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Developmental toxicity / teratogenicity

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developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD guideline study predating GLP. QAU statement included

Data source

Reference Type:
study report
Report Date:

Materials and methods

Test guideline
according to
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
but QAU statement included
Limit test:

Test material

Details on test material:
- Physical state: powder
- Storage condition of test material: room temperature

Test animals

Details on test animals and environmental conditions:
- Source: CIBA-Geigy, WST
- Age at study initiation: 2 months
- Weight at study initiation: 180 - 200 g
- Housing: 4 per cage in Makrolon cages
- Diet: NAFAG No. 890, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 6 days

- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 10
- Photoperiod (hrs dark / hrs light): 12 hours/12 hours

Administration / exposure

Route of administration:
oral: gavage
other: 0.5 % aqueous solution of CMC (sodium carboxymethylcellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The suspension of the test material was freshly prepared daily by homogenization and stirring (magnetic stirrer), and administered at a rate of 10 ml/kg of body weight.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1 male / 3 females
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 until day 15 of pregnancy
Frequency of treatment:
once daily
Duration of test:
15 days
Doses / concentrations
Doses / Concentrations:
0, 200, 600, 1200 mg/kg bw
actual ingested
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: On the basis of the preliminary experiment where 12 fertilized rats each were administered orally by intubation with the vehicle and 1000 mg/kg bw of the test substance per day in a 0.5% aqueous solution of sodium carboxymethylcellulose (CMC) from day 6 until day 15 of pregnancy. Treatment at these dose levels caused some depression in both bodyweight gain and food consumption of the mother animals. No adverse effects were recorded for the progeny at sacrifice shortly before term in comparison with the vehicle control. On the basis of the foregoing results the doses for the main study were selected at 0, 200, 600 and 1200 mg/kg of body weight.


Maternal examinations:
- Time schedule: daily

- Time schedule for examinations: daily during the period of treatment

- Time schedule: on days 6, 11, 16 and 21 of pregnancy

- Sacrifice on gestation day 21
- Organs examined: especially ovaries and uterus (mucosa and contents, including amniotic fluid), and placentae as well as abortions and resorption sites
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
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: in one third per litter
- Skeletal examinations: Yes: in two third per litter
Chi square-test

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
The dams of the high-dose (1200 mg/kg d) and intermediate dose (600 mg/kg d) groups reacted to the treatment in a dose-related fashion by a reduced body-weight gain and food consumption in comparison with the vehicle control. Female No. 49 of the intermediate dose group showed some vaginal bleeding on day 15 p.c.). In the high-dose- group diarrhea was noted for female No. 83 on day 8 p.c. Female No. 85 was found moribund and killed for humane reasons on day 14 p.c.; severe inflammation of caecum (distended by a large amount of purulent material) was observed at autopsy. Females Nos. 84 and 94 died spontaneously on days 15 and 13, respectively; abscess of the large intestine was also found in these animals.

The pregnancy rates expressed as average number of implantation sites per female were comparable for all groups in the present experiment. The numbers of embryonic and/or fetal deaths (resorptions) were not increased at either dose. The male to female ratios of the fetuses were also comparable for all groups.

Effect levels (maternal animals)

Dose descriptor:
Effect level:
1 200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
In comparison with the vehicle control, the average body-weight of the live fetuses was not diminished at the intermediate and high-dose groups; a slight but significant increase was noted for the live fetuses of the low-dose group. This finding, however, is not assumed to be of a biological relevance. The gross inspection of the live fetuses revealed one fetus each with brachymelia of hind-limb (unilateral) and omphalocele, respectively, in the intermediate dose group. Omphalocele also occurred in one fetus of the high-dose group. One instance of brachycaudia was recorded for the vehicle control. Carrying out the slicing technique for "visceral" examination, agenesis of testis (unilateral) was found in one fetus of the vehicle control. The skeletal assessment revealed instances of irregular sternebral ossification in the dose groups and in the vehicle control; abnormal "wide suture" associated with incomplete ossification of the basioccipital bone was found in one fetus of the high-dose group, in addition. Concerning the status of skeletal maturation of the fetuses shortly before term, some delay, as indicated by a slightly enhanced number of still incompletely ossified calcanei and 5th sternebra, was recorded for the high-dose group in comparison with the vehicle control.

Effect levels (fetuses)

Dose descriptor:
Effect level:
>= 1 200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: highest dose tested

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion