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Developmental toxicity / teratogenicity

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developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
testing lab.
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
other: liquid
Details on test material:
Name of the test substance used in the study report: N,N'Dimethylpropylene Urea
Purity: 99.7%

Test animals

Details on test animals or test system and environmental conditions:
Acclimatization: 10 days minimum prior to pairing with evaluation of health
Age at pairing: 11 weeks minimum
Body weights: 183 - 243 g
Identification: individual animal number tattooed on the pinnae
The animals were housed under standard laboratory conditions: air-conditioning with 10-15 air changes per hour; the environment monitored continuously with hourly recordings of temperature (22 ± 3°C) and relative humidity (40-70%), 12 hours artificial fluorescent light / 12 hours dark with background music played at a centrally defined bw volume for at least 8 hours during the light period.
The animals were housed individually in Makrolon cages with wire mesh tops and standardized granulated softwood bedding.
Pelleted standard Kliba 3433 rat/mouse maintenance diet and tap water in bottles were available ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
The mixtures of the test article and vehicle were prepared daily before administration.
The test substance was weighed into a glass beaker on a tared precision balance and die vehicle added (w/v). The mixtures were prepared using a magnetic stirrer. During die daily administration period, homogeneity was maintained using a magnetic stirrer.
Details on mating procedure:
After acclimatization, the females were housed with the males (one male one female) in special automatic mating cages, i.e. with synchronized timing to initiate the nightly mating period, until evidence of copulation was observed. This system reduced the variation in the copulation times of the different females. The females were removed and housed individually if: a) the daily vaginal smear was sperm-positive or b) a copulation plug was observed. This day was designated day 0 post coitum. The male rats used for mating were in the possession of RCC. The fertility of these males was proved and was continuously controlled.
Duration of treatment / exposure:
day 6 - day 20 post coitum
Frequency of treatment:
once daily
Duration of test:
until day 21 post coitum
Doses / concentrations
Doses / Concentrations:
0, 5, 15, and 60 mg/kg bw

No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Details on study design:
The rat is a suitable rodent species for development toxicity studies. The oral route is one possible route of test article exposure. Dose levels were selected, in conjunction with the Sponsor, based on the results of a previous dose range-finding study performed with the test substance.


Maternal examinations:
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
The following statistical methods were used to analyze body weights, food consumption, reproduction and skeletal examination data:
- Means and standard deviation of various data were calculated and included in the report.
- The Dunnett many-one t-test, based on a pooled variance estimate, was used for intergroup comparisons (i.e. single treatment groups against the Control group).
- The Steel test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
- Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
All females survived until scheduled necropsy. No test article-related clinical signs were observed during the course of the study.
Mean food consumption was slightly reduced in the females of the 60 mg/kg body weight group (between 6.5 and 9.4%) when compared with the control group. This reduction is considered to be due to the test article administration.
The body weight, the body weight gain, and the body weight gain corrected for the uterus weight were slightly reduced in the females of the 60 mg/kg body weight group. When compared with the control group mean body weight on day 21 p.c. was 4.3% lower, and body weight gain between days 6 to 21 p.c. was 12.2% lower (86 g gain versus 98 g for control).
The mean gravid uterus weights of the females treated with 60 mg/kg body weight of the test article was slightly reduced. This reduction was considered to be the consequence of the marginally reduced fetal body and placental weights in this group.
No macroscopical changes were observed in any female during necropsy.
There were no differences noted between control and test article treated groups which indicated an embryotoxic effect.

Effect levels (maternal animals)

Dose descriptor:
Effect level:
15 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
The sex ratios of fetuses in the vehicle control group and in the dose groups were within the normal range of variation for fetuses of this rat strain.
Mean placental weights, calculated on a litter basis, were slightly lower than for the control in the 15 and 60 mg/kg groups (4.7 and 7.0%, respectively), but statistical significance occurred only at 60 mg/kg. lt is possible that this difference in the 60 mg/kg group was associated with the slight reduction in fetal body weight seen at this dosage.
Mean female fetal body weight, assessed on a litter basis, was slightly reduced (4.3%) in the 60 mg/kg group compared with the control group, and the difference was statistically significant. Mean fetal body weight values (litter basis) for males (4.1%) and overall (4.2%), were also slightly lower than for the control group. There were no statistically significant effect on fetal body weights in the 5 and 15 mg/kg groups.
There were no fetuses with changes considered to warrant classification as a malformation.
No visceral variations were observed for fetuses in any group.
Less common skeletal variations occurred in the fetal skeletons of single fetuses in the 5 and 15 mg/kg groups. One fetus of the 5 mg/kg group and one fetus of the 15 mg/kg had bilateral wavy ribs. No association with the test-article was considered to be indicated. Analysis of other skeletal variations on an individual basis showed isolated statistically significant differences in all groups receiving the test article, caused by lower or higher stages
of development. These findings in the 5, 15 or 60 mg/kg groups were considered incidental as a dose dependency was not evident for the statistical significances when calculation was performed on a litter basis. The examination of the cartilage did not reveal differences between control or test article treated groups.

Effect levels (fetuses)

Dose descriptor:
Effect level:
> 60 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Under die conditions of this study, the oral administration (by gavage) of the test substance to mated female Wistar rats caused only slight adverse effects on the maternal food cansumption and body weight as well as an the placental weights and the fetal body weights at the highest dose level (60 mg/kg). There were no test substance-related influences on other gestational parameters or any signs af teratagenicity up to and including the highest dose level (60 mg/kg).