.33	1 .263	4	47.35	4.044	4	44.88	1.773	4	45.75	3.652	4	43.33	1.706	4
	4	41.78	0.991	4	42.40	1 .627	4	41 .03	1 .179	4	41 .70	3.263	4	39.63	4.332	4
	8	40.55	1.559	4	41.68	2.895	4	41 .60	0.432	4	41 .20	1 .813	4	37.83	3.393	4
	12	39.75	2.585	4	42.58	0.727	4	40.75	1 .567	4	39.83	2.816	4	38.03	1 .660	4
MCV fl	-2	62.00	0.726	4	62.43	1 .580	4	61 .63	2.364	4	61 .05	2.133	4	64.13	2.431	4
	-1	63.23	0.624	4	63.43	1 .806	4	62.28	2.435	4	62.30	2.146	4	65.75	2.363	4
	4	63.75	0.995	4	64.23	1 .812	4	63.63	2.941	4	63.63	2.540	4	65.35	2.217	4
	8	63.00	1 .227	4	63.08	2.076	4	62.30	2.471	4	63.28	2.500	4	64.78	2.105	4
	12	64.25	0.755	4	64.53	2.193	4	63.25	2.082	4	64.08	3.038	4	65.93	2.687	4
MCH pg	-2	22.83	0.096	4	23.20	0.744	4	22.10	1 .257	4	22.50	0.963	4	23.28	0.780	4
	-1	22.95	0.370	4	23.10	0.632	4	22.50	0.913	4	22.68	0.793	4	23.40	0.983	4
	4	22.60	0.337	4	22.68	0.718	4	22.45	1 .002	4	22.45	0.777	4	23.03	1 .005	4
	8	22.90	0.294	4	22.78	0.602	4	22.40	0.942	4	22.78	0.950	4	23.48	0.981	4
	12	22.80	0.497	4	22.90	1 .023	4	22.20	0.821	4	22.60	0.906	4	23.00	1 .061	4
MCHC g/dl	-2	36.83	0.556	4	37.18	0.519	4	35.93	0.866	4	36.88	0.580	4	36.28	0.624	4
	-1	36.25	0.311	4	36.48	0.330	4	36.13	0.435	4	36.38	0.320	4	35.63	0.826	4
	4	35.48	0.096	4	35.28	0.287	4	35.28	0.096	4	35.25	0.265	4	35.25	0.557	4
	8	36.38	0.854	4	36.15	0.436	4	35.95	0.238	4	36.00	0.316	4	36.28	0.556	4
	12	35.48	0.699	4	35.48	0.602	4	35.10	0.258	4	35.25	0.370	4	34.90	0.469	4
Platelets 103/µL	-2	283.3	23.89	4	398.0	42.85	4	350.0	43.89	4	378.3	110.68	4	292.5	43.15	4
	-1	267.0	45.06	4	351.8	41 .45	4	325.5	41 .73	4	351 .3	74.51	4	286.5	92.27	4
	4	313.8	35.70	4	287.0	61 .64	4	301 .8	23.16	4	319.0	67.59	4	243.5	47.49	4
	8	326.3	21 .23	4	324.0	46.22	4	322.3	54.38	4	346.5	65.54	4	283.5	49.92	4
	12	310.0	28.67	4	352.0	48.67	4	363.8	47.35	4	353.5	63.66	4	290.8	60.19	4
RDW %	-2	13.35	0.208	4	13.35	0.465	4	13.15	0.451	4	13.15	0.592	4	12.90	0.245	4
	-1	12.95	0.507	4	12.80	0.516	4	12.65	0.058	4	12.68	0.591	4	12.55	0.252	4
	4	13.00	0.392	4	12.90	0.374	4	12.48	0.299	4	13.13	0.427	4	12.60	0.408	4
	8	12.40	0.337	4	12.88	0.556	4	12.10	0.115	4	12.93	0.330	4	12.80	0.283	4
	12	12.78	0.403	4	12.93	0.096	4	12.33	0.263	4	12.80	0.408	4	12.73	0.330	4
Absolute Reticu- locytes 103/µL	-2	25.28	11.598	4	31.58	12.309	4	42.23	21.783	4	37.45	25.376	4	23.10	7.008	4
	-1	26.58	10.465	4	27.13	6.761	4	30.05	13.179	4	31 .65	15.608	4	19.93	5.954	4
	4	31.23	6.028	4	31.43	8.472	4	32.25	7.341	4	33.48	16.742	4	30.90	18.189	4
	8	23.73	10.950	4	37.75	14.627	4	37.13	10.067	4	38.95	18.545	4	36.95	8.051	4
	12	31.28	13.732	4	43.30	10.430	4	36.83	6.874	4	37.05	4.619	4	45.75	6.560	4
Percent Reticu- locytes %	-2	0.33	0.150	4	0.43	0.171	4	0.55	0.238	4	0.50	0.356	4	0.33	0.096	4
	-1	0.35	0.129	4	0.38	0.096	4	0.43	0.189	4	0.45	0.265	4	0.30	0.082	4
	4	0.50	0.082	4	0.48	0.096	4	0.48	0.150	4	0.53	0.222	4	0.53	0.250	4
	8	0.35	0.173	4	0.58	0.206	4	0.55	0.129	4	0.63	0.287	4	0.65	0.100	4
	12	0.50	0.216	4	0.65	0.173	4	0.58	0.096	4	0.63	0.126	4	0.78	0.126	4
Neutrophils 103/µL	-2	6.170	0.8753	4	6.310	1.7116	4	7.863	1.6274	4	7.575	2.3189	4	6.863	2.0024	4
	-1	5.553	1.4500	4	6.598	1 5137	4	7.305	1.5155	4	6.448	1.9301	4	6.188	0.7390	4
	4	6.293	2.0674	4	5.368	1.5886	4	6.713	1.5148	4	5.793	1.2565	4	5.593	1.2291	4
	8	5.070	1.9533	4	5.905	1.7607	4	5.968	1.1280	4	5.878	0.7881	4	5.398	0.8883	4
	12	5.185	0.9173	4	6.088	1.9774	4	7.673	1.2746	4	6.235	1.5821	4	5.180	0.7880	4
Lymphocytes 103/µL	-2	2.333	0.3524	4	2.510	0.7276	4	2.608	0.6002	4	2.655	0.3940	4	2.200	0.4347	4
	-1	2.343	0.3313	4	2.508	0.6356	4	2.553	0.4084	4	2.818	0.6053	4	2.138	1.0582	4
	4	2.728	0.3562	4	2.620	0.6750	4	2.640	0.3945	4	3.105	0.3135	4	2.608	0.7066	4
	8	2.545	0.6424	4	2.573	0.7406	4	2.555	0.3899	4	2.905	0.3190	4	2.723	0.9172	4
	12	2.660	0.4856	4	2.485	0.4241	4	2.413	0.1159	4	2.850	0.2241	4	2.418	0.7083	4
Monocytes 103/µL	-2	0.470	0.0542	4	0.483	0.2053	4	0.550	0.1904	4	0.605	0.0843	4	0.503	0.0714	4
	-1	0.443	0.2084	4	0.533	0.2825	4	0.535	0.1586	4	0.538	0.1931	4	0.665	0.3003	4
	4	0.430	0.0938	4	0.405	0.1493	4	0.463	0.0960	4	0.460	0.1512	4	0.438	0.0922	4
	8	0.313	0.1115	4	0.420	0.2503	4	0.353	0.0978	4	0.378	0.0718	4	0.305	0.2042	4
	12	0.288	0.0850	4	0.430	0.1208	4	0.428	0.0714	4	0.353	0.0911	4	0.345	0.0443	4
Eosinophils 103/µL	-2	0.158	0.0250	4	0.210	0.1219	4	0.243	0.1603	4	0.215	0.0988	4	0.150	0.0365	4
	-1	0.113	0.0386	4	0.230	0.1122	4	0.213	0.0427	4	0.203	0.0911	4	0.110	0.0845	4
	4	0.210	0.0726	4	0.220	0.0931	4	0.268	0.0695	4	0.308	0.2265	4	0.300	0.2753	4
	8	0.128	0.0359	4	0.238	0.1429	4	0.300	0.1481	4	0.180	0.0876	4	0.408	0.5168	4
	12	0.170	0.0294	4	0.263	0.1662	4	0.263	0.0789	4	0.305	0.2575	4	0.305	0.2509	4
Basophils 103/µL	-2	0.040	0.0163	4	0.043	0.0096	4	0.065	0.0370	4	0.068	0.0299	4	0.043	0.0287	4
	-1	0.053	0.0150	4	0.050	0.0082	4	0.058	0.0171	4	0.065	0.0238	4	0.030	0.0294	4
	4	0.035	0.0058	4	0.030	0.0183	4	0.040	0.0216	4	0.055	0.0238	4	0.013	0.0150	4
	8	0.033	0.0150	4	0.050	0.0141	4	0.043	0.0171	4	0.050	0.0115	4	0.018	0.0171	4
	12	0.030	0.0141	4	0.045	0.0058	4	0.043	0.0189	4	0.040	0.0141	4	0.018	0.0171	4
Large Unstained Cells 103/µL	-2	0.015	0.0058	4	0.020	0.0141	4	0.023	0.0126	4	0.038	0.0250	4	0.023	0.0189	4
	-1	0.043	0.0263	4	0.033	0.0126	4	0.035	0.0129	4	0.043	0.0171	4	0.028	0.0359	4
	4	0.023	0.0050	4	0.033	0.0250	4	0.050	0.0283	4	0.0453	0.0100	4	0.013	0.0150	4
	8	0.025	0.0129	4	0.030	0.0216	4	0.030	0.0082	4	0.045	0.0129	4	0.013	0.0126	4
	12	0.033	0.0189	4	0.028	0.0050	4	0.033	0.0096	4	0.035	0.0129	4	0.015	0.0129	4
APTT sec	-2	10.58	0.377	4	10.90	0.735	4	10.93	0.660	4	11 .33	0.900	4	10.73	0.532	4
	-1	10.80	0.416	4	10.90	0.424	4	11.18	0.785	4	11 .45	0.957	4	10.95	0.719	4
	4	11.28	0.585	4	11.20	0.245	4	11.38	0.499	4	11 .53	0.513	3	11 .10	0.920	4
	8	11.13	0.340	4	11.13	0.250	4	11 .10	0.825	4	11 .18	0.727	4	11 .00	0.800	4
	12	10.65	0.465	4	11.10	0.583	4	10.80	0.837	4	10.93	0.780	4	10.98	0.723	4
Prothrombin Time sec	-2	6.65	0.058	4	6.68	0.350	4	6.90	0.316	4	6.70	0.183	4	6.68	0.263	4
	-1	6.53	0.171	4	6.70	0.271	4	7.00	0.365	4	6.78	0.126	4	6.63	0.299	4
	4	6.88	0.171	4	6.73	0.287	4	7.15	0.238	4	7.00	0.100	3	6.80	0.365	4
	8	6.88	0.171	4	6.85	0.129	4	6.63	0.419	4	6.78	0.171	4	6.78	0.287	4
	12	6.85	0.129	4	6.88	0.250	4	7.18	0.377	4	7.13	0.206	4	6.90	0.346	4

	Dose group (ppm)
Tissue/Observation	Severity	Control	250	1250	5000	15000
Males
Number of animals		4	4	4	4	4
all tissues
within normal limits		4	4	3	4	3
heart
cyst	mild	0	0	0	0	1
stomach, pylorus
focus, foci, red	mild	0	0	1	0	0
Females
Number of animals		4	4	4	4	4
all tissues
within normal limits		4	4	4	4	3
animal/whole body
body fat depleted	mild	0	0	0	0	0
ovaries
cyst	mild	0	0	0	0	1
vulva
enlarged	mild	0	0	0	0	1

		Dose group
Tissue/Observation	Severity	Control	1250	15000
Males
epididymides		(4)	(0)	(4)
infiltration, mononuclear cell	minimal	1	0	0
within normal limits		3	0	4
heart		(4)	(0)	(4)
haematocyst, valvular	moderate	0	0	1
within normal limits		4	0	3
kidneys		(4)	(0)	(4)
mineralization	minimal	4	0	4
regeneration, tubular	minimal	3	0
liver		(4)	(0)	(4)
fibrosis	mild	1	0	0
hyperplasia, bile duct	mild		0	0
inflammation, subacute		4	0	3
	minimal	3	0	3
	mild	1	0	0
within normal limits		0	0
lung		(4)	(0)	(4)
inflammation, chronic	minimal	0	0	1
inflammation, subacute	minimal	1	0	0
within normal limits		3	0	3
pancreas		(4)	(0)	(4)
atrophy, acinar	minimal	0	0	1
within normal limits		4	0	3
Females
adrenal glands		(4)	(0)	(4)
ectopic tissue	mild	1	0	0
within normal limits		3	0	4
eyes		(4)	(0)	(4)
fold/rosette, retinal	minimal	0	0	1
within normal limits		4	0	3
kidneys		(4)	(0)	(4)
mineralization	minimal	4	0	4
regeneration, tubular	minimal		0	0
liver		(4)	(0)	(4)
inflammation, subacute	minimal	4	0	3
within normal limits		0	0
lung		(4)	(0)	(4)
inflammation, chronic	minimal	1	0	0
inflammation, subacute	minimal	0	0
within normal limits		3	0	3
mammary gland		(4)	0	(4)
area normal, no mammary tissue present		0	0	1
within normal limits		4	0	3
ovaries		(4)	(1)	(4)
cyst, follicular	mild	0	1	0
within normal limits		4	0	4
skin		(4)	(0)	(4)
inflammation, hair follicle, demodectic	minimal	0	0	1
within normal limits		4	0	3
spinal cord, cervical		(4)	(0)	(4)
infiltration, lymphoid, perivascular	minimal	0	0	1
within normal limits		4	0	3
thymus gland		(4)	(0)	(4)
depletion, lymphoid	mild	1	0	1
within normal limits		3	0	3

						Plasma Concentration (ng/mL) b
Analyte	Number of animals	Group	Dietary Concentration (ppm)	Dietary Intake (mg/kg/day)a	Mean		SDc
Test substance	4	1M	0	0	< 10.0d		NA
	4	2M	250	6.43	1968		272
	4	3M	1250	34.15	10398		2091
	4	4M	5000	134.37	31575		6108
	4	5M	15000	426.82	63000		3366
	4	1F	0	0	< 10.0		NA
	4	2F	250	7.38	3193		493
	4	3F	1250	39.52	14875		2767
	4	4F	5000	124.08	37650		8060
	4	5F	15000	394.25	82575		9557
Metabolite		1M	0	0	< 10.0		NA
	4	2M	250	6.43	< 10.0		NA
	4	3M	1250	34.15	< 10.0		NA
	4	4M	5000	134.37	< 10.0		NA
	4	5M	15000	426.82	11.7		1.4
	4	1F	0	0	< 10.0		NA
	4	2F	250	7.38	< 10.0		NA
	4	3F	1250	39.52	< 10.0		NA
	4	4F	5000	124.08	< 10.0		NA
		5F	15000	394.25	11.6		1.2

Group (ppm)	Total Cytochrome P-450 Contenta(nmol/mg)	Cytochrome P-450 1A1 Contenta (net intensity)	Cytochrome P-450 1A2 Contenta (net intensity)	Cytochrome P-450 2B1/2 Contenta (net intensity)	Cytochrome P-450 2E1 Contenta (net intensity)	Cytochrome P-450 3A2 Contenta (net intensity)	Cytochrome P-450 4A1/2/3 Contenta (net intensity)
Males
Control	0.407 ± 0.103	173 ± 78 b	c ± c	6466 ± 195	774 ± 526d	14061 ± 7742	5614 ± 5614
250	0.409 ± 0.115	255 ± 212 d	c ± c	8097 ± 303	890 ± 300	8054 ± 4453	8517 ± 8517
1250	0.367 ± 0.047	f ± f	c ± c	6673 ± 195	709 ± 215 b	10164 ± 4440	2079 ± 2079
5000	0.320 ± 0.046	869 ± 279b @	c ± c	14537 ± 687*	1121 ± e	8635 ± 4759	102521 ± 6806
15,000	0.405 ± 0.163	899 ± 502	c ± c	12333 ± 300	487 ± 5 d	10505 ± 6058	99175 ± 4382*
Females
Control	0.421 ± 0.060	781 ± 204	b ± b	13086 ± 651	481 ± 120	19631 ± 9223	104017 ± 6971
250	0.396 ± 0.078	835 ± 407	b ± b	7477 ±314	693 ± 92	19028 ± 12474	111144 ± 1494
1250	0.378 ± 0.042	1086 ± 327	b ± b	6963 ± 610	900 ± 194*	20628 ± 5434	5892*
5000	0.394 ± 0.049	979 ± 270c	b ± b	25237 ± 583*	594 ± 300	23226 ± 3427	113233 ± 5705
15,000	0.415 ± 0.054	1033 ± 176	b ± b	17513 ± 865	523 ± 211	22411± 2447	1655*

Male
Groups Concentration (ppm)	Control	600	2000	6000	18000
AST (U/L)
DAY 94-95	72	70	84	78	70
	10(10)	15(10)	21(10)	11(10)	16(10)
ALT (U/L)
DAY 94-95	26	26	27	30	24
	3(10)	3(10)	6(10)	5(10)	2(10)
SDH (U/L)
DAY 94-95	14.8	12.9	12.5	13.2	12.0
	4.2(10)	3.4(10)	8.2(10)	4.1(10)	3.6(9)
ALKP (U/L)
DAY 94-95	84	88	76	82	74
	23(10)	16(10)	9(10)	20(10)	23(10)
BILI (mg/dL)
DAY 94-95	0.14	0.13	0.13	0.14	0.13
	0.03(10)	0.02(10)	0.01(10)	0.02(10)	0.01(10)
BUN (mg/dL)
DAY 94-95	13	14	13	13	13
	2(10)	2(10)	2(10)	2(10)	2(10)
CREA (mg/dL)
DAY 94-95	0.41	0.40	0.41	0.41	0.40
	0.05(10)	0.05(10)	0.04(10)	0.06(10)	0.05(10)
CHOL (mg/dL)
DAY 94-95	54	51	49	55	60
	9(10)	6(10)	10(10)	13(10)	17(10)
TRIG (mg/dL)
DAY 94-95	63	53	50	53	47
	20(10)	29(10)	11(10)	14(10)	14(10)
GLUC (mg/dL)
DAY 94-95	132	136	145	142	131
	23(10)	34(10)	35(10)	26(10)	27(10)
TP (g/dL)
DAY 94-95	6.7	6.6	6.7	6.6	6.5
	0.3(10)	0.3(10)	0.2(10)	0.2(10)	0.2(10)
ALB (g/dL)
DAY 94-95	3.4	3.3	3.4	3.3	3.3
	0.2(10)	0.1(10)	0.1(10)	0.1(10)	0.2(10)
GLOB (g/dL)
DAY 94-95	3.3	3.2	3.4	3.3	3.2

Male
Groups Concentration (ppm)	Control	600	2000	6000	18000
UVOL (mL)
DAY 94-95	12.0	9.7	10.2	8.3	6.2@
6.1(10)	6.4(10)	4.9(10)	5.6(10)	3.7(10)
UOSM (mOsm/kg)
DAY 94-95	1276	1552	1168	1728	1693
1163(10)	1079(10)	479(10)	997(10)	791(10)
pH
DAY 94-95	6.7	6.6	7.0	6.5	6.5
0.3(10)	0.3(10)	0.3(10)	0.4(10)	0.3(10)
URO (EU/dL)
DAY 94-95	0.2	0.4	0.2	0.4	0.3
0.0(10)	0.3(10)	0.0(10)	0.4(10)	0.3(10)
UMTP (mg/dL)
DAY 94-95	107	81	67	89	85
121(10)	60(10)	29(10)	55(10)	31(10)
Female
Groups Concentration (ppm)	Control	600	2000	6000	18000
UVOL (mL)
DAY 96-97	5.7	6.8	6.5	7.7	4.3
	2.3(10)	4.2(10)	4.2(10)	3.9(10)	2.4(9)
UOSM (mOsm/kg)
DAY 96-97	1211	1375	1175	1140	1860
	767(10)	974(10)	477(10)	1177(10)	1627(9)
pH
DAY 96-97	6.8	6.6	6.5	6.9	6.2@
	0.4(10)	0.5(10)	0.4(10)	0.6(10)	0.3(9)
URO (EU/dL)
DAY 96-97	0.2	0.2	0.2	0.2	0.2
	0.0(10)	0.0(10)	0.0(10)	0.0(10)	0.0(9)
UMTP (mg/dL)
DAY 96-97	19	19	17	47	27
	15(10)	14(10)	11(10)	95(10)	25(9)

Males	Baseline					Week 4					Week 8					Week 13
Concentration	control	600	2000	6000	18000	control	600	2000	6000	18000	control	600	2000	6000	18000	control	600	2000	6000	18000
Number examined	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10
Home cage - Posture
Limbs spread out or lying on one side	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Curled up	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Sitting, standing or rearing normally, alert	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10
Jumping	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Removal from cage:
Ease of removal:
Too easy (rat sits quietly, no resistance)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Some resistance (rears, follows observer's hand)	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10
Difficult (runs around cage, may attack)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Ease of handling:
Too easy	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Easy (alert, limbs pulled up against body)	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10
Difficult	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Arousal:
Very low (stupor, little or no responsiveness)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Low	0	1	2	1	2	1	2	3	2	2	0	0	0	1	2	1	3	1	2	0
Normal (alert, exploratory movements)	10	9	8	9	8	9	8	7	7	8	10	10	10	9	8	9	7	9	8	10
High (slight excitement, tense, sudden movements)	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Manipulations:
Approach & touch:
No reaction	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Normal	10	10	8	10	8	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10
Increased reaction (jumps away or attacks)	0	0	2	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Tail pinch:
no response	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
normal	10	10	10	10	9	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10
exaggerate response	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Auditory stimulus:
No reaction	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Normal reaction(rat flinches or flicks ear)	10	10	10	10	8	10	10	10	10	10	10	10	10	10	10	10	10	10	10	10
Exaggerated reaction (rat jumps, flips)	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Posture:
normal	0	0	0	0	0	0	0	0	0	9	0	0	0	0	0	0	0	0	0	0
abnormal	10	10	10	10	10	10	10	10	10	1	10	10	10	10	10	10	10	10	10	10
Gait/coordinations
normal	10	10	10	10	10	10	9	10	10	10	10	10	10	10	10	10	9	10	10	10

	Control			250			1250			5000			15000
Study interval (week)	Mean	SD	N	Mean	SD	N	Mean	SD	N	Mean	SD	N	Mean	SD	N
Males
-1	9.815	1.3224	4	10.715	0.9500	4	10.260	1.3468	4	10.593	1.2318	4	10.008	1.5358	4
1	9.808	1.4786	4	10.770	1.2679	4	10.353	1.2467	4	10.773	1.0746	4	10.190	1.4356	4
2	10.668	1.5999	4	11.285	1.4130	4	10.715	1.4362	4	11.250	1.0122	4	10.705	1.4499	4
3	10.613	1.3594	4	11.678	1.5258	4	10.900	1.3214	4	11.373	1.8386	4	11.050	1.3725	4
4	10.435	0.9658	4	11.703	1.4194	4	10.813	1.7586	4	11.380	1.3770	4	10.940	1.5942	4
5	10.745	1.2494	4	12.145	1.4213	4	11.160	1.5601	4	11.758	1.4282	4	11.155	1.1732	4
6	11.125	1.5058	4	12.275	1.5559	4	11.313	1.5740	4	11.943	1.3190	4	11.403	1.3185	4
7	11.115	1.1270	4	12.488	1.5020	4	11.598	1.6438	4	11.955	1.6002	4	11.415	1.2792	4
8	11.198	1.3066	4	12.708	1.6284	4	11.663	1.5901	4	12.230	1.5503	4	11.608	1.3765	4
9	11.243	1.1639	4	12.900	1.6215	4	11.805	1.6404	4	12.430	1.4146	4	11.800	1.3914	4
10	11.435	1.4062	4	13.010	1.6869	4	11.953	1.6507	4	12.453	1.6261	4	11.838	1.4103	4
11	11.528	1.2018	4	13.040	1.7140	4	11.963	1.7826	4	12.483	1.5883	4	11.845	1.5190	4
12	11.403	1.3002	4	12.860	1.7271	4	11.765	1.5938	4	12.295	1.4401	4	11.710	1.5739	4
13	11.618	0.9731	4	12.915	1.5862	4	12.083	1.7105	4	12.563	1.5477	4	11.908	1.4183	4
Females
-1	8.838	0.5827	4	8.533	0.7043	4	8.848	0.8998	4	8.628	0.5946	4	8.790	0.9489	4
1	9.258	0.5835	4	8.558	0.8214	4	8.860	0.8551	4	8.765	0.7257	4	9.055	0.8910	4
2	9.613	0.5741	4	9.050	0.9330	4	9.425	1.0546	4	9.365	0.8474	4	9.343	0.9676	4
3	9.845	0.6856	4	9.230	1.1155	4	9.598	0.9971	4	9.478	0.6402	4	9.573	1.0158	4
4	9.495	0.6683	4	9.118	0.6863	4	9.315	1.2996	4	9.270	0.9241	4	9.290	0.8632	4
5	9.593	0.6150	4	9.320	0.9179	4	9.633	0.9304	4	9.255	0.6262	4	9.455	0.9132	4
6	9.720	0.7297	4	9.570	0.8605	4	9.820	0.7632	4	9.595	0.6251	4	9.598	0.8553	4
7	9.670	0.8202	4	9.603	1.0293	4	10.083	0.9600	4	9.548	0.7522	4	9.755	0.9414	4
8	9.898	0.8591	4	9.910	0.7885	4	10.115	0.9926	4	9.630	0.7342	4	9.810	1.1382	4
9	9.743	0.7069	4	10.128	0.6257	4	10.310	0.9484	4	9.828	0.5675	4	9.838	1.0649	4
10	10.005	0.8428	4	10.210	0.7671	4	10.333	1.0008	4	9.770	0.3515	4	9.800	1.1088	4
11	10.053	0.7496	4	9.978	0.3813	4	10.450	0.8641	4	9.888	0.5038	4	9.865	1.1658	4
12	9.793	0.9055	4	10.013	0.4896	4	10.330	0.8671	4	9.755	0.6313	4	9.895	1.2094	4
13	10.103	0.7850	4	10.388	0.6084	4	10.535	0.9999	4	9.963	0.5569	4	9.923	1.2421	4

Fortification Level,	Recovery %
ng/mL Plasma	Test substance	Metabolite
Low, 20	108	102
Mid, 400	97	104
High, 10.000	91	100

	Number of	Dietary Concentration		Dietary Intake	Plasma Concentration (ng/mL)^a
Analyte	Animals	Group	(ppm)	(mg/kgbw /day)^b	Mean	SD^c
Test substance	5	1M	0	0.00	< 10.0^d	NA
	5	2M	300	41.26	157	56
	5	3M	1000	142.13	480	106
	5	4M	3000	415.22	1376	629
	5	5M	7000	1004.67	2484	615
	5	1F	0	0.00	< 10.0	NA
	5	2F	300	55.57	121	49
	5	3F	1000	221.57	436	188
	4^e	4F	3000	598.82	1249	315
	4^e	5F	7000	1467.05	2313	901
Metabolite	5	1M	0	0.00	< 10.0	NA
	5	2M	300	41.26	< 10.0	NA
	5	3M	1000	142.13	< 10.0	NA
	5	4M	3000	415.22	< 10.0	NA
	5	5M	7000	1004.67	< 10.0	NA
	5	1F	0	0.00	< 10.0	NA
	5	2F	300	55.57	< 10.0	NA
	5	3F	1000	221.57	< 10.0	NA
	4^e	4F	3000	598.82	< 10.0	NA
	4^e	5F	7000	1467.05	< 10.0	NA

Group		1	2	3	4
Dose Level (mg/kg/day)		0	150	400	1,000
Number Of Animals In Group		10	10	10	10
Males
Day	3	0.0/0.0	0.0/0.0	0.0/0.0	0.1/0.0
Day	10	0.0/0.0	0.0/0.0	0.0/0.0	0.0/0.0
	17	0.0/0.0	0.0/0.0	0.0/0.0	0.0/0.0
	24	0.0/0.0	0.0/0.0	0.0/0.0	0.0/0.0
	28	0.0/0.0	0.0/0.0	0.1/0.0	0.1/0.0
Females
Day	3	0.0/0.0	0.0/0.0	0.0/0.0	0.0/0.0
Day	10	0.0/0.0	0.0/0.0	0.0/0.0	0.0/0.0
	17	0.0/0.0	0.0/0.0	0.0/0.0	0.0/0.0
	24	0.0/0.0	0.0/0.0	0.0/0.0	0.0/0.0
	28	0.0/0.0	0.0/0.0	0.0/0.0	0.0/0.0

Dose Level (mg/kg/day)		Control	150	400	1000
Number Of Animals In Group		9²	10	10	10
Males
Parameter
Hemoglobin Cone. (g/dL)	Mean	16.1	16.0	16.3	16.3
Hemoglobin Cone. (g/dL)	SD	0.3	0.5	0.5	0.6
Hematocrit (%)	Mean	45.8	45.9	46.2	46.8
Hematocrit (%)	SD	1.1	1.7	1.5	1.6
Erythrocyte Count (RBC, X 106/µL)	Mean	8.70	8.77	8.71	8.74
Erythrocyte Count (RBC, X 106/µL)	SD	0.30	0.36	0.42	0.37
Platelet Count (x 103/µL)	Mean	1038	936	1005	901
Platelet Count (x 103/µL)	SD	154	157	158	191
Total Leukocyte Count (WBC, X 103/µL)	Mean	10.77	11.72	11.30	12.05
Total Leukocyte Count (WBC, X 103/µL)	SD	2.16	1.95	1.77	1.71
Mean Corpuscular Volume (fL)	Mean	52.7	52.4	53.1	53.6
	SD	1.0	1.4	1.4	1.5
Mean Corpuscular Hemoglobin (pg)	Mean	18.5	18.3	18.7	18.7
	SD	0.6	0.5	0.4	0.5
Mean Corpuscular Hemoglobin Concentration (g/dL)	Mean	35.1	34.9	35.2	34.8
	SD	0.5	0.3	0.4	0.6
Red Cell Distribution Width(%)	Mean	11.4	11.6	11.5	11.6
	SD	0.3	0.4	0.3	0.3
Absolute Reticulocyte Count (x 103/µL)	Mean	181.5	184.0	181.1	190.9
	SD	21.4	15.8	23.4	16.7
Absolute Neutrophils (x 103/µL)	Mean	1.43	1.79	1.48	1.63
	SD	0.31	0.33	0.30	0.43
Absolute Lymphocytes (x 103/µL)	Mean	8.84	9.29	9.22	9.80
	SD	1.84	1.59	1.69	1.58
Absolute Monocytes (x 103/µL)	Mean	0.20	0.26	0.23	0.24
	SD	0.05	0.07	0.07	0.06
Absolute Eosinophils (x 103/µL)	Mean	0.16	0.21	0.21	0.21
	SD	0.04	0.07	0.09	0.07
Absolute Basophils (x 103/µL)	Mean	0.08	0.10	0.09	0.09
	SD	0.03	0.03	0.03	0.03
Absolute Large Unstained Cells (x 103/µL)	Mean	0.07	0.07	0.07	0.08
	SD	0.02	0.02	0.02	0.02
Coagulation parameters
Number Of Animals In Group		8²	9²	9²	8²
Prothrombin time (seconds)	Mean	13.0	12.8	13.3	13.4
	SD	0.9	0.9	1.1	0.6
Activated Partial Thromboplastin time (seconds)	Mean	16.6	18.7	16.4	16.3
	SD	2.5	8.2	2.3	2.3
Females
Number of animals evaluated		7²	10	10	10
Hemoglobin Cone. (g/dL)	Mean	15.7	15.7	15.8	15.8
	SD	0.4	0.3	0.5	0.5
Hematocrit (%)	Mean	43.3	43.6	43.7	44.0
	SD	1.3	1.0	1.3	1.4
Erythrocyte Count (RBC, X 106/µL)	Mean	8.33	8.34	8.35	8.30
	SD	0.13	0.23	0.31	0.27
Platelet Count (x 103/µL)	Mean	886	940	997	821
	SD	183	186	271	167
Total Leukocyte Count (WBC, X 103/µL)	Mean	7.45	7.76	8.17	7.57
	SD	2.45	1.45	1.84	2.04
Mean Corpuscular Volume (fL)	Mean	52.0	52.3	52.4	53.1
	SD	1.7	1.5	1.0	1.1
Mean Corpuscular Hemoglobin (pg)	Mean	18.9	18.8	18.9	19.1
	SD	0.4	0.5	0.3	0.3
Mean Corpuscular Hemoglobin Concentration (g/dL)	Mean	36.3	36.0	36.0	36.0
	SD	0.5	0.3	0.4	0.6
Red Cell Distribution Width(%)	Mean	10.8	11.4*	11.2	11.3
	SD	0.2	0.6	0.2	0.4
Absolute Reticulocyte Count (x 103/µL)	Mean	176.2	204.4	211.9	218.0
	SD	45.1	66.4	30.3	29.7
Absolute Neutrophils (x 103/µL)	Mean	1.60	1.41	1.38	1.43
	SD	0.64	0.77	0.45	0.44
Absolute Lymphocytes (x 103/µL)	Mean	5.48	5.97	6.39	5.79
	SD	1.80	0.93	1.58	1.69
Absolute Monocytes (x 103/µL)	Mean	0.11	0.12	0.12	0.11
	SD	0.06	0.05	0.05	0.06
Absolute Eosinophils (x 103/µL)	Mean	0.17	0.16	0.16	0.13
	SD	0.05	0.07	0.04	0.04
Absolute Basophils (x 103/µL)	Mean	0.07	0.08	0.08	0.07
	SD	0.05	0.05	0.04	0.05
Absolute Large Unstained Cells (x 103/µL)	Mean	0.03	0.02	0.04	0.03
	SD	0.02	0.02	0.02	0.02
Coagulation parameters
Number of animals evaluated		10	9²	9²	7²
Prothrombin time (seconds)	Mean	14.7	14.8	14.9	14.9
	SD	0.3	0.4	0.5	0.8
Activated Partial Thromboplastin time (seconds)	Mean	14.9	14.8	15.1	15.9
	SD	1.3	2.1	1.3	3.4

Dose group (mg/kg bw/day	Control	150	400	1,000
Number of animals (males)	10	10	10	10
Days
1-7	0	0.042-0.045	0.11-0.12	0.27-0.29
8-14	0	0.044-0.051	0.12-0.13	0.30-0.33
15-20	0	0.047-0.055	0.12-0.14	0.31-0.35
21-27	0	0.049-0.058	0.13-0.15	0.32-0.37
28	0	0.053-0.062	0.13-0.15	0.34-0.42
Number of animals (females)	10	10	10	10
Days
1-7	0	0.030-0.034	0.077-0.084	0.19-0.21
8-14	0	0.031-0.035	0.082-0.095	0.21-0.23
15-20	0	0.034-0.036	0.084-0.097	0.21-0.24
21-27	0	0.035-0.039	0.089-0.100	0.23-0.26
28	0	0.036-0.041	0.095-0.100	0.24-0.27

Registration Dossier

Registration Dossier

Data platform availability banner - registered substances factsheets

Diss Factsheets

6-Amino-5-chloro-2-cyclopyrimidine-4-carboxylic acid

Endpoint summary

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

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Reference 1

Reference 2

Reference 3

Endpoint conclusion

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint conclusion

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint conclusion

Additional information

Justification for classification or non-classification

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