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Registration Dossier
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EC number: 204-673-3 | CAS number: 124-04-9
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
OECD/ICCA HPV 2004: No specific studies on fertility have been conducted. In a two-years feeding study in rats histopathological examination of testes, ovaries, and uterus revealed no evidence of an adverse effect on the reproductive organs up to the highest doses tested (males approx. 3750 mg/kg bw/day, females approx. 750 mg/kg bw/day). Based on the available data there is no reason to expect specific reproductive toxicity of adipic acid.
Link to relevant study records
- Endpoint:
- toxicity to reproduction
- Remarks:
- other: chronic two-year study
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1957
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: No GLP (study of 1957), short description of results, few organs examined, unclear number of animals examined in histopathology, only one dose tested in females, purity not specified.
- Reason / purpose for cross-reference:
- reference to same study
- Principles of method if other than guideline:
- see repeated dose toxicity Horn et al. 1957. Rats were fed either the basal laboratory diet, or the basal diet to which adipic acid was added. Body weights, food consumption, and general appearance were recorded weekly throughout the experimental period. Whenever possible, gross autopsy was performed on those animals that died during the course of the experiment. After two years, surviving rat were weighed, killed, and examined grossly. Organs were weighed. Microscopic examination of several organs, including testis or ovaries and uterus was performed on a representative number of animals.
- GLP compliance:
- no
- Species:
- rat
- Strain:
- other: Carworth Farm strain
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- weight at study initiation: 50-60 g
housing individually in cages with wire mesh floors
free access to food and water - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on mating procedure:
- no mating
- Duration of treatment / exposure:
- Exposure period: 2 years
- Frequency of treatment:
- diet ad libitum
- Details on study schedule:
- 2 year feeding study
- Remarks:
- Doses / Concentrations for males:
0.1, 1, 3, and 5%; (approx. 75, 750, 2250, 3750 mg/kg bw/day)
Basis:
nominal in diet - Remarks:
- Doses / Concentrations in females
1%; (ca. 750 mg/kg bw/day)
Basis:
nominal in diet - No. of animals per sex per dose:
- started with 20 males per treatment groups and in the control group
started with 19 females in the treatment group and 10 females in the control group - Control animals:
- yes, plain diet
- Positive control:
- not applicable
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The following signs were observed among all male groups, including the controls, especially during te final six months: wheezing, blood-tinged crust about the noses and eyes, and body sores. These findings were not significantly different among the groups, although a lower incidence of signs indicative of respiratory infection and body sores occurred in the 5% adipic acid group.
- Description (incidence):
- The per cent survival was not negatively affected by treatment.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Growth of males treated with 0.1 and 1% and females treated with 1% test item in food was comparable to that of the respective controls. During the rapid growth period of the 2-year feeding studies, weight gains for the male rats receiving 3 or 5% adipic acid was significantly less (up to minus > 30%) than the male controls.
(for details see Table 1 in IUCLID chapter 7.5.1) - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- There was a slight but consistent reduction in food consumption by 5% adipic acid.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Microscopic examination of the following reproductive organs was performed: uterus, ovaries and testes on a representative number of animals (no further information)
When surviving animals were sacrificed at the end of the two-year period, there was no significant gross pathology that could be related to ingestion of the compound. The results of microscopic examination appeared to be within normal limits for the representative tissues.
Two of the surviving control animals and one of the experimental animals had ovarian tumors, ovarian cysts were noted in both control and experimental rats. - Dose descriptor:
- NOAEL
- Effect level:
- ca. 750 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: according to 1% in the diet
- Critical effects observed:
- no
- Reproductive effects observed:
- not specified
- Executive summary:
Studies on fertility are not available. In a two-year feeding study in rats (see IUCLID chapter 7.5.1 Repeated Dose Toxicity) histopathological examination of testes, ovaries and uterus revealed no evidence of an adverse effect on the reproductive organs up to the highest tested doses (3750 mg/kg bw/day in males, 750 mg/kg bw/day in females). The NOAEL for maternal toxicity was about 750 mg/bw/day, based on body weight effects at higher doses in males. The NOAEL for effects on reproductive organs was the highest dose tested (3750 mg/kg bw/day in males, 750 mg/kg bw/day in females).
Reference
Males (control, 0.1, 1, 3, 5% adipic acid; 20 male animals/group): When the surviving males were sacrificed there was no significant gross pathology that could be related to adipic acid. Histopathologic examination of the testes revealed no evidence of an adverse effect on the reproductive organs up to the highest dose. Soft edematous testes were noted at least as frequent in the controls as in the experimental animals. Females (10 control animals and 19 animals dosed with 1% adipic acid): When the surviving females were sacrificed there was no significant gross pathology that could be related to adipic acid. Histopathologic examination of the ovaries and uterus revealed no evidence of an adverse effect on the reproductive organs. Two of the surviving control animals and one of the experimental animals had ovarian tumors, ovarian cysts were noted in both control and experimental rats.
In summary: histopathologic examination of the testes, ovaries and uterus revealed no evidence of an adverse effect on the reproductive organs.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 750 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Hazards identified by OECD/ICCA high production volume chemicals program in 2004:
"Fertility assessment:
No specific studies on fertility have been conducted. In a two-years feeding study in rats histopathological examination of testes, ovaries, and uterus revealed no evidence of an adverse effect on the reproductive organs up to the highest doses tested (males approx. 3750 mg/kg bw/day, females approx. 750 mg/kg bw/day). Based on the available data there is no reason to expect specific reproductive toxicity of adipic acid."
As confirmed by recent literature (Mangelsdorf et al 2003, Ulbrich & Palmer 1995, Janer et al 2007a, Dent 2007, Sanbuissho et al. 2009) in rodents histopathological examinations in repeated dose toxicity studies of reproductive tissues are of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. With this respect repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.
------------------------
- Mangelsdorf. et al., 2003: Some aspects relating to the evaluation of the effects of chemicals on male fertility. Regulatory toxicology and Pharmacology 36, 69-98
- Ulbrich & Palmer, 1995: Detection of effects on male reproduction – a literature survey. J am. College of Toxicology 14, 293-327
- Janer et al., 2007: A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reproductive Toxicology 24, 103-113
- Dent, 2007: Strength and limitations of using repeated-dose toxicity studies to predict effects on fertility. Regulatory Toxicology and Pharmacology 48, 241-258
- Sanbuissho et al., 2009: Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats. J Tox. Sci. 34:Special Issue SP1-SP22
Conclusion:
Based on the considerations above no further testing is required for the
fertility assessment as adipic acid has not shown specific effects on
reproductive organs in male and female rats in the lower effect dose
range and there was no evidence of a specifc reproductive toxicity of
adipic acid in a developmental toxicity studies.
Effects on developmental toxicity
Description of key information
Hazards identified by OECD/ICCA high production volume chemicals program in 2004:
"Adipic acid was not embryo- or fetotoxic and not teratogenic after oral administration to rats, mice, and rabbits. NOAELs for rat, mouse and rabbit are 288, 263, and 250 mg/kg bw/day, respectively, the highest doses tested. In none of these studies signs of maternal toxicity have been observed and the highest dose was well below the limit dose of 1000 mg/kg bw which would be a precondition for a valid negative study. In view of the low systemic toxicity of the compound, however, this endpoint seems to be adequately covered despite the limitations of the studies."
Link to relevant study records
- 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.
- 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
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- vigin adult female albino rats
- 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.
- 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
- 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.
- 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
- 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)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 288 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: highest dose tested
- Abnormalities:
- no effects observed
- 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 - 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
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- 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.
- 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.
- 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
- Species:
- mouse
- Strain:
- CD-1
- Details on test animals or test system and environmental conditions:
- vigin adult female albino CD-1 outbred mice
- 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
- 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
- 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.
- 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
- 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
- Dose descriptor:
- NOAEL
- Effect level:
- >= 263 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: highest dose tested
- Abnormalities:
- no effects observed
- 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
- 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
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- 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.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1974
- 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, low number of animals per group, no statistical evaluation. Data on purity of adipic acid are lacking. No justification for dose selection was given
- 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 to 14 animals 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
- Species:
- rabbit
- Strain:
- Dutch
- 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:
- 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 using approximately 20 x 10 EE6 motile sperm.
- Duration of treatment / exposure:
- 13 d
- Frequency of treatment:
- 6.-18. day of gestation, daily
- Duration of test:
- On day 29 all animals were subjected to cesarean section.
- Dose / conc.:
- 2.5 mg/kg bw/day
- Dose / conc.:
- 12 mg/kg bw/day
- Dose / conc.:
- 54 mg/kg bw/day
- Dose / conc.:
- 250 mg/kg bw/day
- No. of animals per sex per dose:
- 13-20 females per group were mated; number of pregnants: 10/11/10/14 for 2.5/12/54/250 mg/kg bw/day
- Control animals:
- yes, concurrent vehicle
- other: positive control animals included (6-aminonicotinamide 2.5 mg/kg bw dosed on day 9)
- Details on study design:
- Sex: female
- 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, 12, 18, and 29 of gestation.
- Ovaries and uterine content:
- On day 29 all does 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 underwent a detailed gross examination for the presence of external congenital abrnormalities. the life fetuses of each litter were then placed in an incubator for 24 hours for the evaluation of neonatal survival. All surviving pups were sacrifi ed and all pups examined for visceral abnormalities (by dissection). All fetuses were then cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
- 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
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- data not completely available
see Table 1 - Description (incidence and severity):
- see Table 1
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- data not completely available
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):
- data not completely available
- Dose descriptor:
- NOAEL
- Effect level:
- >= 250 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: highest dose tested
- Abnormalities:
- no effects observed
- 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 (6 -aminonicotinamide 2.5 mg/kg bw dosed on day 9) many soft tissue abnormalities occured, as e.g. anopia (in 36 pups), cleft palate, short tail;
in one treatment group (2.5 mg/kg bw/day) one pup occued with incomplete closure of skull - Dose descriptor:
- NOAEL
- Effect level:
- >= 250 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Executive summary:
The administration of up to 250 mg/kg bw/day adipic acid by gavage to groups of 10 to 14 pregnant rats from gestation days (gd) 6 - 18 (13 consecutive days)
had no clearly descernible 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.
Referenceopen allclose all
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
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
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 theshamtreated 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 resultes were not evaluated statistically, but inspection of tables shows no effects in the treated groups vs. control.
Table 1: maternal data
| vehicle control animals | positive control animals* | 2.5 mg/kg bw | 12 mg/kg bw | 54 mg/kg bw | 250 mg/kg bw | |
pregnants |
11 | 13 | 10 | 11 | 10 | 14 |
| died or aborted | 0 | - | - | - | 0 | 0 |
| corpora lutea no. | 104 | - | - | - | 107 | 152 |
| corpoa lutea/dam mated | 9.45 | - | - | - | 11.9 | 10.1 |
| live litters no. | 11 | - | - | - | 8 | 12 |
| implant sites no. | 77 | - | - | - | 88 | 102 |
| implant sites average/dam | 7.0 | - | - | - | 8.8 | 7.29 |
| resorptions no. | 10 | - | - | - | 13 | 16 |
| dams with 1 or more sites resorbed | 4 | - | - | - | 3 | 6 |
| live fetuses no. | 67 | 46 | 73 | 67 | 65 | 78 |
| live fetuses average/dam | 6.09 | - | - | - | 6.50 | 5.57 |
| dead fetuses | 0 | - | - | - | 10 | 8 |
| dams with 1 or more dead | 0 | - | - | - | 1 | 1 |
* positive control 6 -aminonicotinamide 2.5 mg/kg bw dosed on day 9
- no data given for positive control, 2.5 and 12 mg/kg bw dosed animals due to incomplete duplication/copy
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. | 67 | 46 | 73 | 67 | 65 | 78 |
| average fetal body weight (g) | 42.3 | - | - | - | - | 41.4 |
| sex ratio (m/f) | 0.72 | - | - | - | 1.03 | 0.66 |
* positive control 6 -aminonicotinamide 2.5 mg/kg bw dosed on day 9
- no data given for positive control, 2.5 and 12 mg/kg bw dosed animals due to incomplete duplication/copy
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 |
67/11 | 46/8 | 73/9 | 67/9 | 65/8 | 78/12 |
| sternebrae incomplete oss. | 8/6 | 11/5 | 9/5 | 4/3 | 9/3 | 10/5 |
| sternebrae missing | 7/4 | 10/6 | 12/5 | 1/1 | 17/5 | 12/4 |
| ribs fused/split | 1/1 | 20/5 | 1/1 | 0 | 0 | 0 |
| vertebrae incomplete oss. | 0 | 5/1 | 0 | 0 | 0 | 0 |
| scoliosis | 0 | 10/6 | 1/1 | 0 | 0 | 0 |
| tail defects | 0 | 39/8 | 0 | 0 | 0 | 0 |
| skul missing | 0 | 0 | 1/1 | 0 | 0 | 0 |
* positive control
6 -aminonicotinamide 2.5 mg/kg bw dosed on day 9
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 263 mg/kg bw/day
- Species:
- other: rat, mouse, rabbit, hamster
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Hazards identified by OECD/ICCA high production volume chemicals program in 2004:
"Adipic acid was not embryo- or fetotoxic and not teratogenic after oral administration to rats, mice, and rabbits. NOAELs for rat, mouse and rabbit are 288, 263, and 250 mg/kg bw/day, respectively, the highest doses tested. In none of these studies signs of maternal toxicity have been observed and the highest dose was well below the limit dose of 1000 mg/kg bw which would be a precondition for a valid negative study. In view of the low systemic toxicity of the compound, however, this endpoint seems to be adequately covered despite the limitations of the studies."
Updated relevant information:
Critical Ingredient Review Expert Panel on the Safety Assessment of Dicarboxylic Acids, Salts and Esters, 2012:
Groups of 20 to 24 gravid albino CD-1 mice weredosed orally, by gavage, with 0, 2.6, 12, 56, or 263 mg/kg bw adipic acid on days 6 to 15 of gestation. All animals were killed on day 17 of gestation. No reproductive, developmental, or maternal effects were observed, and the NOAEL for maternal and developmental toxicity was 263 mg/kg bw. Similar results were obtained in a study in which gravid Wistar ratswere dosed orally, by gavage, with 0, 2.9, 13, 62, or 288 mg/kgbw adipic acid on days 6 to 15 of gestation. The NOAEL for maternal and developmental toxicity was 288 mg/kg bw.
Groups of 21 to 24 gravid hamsters were dosed orally, by gavage, with 0, 2.9, 5, 44, or 205 mg/kg bw adipic acid on days 6 to 10 of gestation. A significant increase in resorption per implant site was observed with 205 mg/kg bw adipic acid, resulting in a decreased number of live fetuses. (This decrease was not evaluated statistically.) No other effects were reported.
Groups of 10 to 14 gravid Dutch-belted rabbits were dosedby oral intubation with 0, 2.5, 12, 54, or 250 mg/kg bw adipic acid on days 6 to 18 of gestation. No reproductive, developmental, or maternal effects were observed. The NOAEL for maternal toxicity was ≥ 250 mg/kg bw and for developmental toxicity was 250 mg/kg bw.
Toxicity to reproduction: other studies
Additional information
A multi-generation reproduction toxicity study is not available. Based on the considerations above no further testing is required as adipic acid has not shown specific effects on reproductive organs in male and female rats and there was no evidence of a specifc reproductive toxicity of adipic acid in developmental toxicity studies on rats, mice and rabbits.
Justification for classification or non-classification
No classification is warranted for reproductive and developmental toxicity of adipic acid according to the EU Regulation no. 1272/2008 (GHS).
Additional information
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