[No public or meaningful name is available]

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Remarks:

Dose-range finding study performed in rats by oral gavage for 2 weeks in the same lab.

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well documented and reported study conducted in a recognized contract research organization. In view of the preliminary nature of this range-finding study, a negative or vehicle control group was not included, the dose group size was small, and only few toxicology parameters were recorded. Therefore, adequacy of this study for assessment of repeated dose toxicity was limited. Specific technical guidelines were not applicable.

Reason / purpose for cross-reference:

reference to other study

Principles of method if other than guideline:

Once daily oral (gavage) dosing on 14 consecutive days.
3 dose groups (3 M + 3 F / group) and a vehicle control group.
Toxicity parameters recorded:
- for inidividual animals: mortality, bodyweight, food consumption and clinical
observations, macroscopic examination, liver and speen weight for each animal
- during week 2: water consumption

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS: Sprague-Dawley Crl:CD® (SD) IGS BR
- Source: Charles River (UK) Ltd., Margate, Kent, England
Nulliparous and nonpregnant females and untreated animals were used at initiation of the study.
- Age at study initiation: 33 to 37 days of age.
- Weight at study initiation: weight at start of treatment was 187.9 - 229.5 g (males) and 151.3 - 192.7 g (females).
- Fasting period before study: no
- Housing: Animals were housed in groups of 3 animals/sex/cage in stainless steel cages with stainless steel mesh lid and floor, suspended above absorbent paper.
- Diet: Free access to standard rodent diet (Rat and Mouse No. 1 Maintenance Diet from Special Diets Services Ltd., Witham, Essex, England).
- Water: Free access to tap water from public suppply.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
Environmental controls for the animal room were set to maintain 19 to 23°C, a relative humidity of 40 to 70%, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

IN-LIFE DATES
From: 2 August to 26 August 2003

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

1% in water

Details on oral exposure:

- Method of formulation: Formulations (w/w) were prepared freshly each week. The required amount of test substance were quantitatively transferred and diluted to volume. A series of suspensions at the required concentrations was prepared by dilution of individual weighings of the test substance. Prior to dosing, the formulations were mixed by inversion and magnetically stirred for at least 5 minutes before dosing commence and throughout the dosing procedure each day.
- Storage conditions of formulations: At ambient temperature
- Dose volume: 5 mL/kg body weight. Actual dose volumes were calculated according to the latest body weight.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Homogeneity and stability of the test substance was confirmed as part of the pre-study chemistry analysis carried out for the main 4-week study (HLS Study Number ADK/240), prior to commencement of treatment.

Duration of treatment / exposure:

The test substance, T-71, was administered over a period of 14 consecutive days with the animals killed on Day 15.

Frequency of treatment:

Once daily, 7 d/w

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Dose / conc.:

1 500 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

3

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dosage levels were selected based on the results of a 90-day rat oral toxicity study on a similar test substance. Therefore a dose regimen of 500, 1000 and 1500 mg/kg/day was chosen for this study.

Positive control:

no

Observations and examinations performed and frequency:

The following observations and examinations were performed on all animals:

- Clinical signs and mortality: At least twice daily.
In addition, detailed physical examination of each animal was performed once each week.
- Observations related to
dose administration: At least four times a day (at least just before administration and at various intervals afterwards) during the first week of treatment. In the second week, these observations were made at the middle and end of the week).
- Bodyweights: All rats were weighed when allocated to treatment groups on arrival (Day -6), on day of commencement of treatment (DAY 1) and on Days 4, 8, 11 and 15.
- Food consumption: Weekly for each cage throughout the study.
- Water consumption: Daily (visual inspection of water bottles for overt changes for each cage group) until Day 8. Accurate daily water comsumption for each cage were than made from Day 9 to study termination.

Sacrifice and pathology:

- Sacrifice and gross pathology (full macroscopic external and internal examination on all animals): End of treatment period (Day 15)
- Organ weights (all animals): Kidneys (all organs together), liver, spleen

Gross lesions were fixed and retained in appropriate fixative but not histopathologically examined. Upon report finalisation all tissues were discarded.

Other examinations:

no

Statistics:

Data were not statistically analysed.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 1500 mg/kg, clinical signs in two females were emaciated build, under active behaviour, piloerrection, pallor and hunched posture (in No. 22 from Day 11 persisting until termination. Female No. 24 showed emaciated build on Day 15).

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

From Day 1 to 4, mean bodyweight losses were noted for both sexes receiving 1500 mg/kg/day. Thereafter (Day 5 - 15) bodyweight gain among females in the highest dose group remained markedly lower than that of control, with further bodyweight losses in females Nos. 22 and 24. However, the mean bodyweight gain for males in the top dose improved and was comparable with the control during Days 4 - 15.

Initially, druing the period Days 1 to 4 of treatment, both sexes receiving 500 or 1000 mg/kg/day showed lower mean bodyweight gains compared with controls, with the means following a dose related trend. However, as with the males in the top dose group, bodyweight gain improved after Day 4 of treatment and was comparable with or superior to that their respective control from Day 4 to 15.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food intake was lower than that of control for females receiving 1500 mg/kg/day througout the two week treatment period, with the magnitude of the difference from control increasing with time. In addition, during the first week of treatment food intake was slightly lower thanthat of control among the remaining treated male and female groups. However, the food intake improved, such that overall (Weeks 1 - 2) food intakes for both sexes receiving 500 or 1000 mg/kg/day and for males recieving 1500 mg/kg/day were combarable with control.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

Food efficiency was lower than that of control for females receiving 1500 mg/kg/day througout the two week treatment period. Food efficiency was also lower than that of control for males receiving 1000 or 1500 mg/kg/day during the first week of treatment, however in the second week of treatment it was comparable to that of control. Food efficiency for females receiving 1000 mg/kg/day and for both sexes receiving 500 mg/kg/day was not considered to have been affected by treatment.

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

The group mean water consumption values for both sexes receiving 1500 mg/kg/day were higher than that of the controls (as assessed by visual inspection). During the period of accurate water consumption measurement (Week 2, Days 9 to 14), water consumption was higher than control among all treated groups, with both sexes receiving 1500 mg/kg/day showing the greatest difference from control. It was also noted that the group mean female values followed a dosage related trend.

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Endocrine findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Assessment of organ weights did not reveal any effects of treatment.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Enlargement of the liver was noted in 1/3 males receiving 1500 mg/kg/day compared with none in the control animals.

The incidence and distribution of all findings were considered to fall within the expected background range of macroscopic changes.

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Key result

Key result

Critical effects observed:

not specified

Conclusions:

Treatment at 1500 mg/kg/day was not well tolerated among female rats, as indicated by bodyweight loss/low weight gain, emaciated build and low food consumption noted for these rats throughout the twoo week treatment period. Treatment among males receiving 1500 mg/kg/day and both sexes receiving 500 or 1000 mg/kg/day was generally well tolerated.

Dose levels of test material chosen for the subsequent main 4-week general toxicity study in the rat were: 0 (vehicle control), 80, 250 and 1000 mg/kg bw/day.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: The United States EPA Health Effects Test Guidelines, OPPTS 870.3050, Repeated Dose 28-day oral Toxicity Study in Rodents

Version / remarks:

July 2000

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

revised 1995

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

458-880-0

EC Name:

-

Cas Number:

85209-93-4

Molecular formula:

Hill formula: C29 H42 O4 P Li

IUPAC Name:

2,4,8,10-tetra(tert-butyl)-6-hydroxy-12H-dibenzo- [d,g][1,3,2]dioxaphosphocin 6-oxide, lithium salt

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS: Sprague-Dawley Crl:CD® (SD) IGS BR
- Source: Charles River (UK) Ltd., Margate, Kent, England
Nulliparous and nonpregnant females and untreated animals were used at initiation of the study.
- Age at study initiation: 42 to 46 days of age.
- Weight at study initiation: weight at start of treatment was 196 - 237 gr (males) and 173 - 212 gr (females).
- Fasting period before study: no
- Housing: Animals were housed in groups of 5 animals/sex/cage in stainless steel cages with stainless steel mesh lid and floor, suspended above absorbent paper.
General: an Aspen chew block (B & K Universal Ltd., Grimston, Kingston-upon-Hull, East Yorkshire, England) as cage enrichment were supplied. Replaced when necessary, but at a minimum frequency of everey two weeks.
- Diet: Free access to standard rodent diet (Rat and Mouse No. 1 Maintenance Diet from Special Diets Services Ltd., Witham, Essex, England).
- Water: Free access to potable water from public suppply.
- Acclimation period: 9 days

ENVIRONMENTAL CONDITIONS
Environmental controls for the animal room were set to maintain 19 to 23°C, a relative humidity of 40 to 70%, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

IN-LIFE DATES
From: 17 September to 24 October (Main Study)/7 November 2003

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Remarks:

1% in water

Details on oral exposure:

- Method of formulation: Formulations (w/w) were prepared freshly each week. The required amount of test substance was ground in a mortar using a pestle and mixed with some vehicle to form a paste. Further amounts of vehicle were quantitatively transferred and diluted to volume and finally mixed using a high-shear homogeniser. A series of suspensions at the required concentrations was prepared by dilution of individual weighings of the test substance.
- Storage conditions of formulations: At ambient temperature
- Dose volume: 5 mL/kg body weight. Actual dose volumes were calculated according to the latest body weight.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Before treatement commenced, the suitability of the proposed mixing procedure was determined and specimen formulations at concentrations of 1 and 300 mg/ml were analysed to assess the homogeneity and stability of the test substance in liquid matrix. Samples of each formulation prepared for administration in Weeks 1 and 3 of treatment were analysed for achieved concentration of the test substance.
The method of analysis was an adaptation of a method supplied by the Sponsor; details were presented in the Formulation Chemistry Report (Annex 1).
All formulations were shown to be homogenous in the vehicle and stable at ambient temperature for 2 days and refrigerated storage (approximately 4 °C) for 8 days. The mean concentration of T-71 in test formulations in Weeks 1 and 3 were between -1 and -3% of nominal, which were within the applied limits of +10 % and -15 %, confirming the accurracy of formulation.

Duration of treatment / exposure:

The test substance, T-71, was administered over a period of 28 consecutive days with the main study animals killed on Day 29. The recovery phase commenced on Day 29: animals completed another 14 days without treatment, and were killed on Day 43 (Day 15 of recovery).

Frequency of treatment:

Once daily, 7 d/w

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

80 mg/kg bw/day (actual dose received)

Remarks:

Main study

Doses / concentrations 2

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Remarks:

Main study

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

Main study

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

Recovery group

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dosages were based on a preliminary two week toxicity study (Huntingdon Life Sciences Report Number: ADK239/030109) in which 500, 1000 and 1500 mg/kg/day were tested in CD rats. In that study a dose level of 1500 mg/kg/day resulted in low bodyweight gain/actual weight loss among female rats. Therefore a dose regimen of 80, 250 and 1000 mg/kg/day was chosen for this study.

Positive control:

Not required.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS:
- Time schedule: At least twice daily.

DETAILED CLINICAL OBSERVATIONS
- Time schedule: Daily throughout the treatment period, detailed observations were performed immediately before dosing and between one and twohours after completion of dosing of all groups. A further observation was performed as late as possible in the working day during the first week of treatment. Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition.

BODY WEIGHT
- Time schedule for examinations: Rats were weighed one week before the treatment commenced (Day -7), on the first day of treatment (Day 1) , on Days 8, 15, 22 and 28 of treatment, then on Days 1, 8 and 14 of recovery. Bodyweight was also recorded before necropsy.

FOOD CONSUMPTION
- The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded for the week before treatment started (Week -1), and each week throughout the treatment and recovery periods. From these records the mean weekly consumption per animal (g/animal/week) was calculated for each cage.

FOOD EFFICIENCY: yes

WATER CONSUMPTION
Water consumption measurement was recorded daily during Days 15 to 20 of Week 3 and daily during Days 9 to 14 of the Recovery period.

OPHTHALMOSCOPIC EXAMINATION
No

HAEMATOLOGY
- Time schedule for collection of blood: on Day 29 of main study, on Day 15 of recovery
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (overnight). Water was provided.
- How many animals: 5 animals/sex/group
- Parameters checked were: According to test guidelines

CLINICAL CHEMISTRY
- Time schedule for collection of blood: on Day 29 of main study, on Day 15 of recovery
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (overnight). Water was provided.
- How many animals: 5 animals/sex/group
- Parameters checked were: According to test guidelines

URINALYSIS:
- Time schedule for collection of urine: collection of urine samples from all main study animals on Day 29 (and similarly on Day 15 of recovery). Animals were placed in individual metabolism cages from 16.00 hours until approximately 07.30 hours the following day
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (no food or water)
- Parameters checked were: Accoridng to test guidelines

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4 of treatment (before dosing)
- Dose groups that were examined: all recovery group animals in Groups 1 and 4, and all animals from Groups 2 and 3
- Battery of functions tested: sensory activity / grip strength / motor activity / other: approach response, auditory startle reflex, tail pinch response, touch response

IMMUNOLOGY: No

Sacrifice and pathology:

GROSS PATHOLOGY:
- All animals were fasted overnight prior to planned necropsy. Animals were killed by carbon dioxide asphyxation.

ORGAN WEIGHTS
All animals:
- Adrenals
- Brain
- Epidiymides
- Heart
- Kidneys
- Liver
- Ovaries
- Seminal vesicles
- Spleen
- Testes
- Thymus

HISTOPATHOLOGY:
- Adrenals
- Brain
- Femur with joint
- Heart
- Ileum
- Kidneys
- Liver
- Lungs
- Spinal cord
- Sternum
- Stomach
- Thyroid
- Uterus and cervix

Statistics:

All statistical analyses were carried out seperately for males and femals, using the individual animal as the basic experimental unit.

The following statistical methods were used to analyze the data:
- The Fisher's Exact-test was applied to categorical data, including pathological findings.
-The Bartlett's test was first applied to continous data, to test the homogeneity of variance between groups. Dependent on the outcome, treated groups were then compared with the control group using appropriate tests and incorporating adjustment for multiple comparisons where necessary.

All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 1000 mg/kg, clinical signs of loose/pale faeces among all animals prior to dosing on Day 3, generally persisting until 1-2 hours after dosing on Day 5. Post dose salivation was observed 1 to 2 hours after dosing on isolated occasions in one male and three females during Week 4. Hair loss on the dorsal and ventral body surface was observed in 4/10 males and 5/10 females from Day 12. Thin appearance was observed in 2/10 females from Day 19, however these animals exhibited bodyweights that were comparable with control (not associated with treatment).

Add effects at 80 mg/kg?

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

From Day 1 to 28, mean bodyweight gain was higher than that of control for females recieving 250 and 100 mg/kg/day, with the mean for females receiving 1000 mg/kg/day attaining statistical significance. Bodyweight gains among females receiving 80 mg/kg/day and all treated male groups were similar to controls.

During the recovery period mean bodyweight gain for both sexes previously treated at 1000 mg/kg/day was lower than that of their control. Thus these differences from control for prevously treated animals of both sexes are not considered to be of toxicological importance.

See figure on body weight attached as background material.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

In females receiving 250 or 1000 mg/kg/day, the efficiency of food utilisation was slightly higher than that of control. During the recovery period the efficiency of food utilisation for both sexes previously treated at 1000 mg/kg/day was found to be lower in both males and females when compared with control.

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

The group mean water consuption values for both sexes receiving 1000 mg/kg/day were higher than that of the controls. During the recovery period, water intake during Week 2 was slightly lower for females previously treated at 1000 mg/kg/day. Water intake for males was similar to control, indicating recovery.

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

At 1000 mg/kg/day, significantly higher than control mean values were observed for the following parameters in females:
- white cell count (WBC)
- neutrophils (N)
- lymphocytes (L)
- basophils (B)
- monocytes (M)
- large unstained cells (LUC).

At 1000 mg/kg/day, lower than control mean values were observed for the following parameters in males:
- lymphocytes (L).

At 250 and 1000 mg/kg/day, lower than control mean values were observed for the following parameters in males:
- APTT.

The differences from control for males wer not considered treatment-related.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Day 29 blood chemistry parameters:

At 250 and 1000 mg/kg/day, significantly higher than control mean values were observed for the following parameters in males:
- alkaline phosphatase (ALP).

At 1000 mg/kg/day, significantly higher than control mean values were observed for the following parameters in males (mainly due to high values of rats Nos. 22 and 25):
- alanine aminotransferase (ALT)
- aspartate aminotransferase (AST)

At 250 (females only) and 1000 mg/kg/day (both sexes), significantly lower than control mean values were observed for the following parameters:
- cholesterol (Chol)

At 1000 mg/kg/day, significantly higher triglycerides than control mean values were observed in males and females.

At 250 and 1000 mg/kg/day, significantly lower than control mean values of total protein (Total Prot.) and globulin were observed in males and resulted in a marginally higher than control mean Albumin/Globulin ratio (A/G) in males receiving 250 and 1000 mg/kg/day.

A marginally lower mean Albumin (Alb) value was seen for females receiving 1000 mg/kg/day, associated with a marginally lower total protein value for females at this dose level.


Day 15 of recovery blood chemistry parameters:

At previous treatment of 1000 mg/kg/day, significantly higher urea than control mean values were observed in females (not treatment-related).

The remaining biochemical parameters were similar to recovery control animals, this indicated that recovery from the changes previously noted at the Day 29 investigation.

Several parameters (AST, Potassium (K) and Billirubin) were statistically different from controls, but these changes were not considered treatment-related.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

On Day 29, in animals receiving 1000 mg/kg/day, significantly lower mean protein values than control mean values were observed in females. In addition, a marginally but statistically significant higher mean pH value was observed in females of the same dose group. No effects were seen in males.

On Day 15 of the recovery phase, in animals previously receiving 1000 mg/kg/day, significantly higher mean protein values than control mean values were observed in females, thus indicating a reversal of the changes previously observed. In addition, a marginally but statistically significant higher mean pH value was observed in females of the same dose group.

The remaining urinary parameters for both sexes were similar to those of control.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

At 1000 mg/kg for males, slightly higher than control liver weights were observed.
At 1000 mg/kg for females, significantly higher than control spleen weights were observed.

Significantly higher epididymides weights for males previously treated at 1000 mg/kg was not associated with treatment. Assessment of the male liver weight and female spleen weight for animals previously treated at 1000 mg/kg revealed mean organ weights that were similar to control, thus indicating recovery from the effects of treatment at the end of the 4 week treatment period.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

At 1000 mg/kg a reduction in contents in parts of the gastro-intestinal-tract (chiefly the small intestine) in 4/5 male rats compared to 0/5 controls was observed. Hair loss was noted in 3/5 male rats and 5/5 female rats receiving 1000 mg/kg compared with 0/5 male and female control rats. A thin appearance was seen in 3/5 female rats receiving 1000 mg/kg compared with 0/5 female control rats. However, this finding was not considered to associated with treatment.

The macroscopic examiantion of the recovery animals did not reveal any changes that were associated with treatment.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

SPLEEN
A slightly higher severity of extramedullary haemopoiesis in the spleen was noted in main study male animals receiving 1000 mg/kg of T-71. Recovery males previously receiving 1000 mg/kg of T-71 showed no difference in extramedullary haemopoiesis when compared with recovery control animals. No differences were noted in the spleen of female animals.

ILEUM - PEYER'S PATCH (PP)
A slight reduction in the germinal centres of the PP was noted in animals receiving 1000 mg/kg of T-71 compared with controls, but no dose response was noted by reviewing tissue from animals treated with 80 and 250 mg/kg T-71. The finding was considered incidental and of no toxicological importance.

Histopathological findings: neoplastic:

not examined

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

serum/plasma biochemistry

urinalysis

Target system / organ toxicity

Key result

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

In conclusion, the changes observed at 80 and 250 mg/kg/day were not considered to be adverse to the survival of the rat, thus a dose level of 250 mg/kg/day is classified as the highest NOAEL for this study.