Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
May - June, 1974
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Older study conducted by the FDA.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1974
Report Date:
1974

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Teratologic evaluation of adipic acid in rabbits
GLP compliance:
no
Remarks:
: study pre-dates GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The test material was adipic acid (FDA substance FDA 71-50). A read across is proposed based on structural similarities between the substances.

Test animals

Species:
rabbit
Strain:
Dutch
Details on test animals and environmental conditions:
The animals were female Dutch-Belted rabbits.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
The test material was administered as a solution in water.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
On day 0, each doe was given an injection of 0.4 ml human chorionic gonadotropin. Three hours later, each doe was inseminated artificially with 0.3 ml diluted semen from a proven donor buck.
Duration of treatment / exposure:
13 days - gestation days 6 to 18
Frequency of treatment:
Daily - gestation days 6 to 18
Duration of test:
29 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2.5, 12.0, 54.0 and 250.0 mg/kg
Basis:
nominal conc.
No. of animals per sex per dose:
Initial group sizes ranged from 13 to 20, the numbers of successfully mated females were: negative control - 11; positive control - 13; 2.5 mg/kg - 10; 12 mg/kg - 11; 54 mg/kg 10; 250 mg/kg - 14.
Control animals:
yes, sham-exposed
Details on study design:
Beginning on day 6 (day 0 was the day of insemination) and continuing daily through day 18, the females were dosed with adipic acid at the relevant dose levels, by gavage.
On day 29 does were subject to Caesarean section under surgical anaesthesia. A positive control was included: does were dosed with 2.5 mg/kg of 6-aminonictominamide on Day 9.

Examinations

Maternal examinations:
Maternal survival and body weights were recorded (days 0, 6, 12, 18 and 29). The urogenital tract of each animal was examined in detail for normality.
Ovaries and uterine content:
On day 29, all does were subjected to Caesarean section under surgical anaesthesia and the numbers of corpora lutea, implantation sites, resorption sites and live and dead foetuses were recorded.
Fetal examinations:
Body weights of the liver pups were recorded. Foetuses were examined for external congenital abnormalities. The live foetuses from each litter were placed in an incubator for 24 hours to evaluate neonatal survival. All surviving pups were sacrificed, and all pups were examined for visceral abnormalities (by dissection). All foetuses were then cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects/
Statistics:
Formal statistical analysis was not performed.
Indices:
Total number of resorptions, total number of foetuses, total number of live litters.
Historical control data:
No information available.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
No maternal toxicity was observed. There was no effect on maternal survival.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
There was no effect on nidation or on foetal survival. The number of abnormalities seen in either soft or skeletal tissue of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. No differences between controls and treated groups were found for corpora lutea, implantations, total number of resorptions, total number of foetuses, total number of live litters and foetal weights.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

The NOAEL for both maternal and developmental toxicity was 250 mg/kg bw/d.

Applicant's summary and conclusion

Conclusions:
The NOAEL for both maternal and developmental toxicity was 250 mg/kg bw/d
Executive summary:

Rabbits were artificially inseminated on day 0, adipic acid (in water) was administered by gavage on gesatational days 6 through 18 at doses of 0, 2.5, 12, 54 and 250 mg/kg. The positive control group received a single dose of 2.5 mg/kg 6 -aminonicotinamide on day 9. On day 29 all does were subject to Caesarean section for examination of urogenital tract and foetal examination. No maternal toxicity was observed. There was no effect on maternal survival. There was no effect on nidation or on foetal survival. The number of abnormalities seen in either soft or skeletal tissue of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. No differences between controls and treated groups were found for corpora lutea, implantations, total number of resorptions, total number of foetuses, total number of live litters and foetal weights. The NOAEL for both maternal and developmental toxicity was 250 mg/kg bw/d.