Registration Dossier

Administrative data

Description of key information

ORAL
NOAEL = 5 mg/kg diet (based on the effects noted in the thymus) in the rat, equivalent to 0.3-0.4 mg/kg bw/day for male animals and 0.3-0.5 mg/kg bw/day for female animals, OECD 422, Waalkens-Berendsen 2004

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
05 November 2003 to 08 March 2004
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted in accordance with the standardised testing guideline OECD 422 and in accordance with GLP with no deviations thought to affect the quality of the presented data. Since the test material DOTO (di-n-octyltin oxide) is in the same category of substances as the registration substance it is considered acceptable to use a read-across approach to address this endpoint.
Reason / purpose:
reference to same study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 10-11 weeks
- Weight at study initiation: The weight variation of the animals for each sex did not exceed 20 %
- Diet: ad libitum
- Water: tap water ad libitum in polypropylene bottles

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

DOSE-RANGE FINDING TEST IN-LIFE DATES: From: 12 November 2003 To: 26 November 2003
MAIN TEST IN-LIFE DATES: From: 14 January 2004 To: 8 March 2004
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): The experimental diets were prepared once shortly before the study
- Mixing appropriate amounts with (Type of food): The test material was weighed and placed in a small grinder. The tray was rinsed with food which was then also added to the grinder and mixed for 2 x 30 seconds. This mixture was moved to a Stephan cutter and the grinder was rinsed with food and moved to the cutter. Approximately 3 kg weighed food was mixed into the cutter for 2 x 2 minutes and moved. This was then moved to the Lödige cutter. The Stephan cutter was rinsed with approximately 3 kg of food and that was also moved to the Lödige cutter. Mixing was continued in the Lödige cutter for 2 minutes with the total amount of food.
- Storage temperature of food: <-18 °C
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The feed was checked for homogenous distribution, stability and concentration of the test material for all the doses in the dose-range finding study. The same dose preparation for the dose-range finding study was also used for the main test. The homogenous distribution and achieved concentration of the low dose in the main test was also analysed.

Directly after preparation of the diet for the dose-range finding study, samples for homogeneity and stability were taken. Five samples were taken (approximately 50 g each) to examine the homogeneity of the dose from the top centre, middle centre, bottom centre, left centre and right centre of the mixer. Secondly samples (around 50 g) were taken from the top centre part of the mixer to measure the stability. The samples taken for measurement of the homogeneity were also used for dose confirmation. In addition the content (achieved concentration) of the test material in the batch of diet used in the main study. Diet samples were taken for analysis immediately after preparation and stored at – 18 °C.

Samples of the 0, 25, 75, 200 and 500 mg/kg diets from the dose-range finding study and doses of 0, 25 and 250 mg/kg from the main study as well as all related calibration samples were derivatised.

A calculated amount of internal standard solution (MHT, DHT and TTPT in methanol) was added to 2.0 g of diet in a 50 mL Corning tube. 10 mL of 100 % acetic acid was then added and the Corning tube was closed and shaken for 60 minutes (250 rpm). 10 mL of acetate buffer solution (pH 4.5) was added along with 10 mL methanol. 2.0 mL of 20 % (m/V) aqueous STEB solutions was added, followed by 10 mL hexane (containing naphthalene, approximately 0.1 mg/L). The tube was shaken for 15 minutes (250 rpm) then placed in an oven at 60 °C for 15 minutes. After phase separation, the hexane layer (approximately 3 mL) was removed and washed with 3 mL of 2 mol/L HCl (30 minutes shaking at 250 rpm). The hexane top layer was diluted with hexane: hexane extracts from sample with dose levels of 0, 25 and 75 mg/kg were diluted five times, the higher doses were diluted fifty times. The resulting solutions were transferred into an amber coloured glass vial and anaylysed using GC-MS.

The procedure for the samples from the main study at doses of 0 and 5 mg/kg followed the same derivatisation procedure, except the initial quantity of the diet was 5.0 g not 2.0 g

The concentration of organotin compounds in the extracts was determined using GC-MS. For calculation of the amount of DOTO in the samples, the peak area of DHT was used as an internal standard. Quantitiation was achieved using the calibration graphs constructed from the calibration solutions.
The following conditions were used:
- Column: Fused silica HP5 MS, 30 m, 0.25 mm ID, 0.25 µm film
- Precolumn: fused silica HP5 MS, 2.5 m, 0.25 mm ID, 0.25 µm film
- Column temperature: after 3 minutes at 45 °C at a rate of 5 °C/min to 80 °C; then at a rate of 15 °C/min to 260 °C; 15 min at 260 °C
- Carrier: helium; 1.5 mL/min constant flow
- Injection volume: 1 µL
- Injection temperature: start at 60 °C, then at a rate of 14.5 °C/s to 300 °C; 5 min at 300 °C
- Injection method: splitless
- Ionisation: electron impact 70 eV
- Mass range: 60-600 amu
- Mass fragments used: DOT m/z = 375*; 263; 151, DHT 347*; 249; 179
Mass fragments marked with an asterisk were used for quantitation
Duration of treatment / exposure:
28 days (treated food was available ad libitum)
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
Range finding study: 0, 25, 75, 200 and 500 mg/kg diet
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
Main study: 0, 5, 25 and 250 mg/kg diet
Basis:
nominal in diet
No. of animals per sex per dose:
22 males and 22 females in the dose range finding study (5 groups of 4 male and 4 female rats)
52 males and 52 females in the 14-day main study (4 groups of 12 male and 12 female rats)
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Doses were selected on the results of the range finding test
- Rationale for animal assignment: Randomised
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Every morning throughout the study, and a second observation in the afternoon of working days.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Prior to the first exposure and then once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights of male and female rats were taken on day -2 (randomisation) and on days 0 (first day of dosing), 7 and 13 of the premating period.
Males were weighed weekly during the mating period until sacrifice. Females were weighed during mating (day 0, 7 and 13) and mated females were weighed on day 0, 7, 14 and 21 during presumed gestation and on day 1 and 4 of lactation. All animals were weighed at sacrifice.

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, also calculated as g/animal/day

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the premating period
- Anaesthetic used for blood collection: Yes, CO2/02 anaesthesia
- Anti-coagulant: K2-EDTA
- Animals fasted: Yes, overnight
- How many animals: 5 rats/sex/group
- Parameters checked:
Haemoglobin
Packed cell volume
red blood cell count
reticulocytes
Total white blood cell count
Prothrombin time
Thrombocyte count
Mean corpuscular volume (MCV)
Mean corpuscular haemoglobin (MCH)
Mean corpuscular haemoglobin concentration (MCHC)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the premating period
- Anaesthetic used for blood collection: Yes, CO2/02 anaesthesia
- Animals fasted: Yes, overnight
- How many animals: 5 rats/sex/group
- Parameters checked:
Fasting glucose
Alkaline phosphatase activity (ALP)
Aspartate aminotransferace activity (ASAT)
Alanine aminotransferace activity (ALAT)
Gamma glutamyl transferase activity (GGT)
Total protein
Albumin
Ratio albumin to globulin
Urea
Creatinine
Bilirubin (total)
Cholesterol (total)
Triglycerides
Phospholipids
Calcium (Ca)
Sodium (Na)
Potassium (K)
Chloride (Cl)
Inorganic phosphate

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Arena testing was performed prior to the first exposure and then once weekly until the end of dosing and in females until the end of lactation. Males and females selected for the functional observation battery test (FOB) and spontaneous activity measurements were excluded from the final arena testing.
At the end of the study, FOB test and spontaneous motor activity measurements were performed on day 27 for males and on post natal day for females.
- Dose groups that were examined: All animals were subject to the arena testing. For the other two tests, 5 animals per sex were randomly selected from each dose group.
- Battery of functions tested:
Autonomic: lacrimation, salivation, pupil response to light, palpebral closure, piloerection, defecation and urination
Neuromuscular: gait, mobility, forelimb and hindlimb gripstrength, landing foot splay, righting reflex
Sensorimotor: response to tail pinch, click, tough and approach of a visual object
Convulsive: clonic and tonic movements
Excitability: ease of removal, handling reactivity, arousal and vocalisations
Activity: rearing and motor activity
Physiological: body temperature

OTHER: Reproductive and developmental indices were also examined as part of the test.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
The following were taken from all animals:
Ovaries
Uterus
Testes
Epididymides
Seminal vesicles
Prostate
Organs and tissues showing macroscopic abnormalities

The following were taken from 5 animals/sex/group:
Adrenals
Axillary lymph node
Bone marrow (femur)
Brain
Caecum
Coagulation glands
Colon
Duodenum
Eyes
Heart
Jejunum
Lungs
Kidneys
Liver
Mammary gland (females only)
Mesentric lymph node
Parathyroids
Peyer's patches
Pituitary
Rectum
Sciatic nerve
Spinal cord
Spleen
Stomach
Thymus
Thyroids
Trachea
Urinary bladder

The following organs were weighed:
Adrenals
Brain
Heart
Kidneys
Liver
Spleen
Thymus

HISTOPATHOLOGY: Yes
Microscopic examination was performed on the collected organs of all rats in the control and high-dose group.
The liver and ovaries of females and the thymus of the male and female rats in the low and mid-dose groups were also evaluated
The following tissues, though collected were not subject to histopathological examination:
Coagulation glands
Mammary gland (females only)
In addition, reproductive organs of males that failed to sire (mated female which was not pregnant) and females that were non-mated or non-pregnant of the mid and low dose groups were microscopically examined.
Other examinations:
As part of the developmental screening, gross observations were performed on the pups.
Statistics:
Clinical findings were evaluated using Fisher’s exact probability test.
Bodyweight, bodyweight gain, organ weights and food consumption was assessed by one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison tests.
Red blood cell and coagulation variables, total white blood cell counts, absolute differential white blood cell counts, clinical chemistry values and organ weights were assessed by one-way ANOVA followed by Dunnett’s multiple comparison tests (treatment period).
Reticulocytes and relative differential white blood cell counts were assessed using Kriskal-Wallis non-parametric ANOVA followed by Mann-Whitney U-tests.
Histopathological changes were evaluated using Fisher’s exact probability test.
The results of the functional observations were measured on different scales. Continuous measurements were analysed by one-way analysis of variance at each time point, if found to be statistically significant, a post-hoc group comparison was performed. Rank order data were analysed by Kruskal-Wallis analysis of variance at each test time point, followed by planned multiple comparisons between dose groups were a significant results occurred. Categorical data were assessed using Pearson chi-square analysis.
Motor activity data were assessed by one-way analysis of variance at each time point with a post-hoc group comparison performed on significant results.
All tests were two sided and the level of probability p<0.05 was considered to be significant. Effects of treatment on habituation were analysed using repeated measures of analysis variance on time blocks. Each session consisted of 5 time blocks of 6 minutes each.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
One female in the high dose group was found dead on gestation day 24.
One male animal in the high dose group showed exopthalmus from week 2 and complete degeneration of the eye from week 3 onwards. This was observed after orbital punction. No other clinical signs were noted in the males.
The only finding during the gestation period (gestation day 21) was a sparsely haired animal in the 250 mg/kg group. During the lactation period, sparsely haired animals were noted in the control (n = 1), 5 mg/kg (n = 1) and in the 250 mg/kg group (n = 1). No other findings were noted in the female animals.

BODY WEIGHT AND WEIGHT GAIN
Mean bodyweights of the treated male animals was comparable to the controls. The bodyweight change of the male animals of the high-dose group was significantly decreased from days 13-21. Mean bodyweights of the dams of the high-dose group was statistically significantly decreased on gestation day 21 and post-natal day 1. Mean bodyweight changes of the dams of the high-dose group were statistically significantly decreased from gestation day 14 to 21. Bodyweights and bodyweight change of the dams of all the treated groups were comparable to the controls group at all other times of the study.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Mean food consumption (g/kg/day) of male animals of the 250 mg/kg diet group was found to be statistically significantly decreased from day 7-13. No other treatment related effects were observed in the male animals.
During the gestation period and lactation period (gestation days 7-14 and 14-21 and post-natal days 1-4), food consumption (expressed as g/animal/day and g/kg bodyweight/day) of the dams in the high-dose group was significantly decreased. No other treatment-related effects were observed.
Test substance intake was as follows:
- Males (listed as low, mid and high dose groups; 5, 25 and 250 mg/kg diet respectively)
premating days 0-7: 0.4, 1.7 and 17.4 mg/kg bodyweight/day
premating days 7-13: 0.3, 1.6 and 15.4 mg/kg bodyweight/day
post-mating days 21-28: 0.3, 1.5 and 14.5 mg/kg bodyweight/day

- Females (listed as low, mid and high dose groups; 5, 25 and 250 mg/kg diet respectively)
premating days 0-7: 0.4, 1.7 and 17.4 mg/kg bodyweight/day
premating days 7-13: 0.3, 1.6 and 15.4 mg/kg bodyweight/day
gestation days 0-7: 0.4, 2.0 and 17.4 mg/kg bodyweight/day
gestation days 7-14: 0.4, 1.9 and 16.7 mg/kg bodyweight/day
gestation days 14-21: 0.3, 1.4 and 11.2 mg/kg bodyweight/day
Post-natal days 1-4: 0.5, 2.4 and 17.4 mg/kg bodyweight/day

HAEMATOLOGY
All treated groups were found to be comparable to controls

CLINICAL CHEMISTRY
Statistically significantly increased alkaline phosphatase levels (U/L) were found in the high-dose males. Bilirubin (µmol/L) was found to be statistically significantly increased in the high-dose females. These findings were considered to be treatment related. Other effects such as the statistically significant increase in chloride in the 25 mg/kg male rats and the significant decrease in calcium in the 5 mg/kg females were not considered to be related to treatment. No other changes were observed.

NEUROBEHAVIOUR
No treatment-related effects were observed.

ORGAN WEIGHTS
The absolute thymus weight in the males of the 250 and 25 mg/kg groups were found to be significantly decreased. Relative thymus weight was found to be significantly decreased in the high dose male rats.
The absolute and relative weight of the female animals of the high dose group was significantly decreased. In the mid-dose group the relative thymus weight was also statistically significantly decreased.
In the female animals of the high-dose group, the relative kidney and liver weights were statistically significantly decreased.
No other effects were observed in either male or female animals.

GROSS PATHOLOGY
At necropsy, a decrease in thymic size was seen in all animals in the 250 mg/kg diet groups, 11 females in the 25 mg/kg diet group, 7 females in the 5 mg/kg group and 5 animals in the control group.
Examination of the female that was found dead revealed hydrothorax, haemorrhagic lungs, dilation of the vena cava and haemorrhagic discharge in the vagina, these were considered to be indicative of problems during parturition.

HISTOPATHOLOGY
Microscopic evaluation of the thymus revealed moderate to very severe lymphoid depletion in all animals (both sexes) of the 250 mg/kg group and in all females of the 25 mg/kg group. Lymphoid depletion was characterised by a decrease in the thymic lobules due to an extensive loss of cortical and medullary small lymphocytes. The distinction between the cortical and medullary areas was unclear. In the more extreme effects observed, the cortex was very small, or absent. The remaining lymphoid cells visible in the cortical areas were mainly lymphoblasts. Lymphoblastic cells and reticuloepithelial cells had increased, and/or higher numbers of these cells were visible due to the disappearance of small lymphocytes and the collapse of the thymic stroma. In 3 high-dose females, lymphoid depletion was accompanied by lymphoid depletion in the PALS (periateriolar lymphocyte sheath areas) in the spleen. The macroscopically observed thymi in 5 control and 7 low dose females exhibited no microscopic abnormalities. In the thymi of the 2 control and 2 low dose females pregnancy/lactation involution was observed. The thymic lobules were decreased in size but exhibited normal structure with the histological appearance of age-involution. Increased glycomeric vacuolation, viz moderate versus very slight was seen in the liver of 4 high dose females and was considered to be a potential cause of the increased weight.
Examination of the reproductive organs revealed a statistically significant increased in the incidence of cysts in the ovaries of 8 high-dose females.

OTHER FINDINGS
In the reproductive and developmental screening observations of this study, increased duration of gestation, increased implantation loss, an increased number of still born pups and pup mortality at postnatal day 4, decreased pup weight at postnatal day and an increased number of runts and postnatal day 1 were all observed in the high dose group.
Dose descriptor:
NOAEL
Effect level:
0.3 - 0.4 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Decreased thymus weight
Dose descriptor:
NOAEL
Effect level:
0.3 - 0.5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Decreased thymus weight and microscopic and macroscopic changes in the thymus
Dose descriptor:
NOAEL
Effect level:
5 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Reduced thymus weights (male and female animals), microscopic and macroscopic changes in the thymus (females only)
Critical effects observed:
not specified

Table 3: Test material concentration in experimental diets

Nominal concentration (mg/kg)

Mean Nominal Measured Concentration (mg/kg)

Percent of Nominal

0 (#1)

<0.05

NA

0 (#2)

<0.05

NA

0 (#3)

<0.05

NA

5 (#1)

4.52

90

5 (#2)

4.93

99

5 (#3)

4.40

88

25 (#1)

24.9

100

25 (#2)

26.5

106

25 (#3)

26.3

105

250 (#1)

247

99

250 (#2)

240

96

250 (#3)

244

98

#3: repeated analysis of batch no. 2

 

Table 4: Summary of relevant treatment related findings

Parameter

Dose levels

5 mg/kg diet

25 mg/kg diet

250 mg/kg diet

Bodyweight: GD 21, PN 1 (females only)

Decreased

Bodyweight change: GD 14-21 (females only)

Decreased

Food consumption: PM 7-13 (males) GD 7-14, 14-21 and PN 1-4 (females only)

Decreased

Bilirubin (females only)

Increased

Alkaline phosphatase (males only)

Increased

Relative liver weight (females only)

Increased

Relative kidney weight (females only)

Increased

Absolute and/or relative thymus weight

Decreased

Decreased

Thymus: lymphoid depletion (males only)

Increased

Thymus: lymphoid depletion (females only)

Increased

Increased

Ovary: cysts (females only)

Increased

Liver: glycogenic vacuolation (females only)

Increased

Conclusions:
Based on the effects noted in the thymus in both male and female rats in the 25 mg/kg diet groups, the NOAEL was concluded to be the lowest group tested, 5 mg/kg diet which was equivalent to 0.3-0.4 mg/kg bw/day for male animals and 0.3-0.5 mg/kg bw/day for female animals.
Executive summary:

The repeated dose toxicity of the test material was assessed in a repeated dose toxicity and reproductive and developmental screening study in rats. The study was performed in accordance with GLP and to the standardised guideline OECD 422. Only one death was noted during the study, and this was not attributed to toxicity of the test material. Based on the effects noted in the thymus in both male and female rats in the 25 mg/kg diet groups, the NOAEL was concluded to be the lowest group tested, 5 mg/kg diet which was equivalent to 0.3-0.4 mg/kg bw/day for male animals and 0.3-0.5 mg/kg bw/day for female animals.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
0.3 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The single study presented under this endpoint was performed and reported to a high standard and as such was assigned a reliability score of 2 in accordance with the criteria for assessing data quality as described in Klimisch (1997).

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

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Oral

The repeated dose toxicity of the test material was assessed in a repeated dose toxicity and reproductive and developmental screening study in rats. The study was performed in accordance with GLP and to the standardised guideline OECD 422. Only one death was noted during the study, and this was not attributed to toxicity of the test material. Based on the effects noted in the thymus in both male and female rats in the 25 mg/kg diet groups, the NOAEL was concluded to be the lowest group tested, 5 mg/kg diet which was equivalent to 0.3-0.4 mg/kg bw/day for male animals and 0.3-0.5 mg/kg bw/day for female animals.

As the study was performed on a read-across substance, the study was assigned a reliability score of 2 (reliable with acceptable restrictions) in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and considered suitable for assessment as an accurate reflection of the test material.

The sub-acute (28 day) repeated dose and reproductive and developmental screening study provides an NOAEL sufficient for classification, which can be extrapolated to represent a 90-day NOAEL for the same route. Further testing for this endpoint is considered to be inappropriate and is therefore omitted.

Inhalation

Inhalation is not considered to be the most appropriate route of exposure; as a more appropriate study is available, testing for this endpoint was omitted.

Dermal

Dermal exposure is not considered to be the most appropriate route of exposure; as a more appropriate study is available, testing for this endpoint was omitted.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
One study was available for evaluation of the repeated dose toxicity of a read across substance. The study was performed to a standardised guideline, in line with GLP and reported to a high standard sufficient to assess the quality of the presented data. As it was possible to derive an appropriate effect level that may be used with appropriate assessment factors in a risk assessment, the study was considered suitable for use as the key study.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
A data waiver has been submitted for this endpoint.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
A data waiver has been submitted for this endpoint.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
A data waiver has been submitted for this endpoint.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
A data waiver has been submitted for this endpoint.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: thymus

Justification for classification or non-classification

In accordance with Regulation (EC) No. 1272/2008 and Directive 67/548/EEC, based on the observations in the thymus, the substance is classified as STOT Rep. Exp. 1: H372: Causes damage to organs (thymus) through prolonged or repeated exposure and T; R48/25 Toxic: danger of serious damage to health by prolonged exposure if swallowed, respectively.