Cyclohexane, oxidized, aq. ext.

Developmental toxicity / teratogenicity

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:

1974

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

No GLP but overall good documentation. 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. No justification for dose selection was given

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1974

Materials and methods

Principles of method if other than guideline:

On day 0, each doe was given an injection of 0.4 ml of human chorionic  gonadotropin. Three hours later, each doe was inseminated artificially  with 0.3 ml of diluted semen from a proven donor buck. Beginning on day 6  and continuing daily through day 18 the females (10-14 animal per dose)  were dosed with the indicated dosages by oral intubation. Body weights  were recorded on days 0, 6, 12, 18 and 29 of gestation, with particular attention to food consumption and body weight.  On day 14 all animals were subjected to cesarean section, and the number of corpora lutea, implantation sites, resorption sites and live and dead fetuses were recorded. The urogenetal tract of each animal was examined in detail for normality. All fetuses underwent a detailed gross examination for the presence of external congenital abnormalities. The live fetuses of each litter were then placed in an incubator for 24 hours for the evaluation of neonatal survival. All surviving pups were sacrificed, and all pups examined for visceral abnormalities and examined  for skeletal defects. 6-Aminonicotinamide (2.5 mg/kg), dosed on day 9,  was used as a positive control.

GLP compliance:

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:

Hexanedioic Acid

Details on test material:

IUCLID4 Test substance: other TS: purity not specified

Test animals

Species:

rabbit

Strain:

other: Dutch-belted

Administration / exposure

Route of administration:

oral: gavage

Details on mating procedure:

On day 0, each doe was given an injection of 0.4 ml of human chorionic  gonadotropin. Three hours later, each doe was inseminated artificially  with 0.3 ml of diluted semen from a proven donor buck.

Duration of treatment / exposure:

13 d

Frequency of treatment:

6.-18. gestation day, daily

Duration of test:

all animals were subjected to cesarean section on GD 29

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 2.5, 12, 54, 250 mg/kg bw/day
Basis:

No. of animals per sex per dose:

10-14 females per dose

Control animals:

yes

Details on study design:

Sex: female

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

>= 250 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

>= 250 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: no adverse effects were found at the highest dose level of 250 mg/kg bw/day.

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

The administration of up to 250 mg/kg bw/day of the compound to pregnant rabbits for 13 consecutive days had no effect on nidation or on maternal or fetal 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 difference between treatment and control groups were found for corpora lutea, implantations, total no. of resorptions, total no. of fetuses, total no. of live litters and fetal weights. No maternal toxicity observed. The results were not evaluated statistically, but inspection of tables shows no effects in the treated groups vs. control.

 

Applicant's summary and conclusion

Executive summary:

No adverse effects were seen in similar experiments after administration of adipic acid to groups of 10 to 14 pregnant rabbits (gd 6-18, up to 250 mg/kg bw/day; Food and Drug Res Labs, Inc. 1974). This study is limited to some extent by the fact that no signs of maternal toxicity have been observed at the highest doses tested, a dose below the limit dose of 1000 mg/kg bw.