Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

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:
The administration of up to 263 mg/kg bw/day of the compound to pregnant mice 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.
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:
hexanedioic acid
Details on test material:
Test substance purity not specified

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
vigin adult female albino CD-1 outbred mice

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
mice were gang-housed in disposable plastic cages in temperature and humidity-controlled quarters with free acess to food and fresh tap water. The controls were treated with the vehicle equivalent to the animals in the test dose groups.
Details on mating procedure:
Virgin adult females (20 animals per group) were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation.
Duration of treatment / exposure:
10 d
Frequency of treatment:
6.-15. day of gestation, daily
Duration of test:
On day 17 all animals were subjected to cesarean section
Doses / concentrationsopen allclose all
Dose / conc.:
2.6 mg/kg bw/day
Dose / conc.:
12 mg/kg bw/day
Dose / conc.:
56 mg/kg bw/day
Dose / conc.:
263 mg/kg bw/day
No. of animals per sex per dose:
25-31 females per group were mated; number of pregnants: 21/23/24/20 for 2.6/12/56/263 mg/kg bw/day
Control animals:
yes, concurrent vehicle
other: positive control animals included (Aspirin 150 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 17 of gestation.
Ovaries and uterine content:
On day 17 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):
see Table 1
Description (incidence and severity):
see Table 1
Description (incidence and severity):
see Table 1
Description (incidence and severity):
see Table 1
Description (incidence and severity):
see Table 1
Changes in pregnancy duration:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 263 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
Visceral malformations:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 263 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 263 mg/kg bw/day of the compound to pregnant mice 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*  2.6 mg/kg bw  12 mg/kg bw  56 mg/kg bw  263 mg/kg bw

 pregnants

  21  21  21  23  24  20
 died or aborted  0  0  0  0  0  0
 corpora lutea no.  307  331  315  293  332  364
 corpoa lutea/dam mated  12.3  11.4  12.6  12.7  13.3  11.7
 live litters no.  21  19  20  22  24  20
 implant sites no.  242  210  250  252  289  235
 implant sites average/dam  11.4  10.4  11.3  10.6  11.1  11.5
 resorptions no.  9  32  27  22  12  16
 dams with 1 or more sites resorbed  8  10  11  8  10  6
 live fetuses no. 229  178  221  229  275  214
live fetuses average/dam  10.9  8.48  10.5  9.96  11.5  10.7
 dead fetuses  4  0  2  1  2  5
 dams with 1 or more dead  4  0  2  1  2  5
 % partial dead  19.1  0  9.52  4.35  8.33  25.0

* positive control Aspirin 150 mg/kg bw/day

Table 2: fetal data

   vehicle control animals  positive control animals*  2.6 mg/kg bw  12 mg/kg bw  56 mg/kg bw  263 mg/kg bw
live fetuses no.  229  178  221  229  275  214
 average fetal body weight (g)  0.87  0.84  0.90  0.90  8.33  25.0
 sex ratio (m/f)  1.04  0.91  0.55  0.68  1.23  0.98

* positive control Aspirin 150 mg/kg bw/day

Table 3: fetal skeletal findings

   vehicle control animals  positive control animals*  2.6 mg/kg bw  12 mg/kg bw  56 mg/kg bw  263 mg/kg bw

 live fetuses examined

(at term)/no. of litters

  158/21  126/19  152/20  161/22  192/24  149/20
 sternebrae incomplete oss.  95/20  47/13  71/19  91/20  129/23  116/19
 sternebrae missing  20/7  24/9 18/9  23/9  18/8  36/10
 ribs wavy  0  1/1  0  0  0  0
 ribs more than 13  18/9  18/10  43/14  17/10  24/12  17/7
 vertebrae incomplete oss.  8/3  16/8  3/2  0  2/2  14/5
 skull incomplete closure  2/1  0  0  0  0  0
 extremities incomplete oss.  8/3  17/8  3/3  9/5  1/1  13/5
 hyoid, missing  57/16  36/14  41/15  50/14  45/16  44/14
 hyoid, reduced  23/13  18/9  21/12  35/16  41/16  31/15
 pelvic bones, incomplete  0  0  0  2/1  0  1/1

* positive control Aspirin 150 mg/kg bw/day

Applicant's summary and conclusion

Executive summary:

The administration of up to 263 mg/kg bw/day adipic acid by gavage to groups of 20 to 24 pregnant mice 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.