2-[(1-amino-9,10-dihydro-4-hydroxy-9,10-dioxo-2-anthryl)oxy]ethyl phenyl carbonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

FAT 93504/B was found to have no reproductive and/or developmental toxicity when tested in the combined repeated dose toxicity study with reproductive/developmental screening.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch number: 20140120-2
- Expiration date of the lot/batch: 25 February 2019
- Purity: 88.5 %

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient temperature and humidity in darkness; used/formulated in light

Species:

rat

Strain:

Wistar

Details on species / strain selection:

Wistar Han™:RccHan™:WIST strain rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: the males were approximately 11 weeks old, and the females were approximately 12 weeks old.
- Weight at study initiation: the males weighed 274 to 358 g, the females weighed 191 to 240 g
- Housing: solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): 15
- Photoperiod: 12 hours darkness

IN-LIFE DATES: From: 12 March 2018 To: 13 May 2018

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on exposure:

- PREPARATION OF DOSING SOLUTIONS:
For the purpose of this study the test item was prepared at the appropriate concentrations in Arachis oil BP. The stability and homogeneity of the test item formulations were determined. Results showed the formulations to be stable for at least twenty-one days when stored refrigerated. Formulations were therefore prepared fortnightly and stored at approximately 4 ºC in the dark.

Details on mating procedure:

- M/F ratio per cage: 1 male: 1 female
- Length of cohabitation: maximum of 14 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): Mated females were housed individually during the period of gestation and lactation

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of test item formulations were taken on two occasions and analyzed for concentration of FAT93504/B. The results indicate that the prepared formulations were within 95 to 111 % of the nominal concentration.

Duration of treatment / exposure:

6 weeks for males, and 8 weeks for females including a 2-week preparing phase, pairing, gestation and early lactation.

Frequency of treatment:

Daily

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

No. of animals per sex per dose:

24

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose levels were chosen in collaboration with the Sponsor and were based on the results of previous toxicity work, including a Fourteen Day Repeated Dose Oral (Gavage) Range-Finding Toxicity Study in the Rat.

- Other: The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test item, and the results of the study are believed to be of value in predicting the likely toxicity of the test item to man.

Positive control:

Not applicable

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Not specified
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: immediately before dosing, soon after dosing, and one hour after dosing during the working week (except for females during parturition where applicable).

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded on Day 1 (prior to dosing) and then weekly for males until termination and weekly for females until pairing. During the pairing phase, females were weighed daily until mating was confirmed. Body weights were then recorded for females on Days 0, 7, 14 and 20 post coitum, and on Days 1, 4, 7 and 14 post partum.

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

Oestrous cyclicity (parental animals):

Vaginal smears were taken daily for females throughout the two week pre-pairing treatment period and in the morning of the day of necropsy. The stage of the estrous cycle was recorded for each day.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: Adult males were killed by intravenous overdose of suitable barbiturate agent followed by exsanguination on Day 44 or 45.
- Maternal animals: Adult females were killed by intravenous overdose of suitable barbiturate agent followed by exsanguination on Day 14 post partum.

GROSS NECROPSY
- Gross necropsy consisted of a full external and internal examinations.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

All offspring, including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded. Examination of offspring was restricted to a macroscopic external examination except where abnormalities were observed, then an additional internal examination was performed.

Statistics:

Where considered appropriate, quantitative data was subjected to statistical analysis to detect the significance of intergroup differences from control; statistical significance was achieved at a level of p<0.05. Statistical analysis was performed on the following parameters: Grip Strength, Motor Activity, Body Weight, Body Weight Change, Food Consumption during gestation and lactation, Pre- Coital Interval, Gestation Length, Litter Size, Litter Weight, Sex Ratio, Implantation Sites, Post-imp lantation Losses, Viability Indices, Offspring Body Weight, Offspring Body Weight Change, Offspring Developmental Parameters, Hematology, Blood Chemistry, Absolute Organ Weights, Body Weight- Relative Organ Weights and Thyroid Hormone (Thyroxine).

Data were analyzed using the decision tree from the ProvantisTM Tables and Statistics Module as detailed as follows:
Where appropriate, data transformations were performed using the most suitable method. The ho mogeneity of variance from mean values was analyzed using Bartlett’s test. Intergroup variances were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covariates. Any t ransformed data were analyzed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for non-parametric data. If no dose response was found but the data shows non-homogeneity of means, the data were analyzed by a stepwise Dunnett’s (parametric) or Steel (non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was performed using the Student t-t st (parametric) or the Mann-Whitney U test (non-parametric).

Probability values (p) are presented as follows:
p <0.01 **
p <0.05 *
p >0.05 (not significant)

Reproductive indices:

Mating Performance and Fertility:
- Pre-coital Interval
- Fertility Indices

Gestation and Parturition Data:
- Gestation Length
- Parturition Index

Offspring viability indices:

- Live Birth Index (%)
- Viability Index 1 (%)
- Viability Index 2 (%)

Clinical signs:

no effects observed

Description (incidence and severity):

There were no clinical signs observed that indicated any systemic effect of treatment for either sex at 100, 300 or 1000 mg/kg bw/day. Red fur staining was observed for all animals receiving 1000 mg/kg bw/day, at a lower incidence in animals receiving 300 mg/kg bw/day and in one male at 100 mg/kg bw/day. This finding was considered to be consistent with the colored nature of the Test Item and was considered to be of no toxicological significance. One male (number 29) receiving 100 mg/kg bw/day showed noisy, labored and decreased respiration on Day 25, with noisy respiration persisting to the following day. Subsequently, this animal showed pilo-erection, hunched posture and noisy respiration on Days 29 and 30. However, on Day 29, it was noted that the animal had broken front teeth, and this was considered to be the underlying cause for these later adverse clinical signs. The animal was isolated and given moistened diet to assist feeding and further clinical signs were restricted to noisy respiration during Days 32, 33, 35 and, during behavioral assessments, Day 40. In the absence of any similar episodes of these adverse clinical signs at higher dosages, these findings for this isolated animal were considered incidental and unrelated to treatment. One female (number 39) receiving 100 mg/kg bw/day showed hunched posture on Day 52 (the day of termination) but, this female had escaped overnight, depriving itself of access to water, and this was considered to be the underlying cause for this observation.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

There was no effect of treatment on body weight and body weight gain of males throughout the study at 100, 300 or 1000 mg/kg bw/day. At 1000 mg/kg bw/day, mean body weight gain of males during Week 5 (Days 29-36) was statistically significantly higher than control, but this difference was considered to reflect normal biological variation. There was no effect of treatment on body weight and body weight gain for females during the pre-pairing treatment phase or during gestation and lactation at 100, 300 or 1000 mg/kg bw/day. At 100 and 1000 mg/kg bw/day, mean cumulative body weight gain was statistically significantly lower than control by Day 20 of gestation, but there was no dosage relationship. These differences in mean body weight at the end of gestation are considered to be due to a lower contribution from the gravid uterus, as litter weights at these dosages were also lower than control. Supporting this, mean body weights for females on Day 1 of lactation were similar to control at all dosages, indicating that there was no underlying effect on maternal body weight.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

no effects observed

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

At all dosages, mean reticulocyte counts for both sexes were statistically significantly higher than control. For treated males mean values showed a dosage relationship and 1/5 individual values at 100 mg/kg bw/day and all individual values at 300 and 1000 mg/kg bw/day exceeded the historical control range compared to 1/5 individual values for the control group. For treated females, although the highest mean value occurred at 1000 mg/kg bw/day, there was no dosage relationship at lower dosages and only 1/5 individual values at both 300 and 1000 mg/kg bw/day exceeded the historical control range. These apparent increases in reticulocyte counts were not associated with any statistically significant differences from control for other erythrocyte parameters, with the possible exception of higher mean corpuscular hemoglobin concentration for females at 300 mg/kg bw/day, nor were there any supporting histopathological changes apparent in the tissues of treated animals. In view of the lack of supporting observations, the higher number of reticulocytes was considered to be of no toxicological significance and insufficient to be regarded as representing an adverse effect.
For females receiving 300 and 1000 mg/kg bw/day, mean platelet counts were statistically significantly lower than control but only one individual value at each dosage was below the historical control range. This finding, in the absence of any supporting histopathological change, was considered to be incidental and unrelated to treatment. As previously discussed, for females at 300 mg/kg bw/day, mean corpuscular hemoglobin concentration was statistically significantly higher than control, with 2/5 values exceeding the historical control range. There was no similar increase apparent for females at 1000 mg/kg bw/day and, in the absence of any supporting histopathological change, this finding was considered incidental and unrelated to treatment. For females receiving 300 mg/kg bw/day, mean activated partial thromboplastin time was statistically significantly longer than control, with 4/5 individual values exceeding the historical control range compared to only one individual control value. There was no similar increase in mean activated partial thromboplastin time apparent for females at 1000 mg/kg bw/day and, in the absence of any supporting histopathological change, this finding was considered incidental and unrelated to treatment.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

For males receiving 300 or 1000 mg/kg bw/day, cholesterol levels were statistically significantly higher than control but, all individual values for these treated animals were within the historical control range. Additionally, at 300 mg/kg bw/day, sodium levels were statistically significantly higher than control and again, all individual values for these treated animals were within the historical control range. In isolation, and in the absence of any supporting histopathological change, these findings were considered to be incidental and unrelated to treatment.

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, non-treatment-related

Description (incidence and severity):

Three females receiving 300 mg/kg bw/day and three females receiving 1000 mg/kg bw/day showed red staining of the urine during behavioral assessments, however, this finding was considered to be consistent with the colored nature of the Test Item and to be of no toxicological significance. As previously discussed, one male receiving 100 mg/kg bw/day showed noisy respiration during behavioral assessments on Day 40. This finding was consistent with similar observations for this animal and in the absence of any occurrence at higher dosages was considered to be unrelated to treatment.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Intergroup differences observed in the scores for sensory reactivity did not indicate any effect of treatment for either sex at 100, 300 or 1000 mg/kg bw/day. Grip strength and motor activity assessments did not indicate any effect of treatment for either sex at 100, 300 or 1000 mg/kg bw/day. For males at 1000 mg/kg bw/day, mean fore limb grip strength was statistically significantly lower than control during trial three and for males at 100 mg/kg bw/day mean hind limb grip strength was statistically significantly higher than control during trial one. No other statistically significant differences from control were apparent and, in isolation, these findings were considered to be incidental and unrelated to treatment.

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Thyroid Gland: Hypertrophy of the follicular epithelium at a minimal level was noted in 2/12 males treated with 1000 mg/kg bw/day. The appearance of the thyroid glands in control and 1000 mg/kg bw/day males and females were varied, and at this low incidence and severity this finding is considered to be incidental and indicative of individual variation. Whilst the organ weight data showed a minor increase in males treated at 1000 mg/kg bw/day, numerous control animals were also above expected limits. There were three non-productive matings within the study in animals treated with 100 and 300 mg/kg bw/day. No significant changes were noted in the tissues examined to explain the lack of fertility in any animal. There were no test item-related microscopic findings in the reproductive tracts following the qualitative examination of the stages of spermatogenesis in the testes (no test item-related abnormalities in the integrity of the various cell types present within the different stages of the sperm cycle) or the evaluation of the uterus or of follicles and corpora lutea in the ovaries.

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Thyroid Hormone Analysis:
Evaluation of Thyroxine (T4) in adult males at Day 13 of age did not identify any obvious effect of treatment or indication of endocrine disruption at 100, 300 or 1000 mg/kg bw/day.

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

Mating performance, as assessed by the number of paired animals that mated, was unaffected by treatment at dosages of 100, 300 or 1000 mg/kg bw/day.

Reproductive performance:

no effects observed

Description (incidence and severity):

Mating performance, as assessed by the number of paired animals that mated, was unaffected by treatment at dosages of 100, 300 or 1000 mg/kg bw/day.

There was no effect on fertility, as assessed by the number of females that achieved pregnancy, at dosages of 100, 300 or 1000 mg/kg bw/day. Two females receiving 100 mg/kg bw/day and one female receiving 300 mg/kg bw/day were non-pregnant, but in the absence of any non-pregnant females at 1000 mg/kg bw/day, this finding was clearly incidental and unrelated to treatment.

The intergroup distribution of gestation lengths observed during the study did not indicate any effect of treatment at 100, 300 or 1000 mg/kg bw/day.

There was no effect of maternal treatment on the number of implantations, post-implantation loss and live birth index, litter size and sex ratio on Day 1 and subsequent offspring survival and sex ratio to Day 13 of age at dosages of 100, 300 or 1000 mg/kg bw/day.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food efficiency

haematology

clinical biochemistry

organ weights and organ / body weight ratios

gross pathology

neuropathology

histopathology: non-neoplastic

reproductive function (oestrous cycle)

reproductive performance

Key result

Critical effects observed:

no

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

Evaluation of ano-genital distance for male offspring on Day 1 post-partum and visible nipple count for male offspring on Day 13 post-partum did not reveal any adverse effect of maternal treatment at 100, 300 or 1000 mg/kg bw/day. Ano-genital distance for female offspring with maternal treatment at 300 and 1000 mg/kg bw/day was statistically significantly higher than control with a dose relationship being apparent. However, only individual litter values from one female at 1000 mg/kg bw/day exceeded the historical control data range and, as such, this apparent effect was considered to be due to normal biological variation and unrelated to treatment.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

clinical signs

mortality

body weight and weight gain

gross pathology

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

No Observed Adverse Effect Level (NOAEL) for reproduction and the survival, growth and development of the offspring was considered to be 1000 mg/kg bw/day.

Executive summary:

This study was designed to investigate the systemic toxicity and potential adverse effects of FAT 93504/B on reproduction (including offspring development), to evaluate some endocrine disruptor relevant endpoints, and is designed to be compatible with the requirements of the OECD Guideline 422. The test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for approximately six weeks for males and throughout a two week pre-pairing phase, pairing, gestation and lactation to Day 14 for females, at dose levels of 100, 300 and 1000 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Arachis oil BP) over the same treatment period. Clinical signs, behavioral assessments, body weight change and food and water consumption were monitored during the study. Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 13 of lactation. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and ano-genital distance and visible nipple count (male offspring only). Extensive functional observations were performed on five selected males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 12 post partum. Hematology and blood chemistry were evaluated prior to termination on five selected males and females from each dose group. Additionally, blood samples were taken at termination from all adult animals and from one male and one female offspring per litter (where possible) on Days 4 and 13 post partum, for thyroid hormone analysis; samples from adult males and Day 13 offspring were analyzed for Thyroxine (T4). Vaginal smears were performed for all females from the day after arrival (enabling the exclusion of females not showing appropriate estrous cycling from dosing) and for all treated females including controls through pre-pairing, pairing and up to confirmation of mating. Vaginal smears were also performed in the morning on the day of termination for all treated females. Adult males were terminated on Day 44 or 45, followed by the termination of all surviving offspring and adult females on Days 13 and 14 post partum, respectively. Any female which did not produce a pregnancy was terminated around the same time as littering females. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed. All offspring were examined externally; where external observations were detected an internal necropsy was performed. There were no unscheduled deaths and no clinical signs observed during the study. No adverse effects of treatment were seen on functional observations. Body weight, food consumption, food conversion efficiency and water consumption were also not affected. No adverse effects were recorded on hematological, clinical biochemistry, pathological, histopathological and organ weight examinations. Evaluation of Thyroxine (T4) in adult males and offspring at Day 13 of age did not identify any obvious effect of treatment or indication of endocrine disruption at 100, 300 or 1000 mg/kg bw/day. Estrous cycles, mating performance, fertility and gestation lengths were unaffected by treatment at dosages of 100, 300 or 1000 mg/kg bw/day. There was no effect of maternal treatment on the number of implantations, post-implantation loss and live birth index, litter size and sex ratio on Day 1 and subsequent offspring survival and sex ratio to Day 13 of age at dosages of 100, 300 or 1000 mg/kg bw/day. There was no effect of maternal treatment on mean offspring body weight on Day 1 and subsequent mean offspring body weight gains to termination on Day 13 of age at 100, 300 and 1000 mg/kg bw/day. Litter weights at 100 and 1000 mg/kg bw/day were lower than control throughout lactation, but differences reflected lower litter size. Ano-genital distances for female offspring at 300 and 1000 mg/kg bw/day were higher than control but this was considered likely to reflect normal biological variation. For males offspring, ano-genital distance on Day 1 post partum and visible nipple count on Day 13 post partum were unaffected by treatment at 100, 300 and 1000 mg/kg bw/day. Offspring clinical signs did not indicate any effect of maternal treatment at 100, 300 or 1000 mg/kg bw/day. Based on the above findings, the No Observed Adverse Effect Level (NOAEL) for adult toxicity was considered to be 1000 mg/kg bw/day. This dosage also represented the No Observed Adverse Effect Level (NOAEL) for reproduction and the survival, growth and development of the offspring.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

High quality GLP study

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The systemic toxicity and potential adverse effects of FAT 93504/B on reproduction (including offspring development), were evaluated in a study conducted according to OECD Guideline 422. The test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for approximately six weeks for males and throughout a two week pre-pairing phase, pairing, gestation and lactation to Day 14 for females, at dose levels of 100, 300 and 1000 mg/kg bw/day. There were no unscheduled deaths and no clinical signs observed during the study. No adverse effects of treatment were seen on functional observations. Body weight, food consumption, food conversion efficiency and water consumption were also not affected. No adverse effects were recorded on hematological, clinical biochemistry, pathological, histopathological and organ weight examinations. Evaluation of Thyroxine (T4) in adult males and offspring at Day 13 of age did not identify any obvious effect of treatment or indication of endocrine disruption at 100, 300 or 1000 mg/kg bw/day. Estrous cycles, mating performance, fertility and gestation lengths were unaffected by treatment at dosages of 100, 300 or 1000 mg/kg bw/day. There was no effect of maternal treatment on the number of implantations, post-implantation loss and live birth index, litter size and sex ratio on Day 1 and subsequent offspring survival and sex ratio to Day 13 of age at dosages of 100, 300 or 1000 mg/kg bw/day. Based on the above findings, the No Observed Adverse Effect Level (NOAEL) for adult toxicity was considered to be 1000 mg/kg bw/day. This dosage also represented the No Observed Adverse Effect Level (NOAEL) for reproduction.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

High quality GLP-study.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

In the OECD 422 study discussed in the 'additional information' section of 'Effects on fertility', the potential of FAT 93504/B to cause developmental toxicity was also investigated. There was no effect of maternal treatment on mean offspring body weight on Day 1 and subsequent mean offspring body weight gains to termination on Day 13 of age at 100, 300 and 1000 mg/kg bw/day. Litter weights at 100 and 1000 mg/kg bw/day were lower than control throughout lactation, but differences reflected lower litter size. Ano-genital distances for female offspring at 300 and 1000 mg/kg bw/day were higher than control but this was considered likely to reflect normal biological variation. For males offspring, ano-genital distance on Day 1 post partum and visible nipple count on Day 13 post partum were unaffected by treatment at 100, 300 and 1000 mg/kg bw/day. Offspring clinical signs did not indicate any effect of maternal treatment at 100, 300 or 1000 mg/kg bw/day. Based on these findings, the No Observed Adverse Effect Level (NOAEL) for the survival, growth and development of the offspring was considered to be 1000 mg/kg bw.

Justification for classification or non-classification

FAT 93504/B was found to have no reproductive and/or developmental toxicity when tested in an OECD 422 study, hence it does not warrant classification for toxicity to reproduction according to Regulation (EC) No. 1272/2008 (CLP) criteria.