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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1972
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No GLP but overall good documentation. Study did not include a high dose that caused maternal toxicity, 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:
1972

Materials and methods

Principles of method if other than guideline:
Virgin adult females (25 animals per group) were mated with young adult males, and observation of a vaginal sperm plug was considered day zero of gestation. Pregnanat females  (20 - 24 animals  per group) were dosed by gavage from gestation days 6-15. Body weights were recorded, and all  animals were observed daily for appearance and behavior with particular  attention to food consumption and weight. On day 20 all animals were  subjected to cesarean section, and the number of implantation sites,  resorption sites, and live and dead fetuses were recorded. The urogenital  tract of each female was examined in detail for gross anatomical  normality. The body weights of the liver pups were recorded, and all  fetuses were examined grossly for the presence of external congenital  abnormalities. One-third of the fetuses of each litter underwent detailed  visceral examinations. The remaining 2/3 were examined for skeletal  defects. Aspirin, 250 mg/kg bw, was used as a positive control.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
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:
Test substance purity not specified

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
vigin adult female albino rats

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
individually housing in mesh bottom cages in temperature and humidity controlled quarters with free access to food and fresh tap water. Application volume 1-6.4 mL/kg bw, depending on dose. The controls were treated with the vehicle equivalent to the animals in the highest test dose.
Details on mating procedure:
Virgin adult females (25 animals per group) were mated with young adult males, and observation of a vaginal sperm plug was considered day zero of gestation. 
Duration of treatment / exposure:
10 d
Frequency of treatment:
6.-15. day of gestation, daily
Duration of test:
On day 20 all animals were subjected to cesarean section.
Doses / concentrationsopen allclose all
Dose / conc.:
2.9 mg/kg bw/day
Dose / conc.:
13 mg/kg bw/day
Dose / conc.:
62 mg/kg bw/day
Dose / conc.:
288 mg/kg bw/day
No. of animals per sex per dose:
25 females per group were mated; number of pregnants: 23/24/22/20 for 2.9/13/62/288 mg/kg bw/day
Control animals:
yes, concurrent vehicle
other: positive control animals included (Aspirin 250 mg/kg bw/day)
Details on study design:
Sex: female

Examinations

Maternal examinations:
daily observation for appearance and behaviour, with particular attention to food consumption and weight, in order to rule out any abnormalities with may have occurred as a result of anorexic effects in the pregnant female animal. Body weights were recorded on days 0, 6, 11, 15, and 20 of gestation.
Ovaries and uterine content:
On day 20 all dams were subjected to Caesarean section under surgical anesthesia, and the numbers of implantation sites, resorption sites, and live and dead fetuses were recorded. The urogenital tract of each dam was examined in detail for anatomical normality.
Fetal examinations:
body weights of life and dead fetuses were recorded; body weights of live pups were recorded; all fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetuses of each litter underwent detailed visceral examinations. The remaining two/thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
no effect on nidation

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
only one animal aborted in the positive control group (Aspirin, 250 mg/kg bw)
see Table 1
Description (incidence and severity):
see Table 1
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
only 4 dams with all sites resorbed in the positive control group (Aspirin, 250 mg/kg bw)
see Table 1
Description (incidence and severity):
see Table 1
Description (incidence and severity):
see Table 1
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
only one animal aborted in the positive control group (Aspirin, 250 mg/kg bw)

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 288 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: highest dose tested

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
see Table 2
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
see Table 2
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Description (incidence and severity):
see Table 3
Description (incidence and severity):
soft tissue abnormalities:
in the positive control (Aspirin 250 mg/kg bw/day) encephalomyelocele occured in 9 pups, twice in combination with umbilical hernia; 3 pups showed meningoencephalocele;
in one treatment group (13 mg/kg bw/day) one pup occued with meningoencephalocele

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 288 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose tested

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

The administration of up to 288 mg/kg bw/day of the compound to pregnant rats for 10 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 maternal toxicity observed. The results were not evaluated statistically, but inspection of the tables shows no effects in the treated groups vs. control.

Table 1: maternal data

   vehicle control animals  positive control animals*  2.9 mg/kg bw  13.0 mg/kg bw  62 mg/kg bw  288 mg/kg bw

 pregnants

  20  24  23  24  22  20
 died or aborted  0  1  0  0  0  0
 corpora lutea no.  292  264  314  303  279  263
 corpoa lutea/dam mated  11.7  10.2  12.6  12.1  11.2  11.4
 live litters no.  20  17  23  24  22  20
 implant sites no.  227  238  260  254  245  230
 implant sites average/dam  11.4  10.4  11.3  10.6  11.1  11.5
 resorptions no.  2  81  6  3  0  7
 dams with 1 or more sites resorbed  0  4  0  0  0  0
 live fetuses no. 224  150  254  248  245  223
live fetuses average/dam  11.2  6.52  11.0  10.3  11.1  11.2
 dead fetuses  1  7  0  3  0  0
 dams with 1 or more dead  1  4  0  3  0  0

* positive control Aspirin 250 mg/kg bw/day

Table 2: fetal data

   vehicle control animals  positive control animals*  2.9 mg/kg bw  13.0 mg/kg bw  62 mg/kg bw  288 mg/kg bw
live fetuses no.  224  150  254  248  245  223
 average fetal body weight (g)  3.88  2.46  3.89  3.83  4.01  3.99
 sex ratio (m/f)  0.85  0.88  1.00  0.89  1.02  0.99

* positive control Aspirin 250 mg/kg bw/day

Table 3: fetal skeletal findings

   vehicle control animals  positive control animals*  2.9 mg/kg bw  13.0 mg/kg bw  62 mg/kg bw  288 mg/kg bw

 live fetuses examined

(at term)/no. of litters

  159/20  100/16 (a)  176/23  175/24  171/22  157/20
 sternebrae incomplete oss.  66/19  80/16  46/18  60/13  61/17  44/15
 sternebrae missing  17/8  85/16 20/9  4/3  7/2  9/5
 ribs fused/split  0  10/5  0  0  0  0
 ribs wavy  16/7  45/14  12/5  26/11  12/7  29/10
 ribs more than 13  1/1  81/13  6/3  1/1  5/3  0
 vertebrae incomplete oss.  20/10  92/16  19/8  25/9  12/7  19/8
 skull incomplete closure  21/11  43/15  25/12  35/10  23/11  26/11
 skull missing  0  9/3  0  0  0  0
 extremities incomplete oss.  0  4/3  0  0  0  0
 hyoid, missing  19/8  52/15  14/9  26/12  23/10  19/11
 hyoid, reduced  3/3  7/5  18/8  24/10  18/12  24/11

* positive control Aspirin 250 mg/kg bw/day

(a) one litter lost in processing

Applicant's summary and conclusion

Executive summary:

The administration of up to 288 mg/kg bw/day adipic acid by gavage to groups of 20 to 24 pregnant rats from gestation days (gd) 6 - 15 (10 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. Thus, neither embryo- or fetotoxicity nor teratogenicity was observed. This study is limited to some extent by the fact that no signs of maternal toxicity have been observed and the highest doses tested, a dose below the limit dose of 1000 mg/kg bw.