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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-12-21 - 2005-09-06
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The GLP-compliant study is scientifically valid and is acceptable for assessment.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guidelineopen allclose all
according to guideline
other: Note for guidance on reproductive toxicology: detection of toxicity to reproduction for medicinal products. Committee for proprietary medicinal products (CPMP/ICH/386/95). European Agency for Evaluation of Medicinal Products, adopted September 1993.
equivalent or similar to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
Limit test:

Test material

Constituent 1
Test material form:
solid: bulk
Details on test material:
Please refer to "Confidential details on test material".

Test animals

Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories France, L'Arbresle, France
- Age at study initiation: 10-11 weeks old
- Weight at study initiation: mean body weight of 268 g (range: 224 g to 306 g)
- Housing: individually housed in suspended wire-mesh cages (43.0 x 21.5 x 18.0 cm). A metal tray, containing autoclaved sawdust (SICSA, Alfortville, France), was placed under each cage.
- Diet: A04 C pelleted maintenance diet, (SAFE, Villemoisson, Epinay-sur-Orge, France), ad libitum
- Water: tap water, filtered with a 0.22 µm filter, ad libitum
- Acclimation period: at least 5 days before the beginning of the mating period

- Temperature: 22 ± 2°C
- Humidity: 50 ± 20%
- Air changes: approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
CMC (carboxymethyl cellulose)
0.5% (w/v) aqueous solution
Details on exposure:
The test item was administered as a suspension in the vehicle. The test item was ground to a fine powder using a mortar and pestle. It was then suspended in the vehicle in order to achieve the concentration of 20, 60 or 200 mg/mL. The suspensions were then homogenized using a magnetic stirrer. The test item dosage forms were prepared weekly, and were stored at +4°C prior to use and protected from light, according to the storage conditions of the test item.

- Concentration in vehicle: 20, 60 or 200 mg/mL
- Amount of vehicle: 5 mL/kg bw
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
On the first and the last day of treatment, duplicate samples were taken at three levels of the container (top, middle and bottom) from each control and test item dosage form (except for the control dosage form on the last day of treatment) and analyzed for concentration of the test item to evaluate the homogeneity of the suspensions. The mean results of the homogeneity analyses were taken as actual values of the concentration of the test item in the dosage forms.
Details on mating procedure:
Monitoring of estrous cycle:
- during the week of mating, determined periodically from a fresh vaginal lavage

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight for the duration of the mating period
- Proof of pregnancy: in situ, vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy (designated as day 0 post-coitum (p.c.))
- Verification of same strain and source of both sexes: yes, males were from the same strain and the same breeder

Allocation to groups:
- before day 3 p.c., the animals were allocated to the groups, according to a stratification procedure based on body weight, recorded on day 0 p.c. to ensure comparatively similar mean body weight among groups
- A larger number of animals than necessary was paired to permit the selection and/or the replacement of individuals before start of treatment
Duration of treatment / exposure:
Test item was administered on gestation days (GD) 6 through 19.
Frequency of treatment:
once a day
Duration of test:
sacrifice on day 20 p.c.
Doses / concentrations
Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
nominal conc.
No. of animals per sex per dose:
24 mated female rats (only the first 20 pregnant females were taken into consideration for fetal examinations)
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for dose-level selection: The dose-levels (100, 300 and 1000 mg/kg bw/day) were selected based on the results of a previous preliminary embryo-fetal development toxicity study conducted in pregnant rats of the same strain, which received, orally, the test item at 300, 600 or 1000 mg/kg bw/day from day 6 to day 19 of gestation (CIT/Study No. 28342 RSR).


Maternal examinations:
- at least twice a day during the treatment period
- at least once a day on the other days

- Time schedule: at least once a day

BODY WEIGHT: Yes (each female)
- Time schedule for examinations: on days 0, 3, 6, 9, 12, 15, 18 and 20 p.c.

FOOD CONSUMPTION: Yes (each female)
- Time schedule: days 0 - 3, 3 - 6, 6 - 9, 9 - 12, 12 - 15, 15 - 18 and 18 - 20 p.c.

- Sacrifice on day 20 p.c.
- Macroscopic post-mortem examination of the principal thoracic and abdominal organs
- Organs examined: ovaries and uterus
- Uterine horn(s) without visible implantation site was (were) immersed (when appropriate) in an aqueous solution of ammonium sulphide to reveal the presence of uterine scars.
- Gross evaluation of placentas was undertaken
- Preservation of tissues: macroscopic lesions from all females were sampled and kept preserved in appropriate buffer
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes (with at least one live fetus).
- Number of corpora lutea: Yes
- Number and distribution of dead and live fetuses: Yes
- Number and distribution of early and late resorptions: Yes
- Number and distribution of uterine scars: Yes
- Number and distribution of implantation sites: Yes
Fetal examinations:
- Body weight: Yes, all per litter
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, remaining live fetuses per litter
- Head examinations: Yes, remaining live fetuses per litter
- Sex of the fetuses: determined before evisceration or at the time of serial sectioning
The fetal findings were described according to the glossary of the International Federation of Teratology Societies (IFTS) and classified as malformations or variations (Wise et al., 1997; Chahoud et al., 1999).

Chahoud I, et al. (1999). Classification terms in developmental toxicology: need for harminization. Reprod Toxicol 13(1): 77-82.
Wise LD, et al. (1997). Terminology of developmental abnormalities in common laboratory mammals (version I). Teratology 55: 249-292.
Mean values were compared by one-way analysis of variance and the Dunnett test (mean values being considered as normally distributed and variances being considered as homogeneous). Percentage values were compared by the Fisher exact probability test.
- Preimplantation loss (in %) [(number of corpora lutea – number of implantations)/number of corpora lutea]
- Post-implantation loss (in %) [(number of implantations - number of live fetuses)/number of implantations]
- Fetal or litter incidence (in %) [total number of fetuses or litters with a particular finding/total number of fetuses or litters examined]
- Mean proportion of affected fetuses (in %) [sum of proportion of fetuses affected in each litter/total number of litters examined]

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: Dose-levels of up to and including the high dose level of 1000 mg/kg bw/d did not evoke any test substance related maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: There was no test substance related developmental toxicity observed in the fetuses in any treated group.

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:

Any other information on results incl. tables



- There were no premature deaths during the study.

Clinical signs

- No treatment-related clinical signs were observed in any test item-treated group.

Body weight and food consumption

- The body weight, the net body weight change from day 6 p.c., the carcass weight and the mean gravid uterus weights were unaffected by treatment with the test item. Treatment had no influence on the mean food consumption in any test item-treated group.

Necropsy findings:

- No treatment-related findings were noted in any test item-treated females.



- There was no effect of treatment on pregnancy parameters at any dose-level.

The numbers of corpora lutea and implantation sites were equivalent between test item-treated and control groups.

When compared to control values, the sex ratio was inverted at 100 and 1000 mg/kg/day. As this finding was not observed at 300 mg/kg/day, and as the mean values of percentage of male and female fetuses from all test item-treated animals were within or very close to the range of historical control data this was considered not to be treatment-related.

The mean fetal body weights recorded in the test item-treated groups were similar to those of the control group.

Fetal evaluation:

- Fetal external and visceral examinations: All fetuses appeared normal except one fetus from the high-dose group that showed mandibular micrognathia associated with microglossia; this fetus also presented marked dilated cerebral ventricles. As only this one fetus was affected, it was considered not to be related to treatment.

- Skeletal examination No treatment-related malformations or variations were noted



- The results of the analyses demonstrated the homogeneity of each dosage form investigated on the first day and the last day of treatment.

- Satisfactory correspondence was noted between the nominal and the measured concentrations of the test item for each administered dosage analyzed (between -9% and - 1% of nominal values).

Applicant's summary and conclusion