Adipic acid, compound with hexane-1,6-diamine (1:1)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study did not include a high dose that caused maternal toxicity, low number of animals per group, no statistical evaluation. Data on purity of adipic acid are lacking, but as no effects were observed up to the highest dose tested this is thought not to impair the validity of the results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1974

Report date:

1974

Materials and methods

Principles of method if other than guideline:

On gestation day 6 through 18, pregnant rabbits were dosed daily with the test substance by oral intubation. Animals were observed daily for clinical signs, food consumption and body weight were determined. On Day 29 all does were subjected Caesarean section, the uterine contents were examined, and the foetuses were examined for fetotoxicity and teratogenicity.

GLP compliance:

no

Remarks:

pre-GLP data

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Adipic acid

EC Number:

204-673-3

EC Name:

Adipic acid

Cas Number:

124-04-9

Molecular formula:

C6H10O4

IUPAC Name:

adipic acid

Details on test material:

Component of the test substance.

- Name of test material (as cited in study report): Adipic acid
- Physical state: fine white crystalline
- Analytical purity: not stated
No further data

Test animals

Species:

rabbit

Strain:

Dutch

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Virgin adult, Dutch-belted female rabbits
- Housing: individually in mesh bottom cages
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
temperature and humidity controlled quarter

No further data.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: artificial insemination
On Day 0, each doe was given an injection of 0.4 ml of human chorionic gonadotropin (400 IU) via the marginal ear vein. Three hours later, each doe was inseminated artificially with 0.3 ml of diluted semen from a proven donor buck using approximately 20 x 10E6 motile sperm.
No further details.

Duration of treatment / exposure:

days 6 through 18 of gestation

Frequency of treatment:

daily

Duration of test:

until day 29 of gestation

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

2.5 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

12 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

54 mg/kg bw/day (actual dose received)

Doses / concentrations 4

Dose / conc.:

250 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

13 females (2.5 mg/kg bw/d);
15 females (54 mg/kg bw/d);
16 females per group (12 mg/kg bw/d, positive control);
19 females (sham-treated control);
20 females (250 mg/kg bw/d)

Control animals:

yes, sham-exposed

other: Positive control: 6-Aminonicotinamide, 2.5 mg/kg bw (actual ingested), dosed on day 9 of gestation

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS and DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
All animals were observed daily for appearance and behavior.

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6, 12, 18, and 29 of gestation.

FOOD CONSUMPTION: Yes
- Time schedule: daily
All animals were observed daily with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal.

WATER CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
All does were subjected to Caesarean section under surgical anesthesia.
- Organs examined: gravid uterus, urogenital tract

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

The live fetuses of each litter were placed in an incubator for 24 hours for the evaluation of neonatal survival.
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No
Other: The body weights of the live pups were recorded.

Statistics:

The results were not evaluated statistically.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Mortality:

no mortality observed

Description (incidence):

The administration of the test substance up to the highest dose level had no clearly discernible effect on nidation or on maternal survival.

Maternal developmental toxicity

Early or late resorptions:

no effects observed

Description (incidence and severity):

No differences between treatment and control groups were found for total number of resorptions.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (actual dose received)

Basis for effect level:

other: no adverse effects observed up to and including the highest tested dose

Results (fetuses)

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): No differences between treatment and control groups were found for fetal weight.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

No differences between treatment and control groups were found for total number of live litters.

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

The administration of the test substance up to the highest dose level had no clearly discernible effect on fetal survival.

Skeletal malformations:

no effects observed

Description (incidence and severity):

The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Visceral malformations:

no effects observed

Description (incidence and severity):

The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Details on embryotoxic / teratogenic effects:

No differences between treatment and control groups were found for corpora lutea, implantations, and total number of fetuses.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (actual dose received)

Basis for effect level:

other: no adverse effects observed up to and including the highest tested dose

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

For details, see attached documents.

Applicant's summary and conclusion

Executive summary:

The administration of the test substance, adipic acid, at doses of up to 250 mg/kg bw/d to pregnant rabbits for 13 consecutive days (gd 6 - 18) had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.