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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 from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study performed according to GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): MRD-54-616
- Substance type: clear yellow liquid
- Analytical purity: assumed 100% for testing
- Storage condition of test material: room temperature

Test animals

Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 9-11 weeks
- Weight at study initiation: 170-290 g
- Fasting period before study: n/a
- Housing: individually except during mating
- Diet (e.g. ad libitum): certified rodent chow, ad libitum
- Water (e.g. ad libitum): as libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Administered neat

Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: until observation of copulatory plug
Duration of treatment / exposure:
Gestation day 6-15
Frequency of treatment:
Daily
Duration of test:
gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 250, 600, 800 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
22
Control animals:
yes, concurrent no treatment

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: gestation days 0, 3, 6, 9, 12, 16, and 20
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:
- Soft tissue examinations: Yes:
- Skeletal examinations: Yes:
- Head examinations: Yes:
Statistics:
Yes
Indices:
Yes
Historical control data:
Yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Morbidity and Mortality
- 4 animals died in the 800 mg/kg group

Necropsy Observations
- Increased incidences of mottled discoloration of the lung (250, 600, or 800 mg/kg). The increase was not dose-dependent.

Pregnancy Rate
- No adverse effects

Gestation Body Weight
- The 600 and 800 mg/kg dose groups displayed significantly reduced maternal body weights
- Gestation food consumption was also significantly reduced in these dose groups

Uterine Data
For the 800 mg/kg group there were significant increases in mean number of resorptions in the litter and the mean fraction of implantations in the litter which were resorbed. The resorptions were predominately “early”. At 800 mg/kg there were corresponding decreases in the mean number of live fetuses. No full term dead fetuses were found in this study. Dams with greater than 3 resorptions were observed at a significantly elevated incidence at 600 and 800 mg/kg.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Fetal Body Weight and Crown-Rump Distance
- The 800 mg/kg group showed significantly reduced body weight and crown-rump distance of male and female fetuses.

Fetal Malformations
- External malformations were unique to individual fetuses and their incidences were not statistically significant.
- There were statistically significant incidences of hydrocephalus for the 600 and 800 mg/kg groups.
- Examination of fetal skeleton revealed minor and major structural malformations of thoracic ribs in fetuses of the 600 and 800 mg/kg groups.
- Total malformation incidences were significantly increased for the 600 and 800 mg/kg groups when calculated as malformed fetuses/live fetuses.

Fetal Variations
- Variations of skin color, aortic arch, and renal/ureter were noted in the 800 mg/kg group.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There was no statistically significant evidence of developmental toxicity at dose levels of 50 or 250 mg/kg.
Executive summary:

In this study, pregnant rats, n=22 per dose, were treated by oral gavage to 50, 250, 600 or 800 mg/kg/day Neoheptanoic acid during gestation days 6-15. On gestation day 21, the dams were euthanized and the pups were examined for signs of developmental toxicity. Under the conditions of the experimental methods, the test material produced maternal toxicity at dose levels of 600 and 800 mg/kg with maternal lethality at 800 mg/kg. The test material was severely embryotoxic at 800 mg/kg with less than 20% of embryos surviving. Offspring of the 800 mg/kg group had reduced body weight, reduced crown-rump distance, displayed variations signifying delayed development, and a significant percentage (25%) were malformed. In the 600 mg/kg group, there was an increase number of dams with 3 or more resorptions. Offspring of the 600 mg/kg group displayed significant incidences of major (hydrocephalus) and minor (knobby or angular ribs, extra lumbar vertebrae) malformations but showed few signs of delayed development and were not runted. There was no statistically significant evidence of maternal toxicity at dose levels of 50 or 250 mg/kg. There was a slight, but not statistically significant, increase in embryonic resorption noted for the 250 mg/kg group. There was no statistically significant evidence of developmental toxicity at doses for 50 or 250 mg/kg. The NOAEL for maternal toxicity is 600 mg/kg and the NOAEL for developmental toxicity is 250 mg/kg.