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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
06 SEP 1994 to 24 NOV 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to the OECD and it is GLP
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. certificate)
Remarks:
according to Anhang 2 deutsches Chemikaliengesetz (1990)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH
- Age at study initiation: 69-72 days
- Weight at study initiation: males: 313-340g and female: 216-242g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil, DAB 10
Details on exposure:
Administration volume: 2 mL/kg b.w. /day

PREPARATION OF DOSING SOLUTIONS:
- Rate of preparation of dosing solution (frequency): daily immediately before gavage treatment

VEHICLE
- Justification for use and choice of vehicle (if other than water): none given
- Amount of vehicle (if gavage): 2 ml/kg bw/day
- Lot/batch no. (if required): 12815; H. Lamotte, Bremen, Germany
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
concentration and stability: immediately after the mixture as well as 8 and 24 h after storage
homogeneity: at the strat of administration, during administration as well as before administration to the last animal of each dose group.
concentration: during treatment with the test item always before administration to the last animal/dose-level group.
Details on mating procedure:
Mating was monogamous: 1 male and 1 female animal were placed together in one cage during the dark period.
Each morning the female were examined for the presence of sperm. If findings were negative, mating was repeated.
Duration of treatment / exposure:
Males: 14 days prior to mating and during the 14-day mating period
Female: 14 days prior to mating and during the mating period, pregnancy and lactation period.
Frequency of treatment:
administered orally at a constant volume of 2 mL/kg b.w/day on 7 days per week during the following periods:
males: two weeks prior to mating period and approx. 2 weeks post mating at least until the minimum total dosing period of 28 days had been completed.
females: throughout the study beginning two weeks prior to mating and continuing up to, and including, day 3 post partum or the day before sacrifice.
Duration of test:
1 adaptation week and approx. 54 test days [14 days premating, (up to) 14 days mating, 22 days gestation. 4 days lactation]
No. of animals per sex per dose:
control, low dose, low intermediate dose, high intermediate dose and high dose [ 10 males / 10 females] for all doses.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: 14 day pilot study with 30, 100, 300 and 900 mg/kg bw/day reveled that 30 an 100 mg/kg bw/day were tolerated well, 900 mg/kg bw was lethal.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: first day of dosing , weekly thereadter and at termination

FOOD CONSUMPTION:
- Food consumption for each animal determined : Yes weekly

WATER CONSUMPTIO: No data
Ovaries and uterine content:
number of corpora lutea and implants determined.
Fetal examinations:
SACRIFICE
- The F1 offspring were sacrificed at day 4 of age.
- These animals were subjected to postmortem macroscopic examinations
Statistics:
For all numerical values homogeneity of variance was tested using the bartlett chi-square test. When the varinances were homogenous, the Dunnett test (P<=0.01) was used t ocompare the experimental groups with the control group. In case heterogeneity of variances, Student´s t-test (p<=0.01) was carried out.. For the comparison of classificaton measurements, the chi2-test with Yates correction for continuity (n>=100) or FISHER´s exact test (n<100); p<=0.05 were used.
Reproductive indices

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
for details on maternat toxicity see 7.8.1

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects. Remark: reduced number of pups alive ia s secondary effect to maternal toxicity

Details on embryotoxic / teratogenic effects:
No effects were seen at 50 mg/kg bw/day.

VIABILITY (OFFSPRING):
At 150 mg/kg bw/day the number of pups alive on day of delivery was significantly reduced, the rate of stillbirth increased.

BODY WEIGHT (OFFSPRING)
At 150 mg/kg bw/day the birth weight of the male pups was significantly reduced, the weight of the female pups was within the normal range.

OTHER FINDINGS (OFFSPRING)
At 150 mg/kg bw/day the mean post-implantation loss was significantly increased.

After treatment with 300 mg/kg bw/day only one female pup was alive.

No teratogenic effects were observed.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
yes
Lowest effective dose / conc.:
150 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
no

Applicant's summary and conclusion

Conclusions:
In this reproduction / devolopment toxicity screening test with rats the no-observed-effect level (NOEL) for both parent animals and their pups was 50 mg test item/ kg b.w./day, by gavage. 150 mg/kg b.w./day were in the beginning lethal range for pregnant rats and in the toxic range for embryos/fetuses/pups.
Only one dam of the group treated with 300 mg/kg b.w./day delivered one female pup alive.
At 150 mg/kg b.w./day the number of pups alive war reduced. It can be concluded that effects in pubs were a consequence of maternal toxicity and not directly related to the applied substance.
Executive summary:

In a reproduction/ development toxicity screening test according to OECD guideline 421 the test subatance was administered orally via gavage to male and female Sprague -Dawley rats. 14 days prior to mating and for the female rats until day four after delivery animals were treated with 0, 50, 150 , 300 or 450 mg/kg bw/day. Under the test conditions the no-observed-effect level (NOEL) for both parent animals and their pups was 50 mg test item/ kg b.w./day, by gavage. 150 mg/kg b.w./day were in the beginning lethal range for pregnant rats and in the toxic range for embryos/fetuses/pups. It can be concluded that effects in pubs were a consequence of maternal toxicity and not directly related to the applied substance. Only one dam of the group treated with 300 mg/kg b.w./day delivered one female pup alive. Reproduction was not affected except at already lethal concentrations.