Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04 November 2016 (animal arrival) to 29 November 2016 (In-life end date)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
other: current requirements of the European Council (EC)
Deviations:
no
Qualifier:
according to
Guideline:
other: current requirements of the Japanese Ministry of Agriculture, Forestry, and Fisheries (JMAFF)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
- Appearance: Dark orange /red liquid
- Storage conditions of test material: Sealed container, refrigerated (2 to 8 °C), in the dark

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: Crl:CD(SD)
- Age at study initiation: At the time of mating, females were 8 to 10 weeks old
- Weight at study initiation: At least 140 g at mating; females weighed between 203.9 and 311.2 g at the start of dosing
- Fasting period before study: No
- Housing: Animals were individually housed in cages. Bedding was provided on a weekly basis to each cage by use of clean Aspen wood chips. Animals were provided with wooden Aspen chew blocks and nesting materials as forms of environmental enrichment.
- Diet: Animals had ad libitum access to the diet
- Water: Water from the main tap supply was provided ad libitum via water bottles
- Acclimation period: Acclimatisation was limited by mated status, and an inspection was performed before the start of dosing to ensure suitability for the study.

ENVIRONMENTAL CONDITIONS
- Temperature: 19 to 25 °C
- Humidity: 30 to 70 % (relative)
- Air changes: The room was air conditioned to provide a minimum 15 to 20 air changes/hour
- Photoperiod: Fluorescent lighting was controlled automatically to give a cycle of 12 hours of light and 12 hours of dark, with the exception of when experimental procedures dictated.

IN-LIFE DATES
- From: 04 November 2016
- To: 29 November 2016

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Formulations were prepared weekly. The test material was formulated as a suspension in PEG 400 and the formulations were stored refrigerated (2 to 8 °C) in a sealed container, protected from light. The formulations were stirred on arrival at the animal room and were stirred continuously for 30 minutes before dosing commenced (excluding the control) and throughout dosing.

VEHICLE
- Amount of vehicle (if gavage): A dose volume of 10 mL/kg was used
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
STABILITY
Stability was previously confirmed at concentrations of 5.1, 76.5, and 560 mg/mL for 10 days at 4°C and the formulations were considered stable for up to 6 days at room temperature and up to 11 days when stored at 2 to 8 °C.

HOMOGENEITY
Visual homogeneity was previously confirmed at 5.1, 76.5, and 560 mg/mL. The low and high test material formulations were confirmed to be homogenous.

CONCENTRATION VERIFICATION
Concentration verification was carried out. The mean % target range for the preparation of the formulations was 90 to 110 % of the nominal concentration. Results were within this range. The test material was not detected in control samples.
Details on mating procedure:
- Impregnation procedure: Time-mated. At the time of mating, females were 8 to 10 weeks old and weighed at least 140 g.
- Proof of pregnancy: Mating (overnight at the supplier’s laboratory) was confirmed by the presence of a vaginal plug in situ, or other evidence of mating, if necessary. The day on which mating was confirmed was designated as GD 0. Animals were delivered to the testing facility by GD 3.
Duration of treatment / exposure:
Animals were dosed from GD 6 to 20
Frequency of treatment:
Once daily
Duration of test:
Females were maintained to GD 21
Doses / concentrationsopen allclose all
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:
20 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The high-dose level of 1000 mg/kg/day was selected as it is the limit dose. Maternal toxicity was expected on the basis of some organ weight increases and marginal haematological effects observed at the limit dose in a 28 day rat gavage study. These parameters were not evaluated in this study. The intermediate dose of 300 mg/kg/day was selected as it approximated top dose/root 10. It was expected to be the maternal no observed effect level (NOEL) on the basis of a 28 day rat gavage study. The low dose of 100 mg/kg/day was selected as it approximated the mid dose/root 10. It was included as a potential NOEL if effects were observed at the intermediate dose level.
The dose levels were selected based on a previous 28 day rat gavage toxicity study. Treatment-related observations were confined to reduced haemoglobin, haematocrit, red blood cells and mean cell haemoglobin concentration for females administered 1000 mg/kg/day. Elevated absolute and body weight relative adrenal weights were also observed but no microscopic changes were noted.
- Rationale for animal assignment: Animals were assigned to dose groups based on GD 0 body weight data obtained from the Supplier (i.e., all animals confirmed as mated on a specific day were randomly allocated to dose groups).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at the beginning and the end of the working day for signs of ill health or overt toxicity. Animals were observed immediately post-dose and approximately at the end of the day.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each animal was given a detailed physical examination daily from the start of dosing until the day of necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded on GD 3, 6, 9, 12, 15, 17, 20 and 21.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: The amount of food consumed was determined daily from GD 3. Food consumption was calculated as g/animal/day.

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21. Food was not removed prior to the necropsies. Females were sacrificed on GD 21 by cervical dislocation following isoflurane anaesthesia; death was confirmed by exsanguination and animals were examined macroscopically.
- Organs examined: All lesions were recorded and retained in the relevant fixative.
- Terminal body weight: The terminal body weight was recorded for adjusted gravid uterus weight calculations only and was not reported.
- Other: Animal 53 (Group 3), which died prior to the scheduled sacrifice, was examined macroscopically for abnormalities of the thoracic and abdominal viscera.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes

The ovaries and uteri were removed and examined, and the following data were recorded: Pregnancy status, gravid uterus weight, number of corpora lutea, number and intrauterine position of implantations (subdivided into: live foetuses, early intrauterine deaths, late intrauterine deaths and dead foetuses).

Early intrauterine deaths were classified as those which showed decidual or placental tissue only. Late intrauterine deaths showed embryonic or foetal tissue in addition to placental tissue. Dead foetuses were classified as those which appeared to have died shortly before necropsy. Implantations were allocated numbers relating to their position in utero. The uterus of any apparently non pregnant female was immersed in a 10 % ammonium sulfide solution to reveal any evidence of implantation.
From animal 53 (Group 3), which died prior to the scheduled sacrifice, the uterus and ovaries were examined for implantations and corpora lutea, respectively. The extent of development of the implantation sites was determined as near as possible. An evaluation of the uterus was made to indicate dead or live implantations.
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: No

Live foetuses were sacrificed by a subcutaneous injection of sodium pentobarbitone, followed by confirmation of cessation of circulation.
Individual foetal and placental weights were recorded and foetuses were examined externally and sexed. Approximately one-half of the foetuses in each litter, selected by systematic sampling, were dissected, and the visceral abnormalities were examined. They were then eviscerated, and the carcasses were processed for skeletal examination. The skeletons were examined in 50 % glycerol and retained in glycerol/propylene glycol.
The remaining foetuses were fixed in Bouin's fluid and examined. The foetuses fixed for visceral examination were retained in the relevant fixative.
Foetal abnormalities were classified as malformations (rare and/or potentially lethal defects) and variations (commonly occurring non lethal abnormalities).
Statistics:
Data from treated animals were compared with control data. Statistical analyses were performed where appropriate.
Except where otherwise stated, tests were performed using a two-sided risk and were considered significant where P≤0.05.
Body weight, body weight gains, and food consumption were analysed using analysis of variance (ANOVA).
Mean foetal weight (male, female, and combined) was analysed using analysis of covariance (ANCOVA), with litter size (live and dead foetuses) as the covariate. The number of corpora lutea, implantation sites, early and late resorptions, dead foetuses, live foetuses, percent pre- and post-implantation loss and percent male foetuses were analysed using the Kruskal-Wallis and Wilcoxon rank sum test.
Gravid uterine weights and corrected body weights (carcass weights) were analysed using analysis of variance (ANOVA).
The percentage of foetuses affected (mean litter percent) was analysed using the Kruskal-Wallis and Wilcoxon rank sum test.
Proportion of litters affected was analysed using a one-sided upper tail Fisher’s exact test.
Indices:
% Pre-Implantation Loss = [(Number of corpora lutea - number of implantations) / Number of corpora lutea] x 100
% Post-Implantation Loss = [(Number of implantations - number of live embryos) / Number of implantations] x 100
Carcass Weight = Terminal body weight - uterus weight
Total Weight Change = Day 21 body weight - Day 3 body weight
% Male Foetuses = (Number of male foetuses / Number of foetuses of determined sex) x 100

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
One animal administered 1000 mg/kg/day (Animal 62F) had a convulsive episode (lasting 5 to 10 seconds) on GD 8, with complete recovery thereafter. One animal administered 1000 mg/kg/day (Animal 63F) was noted with transient hunched posture from GD 9 to 14, and one animal administered 1000 mg/kg/day (Animal 72F) was thin from GD 9 to 21. One animal administered 1000 mg/kg/day (Animal 75F) was recorded with red tears in the left eye on GD 21. Isolated instances of raised fur were observed on GD 13 and 15 for one animal administered 1000 mg/kg/day (Animal 64F).
An isolated instance of raised fur was observed on GD 10 for one animal administered 100 mg/kg/day (Animal 28F). In the absence of a dose related response, this finding was considered to have arisen incidentally.
Fur loss/thinning, fur staining, teeth pallor and instances of sores/lesions on the skin were observed in all dose groups, including controls, and are commonly observed in studies of this type, with no relationship to test material administration. Faecal changes (liquid/soft/loose/brown faeces) were evident in all dose groups, including controls, and were therefore considered attributed to the control material (vehicle) used on the study, and not test material related.

- Post-dose Observations
Instances of paddling and salivation were noted immediately post-dose for a few animals administered 1000 mg/kg/day, which was considered related to the unpleasant taste of the test material.
Mouth rubbing was observed for animals from all dose groups, including controls, immediately after dosing. These findings were considered most likely attributed to the unpleasant taste of the control material (vehicle), and unrelated to test material toxicity.
An instance of paddling was observed on GD 19 for one animal administered 100 mg/kg/day (Animal 22F). In isolation, this was considered to have arisen incidentally.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No test material-related unscheduled deaths occurred.
One female administered 300 mg/kg/day (Animal 53F) was found dead on GD 14. Macroscopic examination revealed the cause of death to be unrelated to test material toxicity (findings were consistent with inappropriate dosing technique).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slightly lower body weight gains were evident between GD 6 and 9 for all animals administered the test material, compared with controls (-10, -15, and -30 % for animals administered 100, 300, or 1000 mg/kg/day, respectively). Body weight gain values were comparable with controls thereafter. Overall body weight was gain (GD 6 to 21) for animals administered 1000 mg/kg/day was only slightly lower than controls (-5 %).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
For animals administered 1000 mg/kg/day, statistically significant reductions in food consumption were evident from GD 6 to 9 (P<0.001; -46 to -36 %), GD 10 (P<0.01; -22 %), and GD 12 (P<0.05; 11 %), compared with controls. This resulted in a 15 % lower overall mean food consumption for animals administered 1000 mg/kg/day, compared with controls. On the day of necropsy (GD 21), food consumption was significantly lower than controls (P<0.001; -28 %).
No adverse effect on food consumption was noted for females administered 300 or 100 mg/kg/day. A reduction in food consumption was evident after the first dose at these dose levels (P<0.01), compared with controls. Values were essentially similar to controls thereafter and, as such, the initial insult was considered not to represent an adverse effect.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test material-related macroscopic findings were noted.
The 300 mg/kg/day decedent (Animal 53F) was noted with macroscopic findings consistent with inappropriate dosing technique (clear fluid in the thoracic cavity and oesophageal rupture).
The remaining macroscopic findings were considered low incidence findings, occasionally observed in laboratory maintained rats, and unrelated to test material toxicity.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No effect on implantation sites were observed across the dose groups.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
No effect on in utero deaths were observed across the dose groups.
18, 15, 17, and 17 animals administered 0, 100, 300, or 1000 mg/kg/day, respectively, had live foetuses at necropsy on GD 21.
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Two, five, two and three animals from the groups administered 0, 100, 300 or 1000 mg/kg/day arrived from the animal supplier as non-pregnant. These non-pregnant animals were unrelated to test material administration.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Mean placenta weights for animals administered 1000 mg/kg/day were approximately 12 % lower than controls. Slightly lower foetal weights were observed in the 1000 mg/kg/day litters, compared with controls, when adjusted for litter size (P<0.01 males; P<0.001 females).
No such effects were evident for the 300 or 100 mg/kg/day litters.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
organ weights and organ / body weight ratios
other: Lower foetal weights at 1000 mg/kg/day

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slightly lower foetal weights were observed in the 1000 mg/kg/day litters, compared with controls, when adjusted for litter size (P<0.01 males; P<0.001 females).
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No effect on in utero deaths were observed across the dose groups.
18, 15, 17, and 17 animals administered 0, 100, 300, or 1000 mg/kg/day, respectively, had live foetuses at necropsy on GD 21.
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Two, one, three and three foetuses from the litters of animal administered 0, 100, 300 or 1000 mg/kg/day showed malformations (see Table 1).
Remaining malformations were observed in one animal only, or were present in controls, and as such were considered to have arisen incidentally.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
Two, one, three and three foetuses from the litters of animal administered 0, 100, 300 or 1000 mg/kg/day showed malformations (see Table 1).
Two foetuses from two 1000 mg/kg/day litters showed ocular malformations, which, in the absence of these findings in the historical control background data (HCBD), was considered test material related.
Remaining malformations were observed in one animal only, or were present in controls, and as such were considered to have arisen incidentally.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
VARIATIONS (Table 2)
A higher incidence of supernumerary liver lobe was observed in 1000 mg/kg/day litters, compared with controls, with statistical significance achieved following fresh visceral examination.
The skull variation (sutral bone) was present in the HCBD maintained at the testing facility, although the HCBD mean was 5 % litters. The higher incidence would suggest a test material-related effect in litters exposed to 1000 mg/kg/day. Furthermore, the tail variation was not present in the HCBD.
The higher incidence of misshapen scapula for litters from treated dams was noticeably higher than controls, although this variation was considered non adverse.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
visceral malformations

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
visceral/soft tissue: eye
Description (incidence and severity):
Seen at the top dose of 1000 mg/kg/day in two foetuses

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
no
Relevant for humans:
not specified

Any other information on results incl. tables

Table 1: Summary of Malformations

Dose Level (mg/kg/day)

Animal No.

Foetus ID / Sex

Tissue

Malformation

% Foetuses Affected

HBCD % Foetuses

Min.

Max.

0

1F

L6 F

Sternebra

Misaligned - 3, 4, 5

1.39

-

-

0

17F

R12 M

Rib

Abnormal attachment - left, 4, 5

0.69

-

-

Absent - right, 4

0.69

-

-

Interrupted - left, 13

0.69

-

-

Short - left, 1

0.69

0

2.26

Supernumerary articulated full, left 6/7

0.69

-

-

Fused - left 4/5, 6

0.69

-

-

Sternebra

Fused - 2/3

0.69

-

-

Misaligned - 3, 4

1.39

-

-

Vertebra - thoracic

Thoracic vertebra - supernumerary - left hemivertebra 6/7

0.69

-

-

Vertebra - thoracic arch

Misaligned, 7

0.69

-

-

Small, right, 5

0.69

-

-

Vertebral column

Scoliosis - thoracic

0.69

0

0.4

100

22F

L4 M

Heart

Cardiomegaly

0.83

-

-

Ventricle -large, interventricular groove

0.83

-

-

Ventricle - thick, interventricular septum

0.83

-

-

300

50F

R14 M

Eye

Microphthalmia -left

0.84

0

0.4

Skull

Orbital socket - small, left

0.84

0

0.7

Vertebra - cervical arch

Absent - right, 3

0.84

-

-

300

54F

R13 F

Rib

Short - left, 13

1.68

0

2.26

300

54F

R14 F

Rib

Short - left, 13

1.68

0

2.26

1000

69F

R9 M

Eye

Lens - misshapen, bilateral

1.58

-

-

Lens - small, bilateral

1.58

-

-

1000

70F

R11 M

Kidneys

Hydronephrosis - left

0.84

0

0.4

1000

79F

R12 M

Eye

Lens - misshapen, bilateral

1.58

-

-

Lens - small, bilateral

1.58

-

-

F = Female; HBCD = Historical control background data; M = Male; Max. = Maximum; Min. = Minimum

 

Table 2: Noteworthy Variations

Variations

Percentage of affected litters (number of litters/foetuses)

Group 1 (Control)

Group 2

Group 3

Group 4

Tail: fleshy tab

0

0

0

12 (2/3)

Liver: lobe - supernumerary (fresh visceral)

6 (1/1)

20 (3/4)

24 (4/5)

79** (8/11)

Liver: lobe - supernumerary (fixed visceral)

28 (5/6)

33 (5/8)

29 (5/7)

41 (7/10)

Pectoral girdle: scapula - misshapen

6 (1/1)

27 (4/6)

29 (5/5)

29 (5/8)

Skull: sutural bone

0

0

0

12 (2/2)

**P< 0.01 compared with controls

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, the no observed adverse effect level (NOAEL) was established as 300 mg/kg/day for dams and foetuses.
Executive summary:

A study was conducted to determine the effects of the test material on the embryonic and foetal development of the rat in accordance with the standardised guidelines OECD 414, US EPA OPPTS 870.3700 and exceeds the current requirements of the European Council and Japanese Ministry of Agriculture, Forestry, and Fisheries. The study was carried out under GLP conditions.

Four groups of 20 female time-mated Sprague Dawley Crl:CD(SD) rats were administered 0 (vehicle), 100, 300 or 1000 mg/kg/day of the test material once daily by oral gavage from Gestation Day (GD) 6 to 20, inclusive, at a dose volume of 10 mL/kg. The control material was Polyethylene glycol 400 (PEG 400).

Assessment of toxicity was based on clinical observations, body weight and food consumption. On GD 21, females were sacrificed and the progress and outcome of pregnancy was evaluated. Complete necropsies were performed on all animals, with a recording of macroscopic abnormalities for all tissues. Foetuses were evaluated for external, visceral, and skeletal malformations and variations.

No test material-related unscheduled deaths occurred. 18, 15, 17, and 17 pregnant females administered 0, 100, 300 or 1000 mg/kg/day, respectively, had live foetuses on GD 21.

For females administered 1000 mg/kg/day, clinical observations consisted of isolated instances of a convulsive episode, hunched posture, thin appearance, red tears in the eye and raised fur. Paddling behaviour and salivation were noted immediately post-dose for a few animals.

Initial reductions in body weight gains (30 % between GD 6 and 9) compared with controls and lower food consumption were evident following administration of 1000 mg/kg/day.

No macroscopic abnormalities were evident following 1000 mg/kg/day, however, lower placenta weights and lower mean foetal weights were evident and foetal evaluations showed ocular malformations (small and misshapen lens) in two foetuses from two litters. Furthermore, variations only observed at this dose level were noted in the skull (sutral bone) and tail (fleshy tab) and higher incidences of misshapen scapula and supernumerary liver lobe were also evident.

For animals administered 300 or 100 mg/kg/day, test material-related clinical observations included instances of mouth rubbing noted immediately post-dose (with isolated instances of paddling behaviour also noted for animals administered 100 mg/kg/day) and an initial reduction in body weight gain and food consumption. No macroscopic abnormalities or implantation or uterine changes were evident, and foetal weights were essentially similar to controls. Furthermore, no test material-related malformations were noted. The only possible foetal variations noted were higher incidences of misshapen scapula at these dose levels, compared with controls.

In conclusion, the oral administration of 0, 100, 300 or 1000 mg/kg/day to the pregnant Sprague Dawley rat caused test material-related effects in the maternal animal, resulting in lower placenta and foetal weights, and ocular malformations noted in two foetuses following administration of 1000 mg/kg/day.

Maternal effects noted following administration of 300 or 100 mg/kg/day did not result in foetal effects; as such, the no observed adverse effect level (NOAEL) was established as 300 mg/kg/day for dams and foetuses.