Adipic acid

Endpoint summary

Description of key information

In a 2-year oral feeding study adipic acid was of low repeated dose toxicity, however it was not tested according to current standards. The NOAEL was 1% for male rats (approx. 750 mg/kg bw/day) and higher doses (3 and 5%) caused body weight retardation with no indication of specific target organ toxicity. The NOAEL for female rats was 1% (approx. 750 mg/kg bw/day), the highest dose tested in females.

In humans no symptoms were reported after oral administration of up to 7 g adipic acid per day for up to 10 days to 7 individuals to investigate compound excretion.

There is no repeated inhalation toxicity study with histopathological examination of the nose available. There are no studies on repeated inhalation or dermal application available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key 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, only one dose tested in females, purity not specified.

Principles of method if other than guideline:

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. The brain, thyroid, lung, heart, liver, spleen, kidneys and adrenals, stomach of approximately half of each group of males were weighed. The kidneys, spleen, liver and heart of each female were weighed. Microscopic examination of thyroid, lung, heart, liver, spleen, kidneys, adrenals, stomach, pancreas, bone marrow, large and small intestine and testis or ovaries and uterus on a representative number of animals was performed.

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 oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food): basal diet

Duration of treatment / exposure:

2 years

Frequency of treatment:

diet ad libitum

Dose / conc.:

0.1 other: % in diet (approx. 75 mg/kg bw/day)

Remarks:

Dose / concentration for males

Dose / conc.:

1 other: % in diet (approx. 750 mg/kg bw/day)

Remarks:

Dose /concentration for males/females

Dose / conc.:

3 other: % in diet (appros. 2250 mg/kg bw/day)

Remarks:

Dose / concentration for males

Dose / conc.:

5 other: % in diet (approx. 3750 mg/kg bw/day)

Remarks:

Dose / concentration for males

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

Observations and examinations performed and frequency:

Body weights, food consumption and general appearance were recorded weekly throughout the experimental period.

Sacrifice and pathology:

After 2 years, surviving rats were weighed, sacrificed, and examined grossly. The brain, thyroid, lung, heart, liver, spleen, kidneys, adrenals, stomach and testes of the animals were weighed. Microscopic examination of thyroid, lung, heart, liver, spleen, kidneys, adrenals, stomach, pancreas, bone marrow, large and small intestine, uterus, ovaries and testes on a representative number of animals (no further information) was performed.

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 the 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)

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):

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. There was an equal incidence of mottled, granular livers with peripheral thickening in both the control  and experimental animals. 
The results of microscopic examination appeared to be within normal limits for the representative tissues.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

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.

Remarks:

(1% in diet)

Sex:

male/female

Basis for effect level:

body weight and weight gain

Critical effects observed:

not specified

In the course of the study body weights were affected in males at 3% and 5% adipic acid in the diet (see Table 1). In the high dose group males a consistently lower body weight was recorded throughout the study, reaching 32% lower body weights than control males 8 weeks after start of treatment. At the end of the study the body weight of males was reduced by 9% in the 3% dose group and by 18% in the 5% dose group.

Table 1: body weight development in g (percent difference to respective control animals)

week	control males	0.1% males	1% males	3% males	5% males	control females	1% females
0	59	61	63	61	57	49	48
8	269	280	265	224 (-17%)	182 (-32%)	178	175
16	325	333	320	276 (-15%)	233 (-28%)	222	213
24	361	374	354	309 (-14%)	264 (-27%)	242	233
32	377	391	376	329 (-13%)	291 (-23%)	257	249
...
64	426	455	436	385 (-10%)	339 (-20%)	295	284
...
104	440	417	437	400 (-9%)	360 (-18%)	321	304

Table 2: food and test material consumption, survival

level	sex	food consumed (g average/rat/day)	compound consumed (mg average/rat/day)	survival
control	male	16.8	-	82.5%
	female	14.2	-	98.9
0.1% adipic acid	male	17.0	17.0	87.7
1% adipic acid	male	17.5	175	94.7
	female	15.8	158	96.3
3% adipic acid	male	16.8	505	94.5
5% adipic acid	male	15.7	814	97.2

There was no evidence of gross pathology associated with the feeding of adipic acid. There was no significant difference in survival. The results of microscopic examination were to be within normal limits.

Autopsy data for the male animals that died during the course of the two-year feeding program and for the sacrificed rats were analyzed for incidence of tumors and/or lung pathology. The incidence of lung pathology, tumors, soft testes observed in the adipic acid treated groups was as frequent as in the control group.

Female animals, dosed with 1% adipic acid and controls, exhibited signs normally associated with advancing senility in rats in the last six months. There was an equal incidence of blood-tinged crust about the eyes and noses,
unthriftiness, and body scores in both groups. A few control and experimental animals had alopecia, and one experimental
rat appeared to develop a middle ear infection during the 102nd week. One experimental and two control animals died
during the final six months. All three exhibited diarrhea, respiratory infection and loss of body weight prior to
death. Upon autopsy, one control rat and one experimental rat were found to have tumors, while the other control
animal had a granular liver and dark red apexes on both lungs. 

Comparison of the chronic feeding of acipic acid with citric acid (3% and 5% in the diet, also reported in this paper) indicates that adipic acid is comparable with citric acid.

Executive summary:

In a two-year study, groups of 20 male rats were given 0.1, 1, 3 and 5 % of adipic acid in the diet (equivalent to doses of approximately 75, 750, 2250 and 3750 mg/kg bw/day). Groups of 19 or 10 female rats received food containing 1 % adipic acid (approx. 750 mg/kg bw/day) or plain diet, respectively. Body weights, food consumption and general appearance were recorded weekly throughout the experimental period. After 2 years, surviving rats were weighed, killed, and examined grossly. The brain, thyroid, lung, heart, liver, spleen, kidneys, adrenals and stomach of the animals were weighed. Microscopic examination of thyroid, lung, heart, liver, spleen, kidneys, adrenals, stomach, pancreas, bone marrow, large and small intestine uterus, ovaries and testes on a representative number of animals (no further information) was performed.

The percent survival for each test group was not negatively affected by treatment. There were no body weight differences during the test period in female and male rats treated with 0, 0.1 and 1 % adipic acid. The body weights of the male rats receiving 3 and 5 % adipic acid were distinctly lower than the control group. In the 5% males up to minus 32% body weight were recorded. At necropsy there was no treatment related effect on organ weights observed. Results of microscopic examination of the organs revealed no compound related effect. The NOAEL was 1 % for male and female rats (approx. 750 mg/kg bw/day) (Horn et al. 1957). The study does not fully comply with the guidelines for chronic studies because microscopic examination was limited to 15 tissues of a representative number of animals of each group, females received only one dose, the MTD was reached only for males, and the purity of adipic acid is not indicated.

Endpoint conclusion

Dose descriptor:

NOAEL

750 mg/kg bw/day

Study duration:

chronic

Species:

rat

System:

other: reduced body weight gain at 2250 and 3750 mg/kg bw/day

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Hazards identified by OECD/ICCA high production volume chemicals program in 2004:

Animal data

"Oral toxicity:

In a limited three-weeks feeding study four rats were dosed with food containing 2% adipic acid (approximately 1500 mg/kg bw/day) no differences were observed compared to control animals in general behavior, liver size, peroxisome proliferation, hepatic activities of catalase and carnitine acetyltransferase, and no hypolipidemia was seen (Moody and Reddy 1978).

Groups of 8 to 10 male rats received neutralized adipic acid (0, 50, 100, 200 and 400 mg/day, approximately 0, 833, 1666, 3333, 6666 mg/kg bw/day) in a protein deficient diet for 19 weeks. After 7 weeks and (probably) at the end of the experiment, rats were killed and examined grossly. Weight gain and general behaviour were recorded and histopathology of liver, kidneys and intestine was performed. Rats fed with 400 mg/day showed lower weight after 19 weeks. No obvious symptoms were observed. Several unexplained intercurrent deaths in control and dose groups occurred, and only 5-7 animals survived 19 weeks. Only at 400 mg/day slight effects were seen on liver and irritation of intestine. The NOAEL is 3333 mg/kg bw (Lang and Bartsch 1953). The study is very limited in its reliability because only kidneys, liver and intestine have been examined histopathologically.

Groups of 13-15 male and female rats received adipic acid (neutralized with NaOH) in a standard diet (0, 400, 800 mg/day, approximately 0, 5000, 10000 mg/kg bw/day) for 33 weeks. Weight gain and general behavior were recorded. After 8, 23 and 25 weeks, rats were killed and histopathology of liver, kidneys and intestine was performed. The administration of 400 mg/day of adipic acid had no effect on weight gain and general behavior of the animals. Ten out of 14 rats fed with 800 mg/day died during the first 4 weeks. The surviving animals showed retarded weight gain, appeared unkempt and apathetic and suffered from heavy diarrhea during the first three weeks. They recovered by the fifth week, and after 33 weeks, the weights of the high-dose rats were the same as that of the 400 mg/day group. Histopathology: slight effects were seen on liver and irritation of intestine at 400 mg/day. No NOAEL was obtained in this study (Lang and Bartsch 1953). The study bis very limited in its reliability because only kidneys, liver and intestine have been examined histopathologically.

In a two-years feeding study rats were fed with food containing different amounts of adipic acid. 20 male rats per group received food containing 0, 0.1, 1, 3 and 5 % of adipic acid (0, approximately 75, 750, 2250, and 3750 mg/kg bw/day), respectively, and 10 or 19 female rats per group received food containing 0 or 1% (0 and approx. 750 mg/kg bw/day), respectively. Body weights, food consumption and general appearance were recorded weekly throughout the experimental period. After 2 years, surviving rats were weighed, killed, and examined grossly. The brain, thyroid, lung, heart, liver, spleen, kidneys, adrenals and stomach of the animals were weighed. Microscopic examination of thyroid, lung, heart, liver, spleen, kidneys, adrenals, stomach, pancreas, bone marrow, large and small intestine uterus, ovaries, and testes on a representative number of animals (no further information) was performed. The percent survival for each test group was higher than for the control group. There were no body weight differences during the test period in female and male rats treated with 0, 0.1 and 1% adipic acid. The weight gains of the male rats receiving 3 and 5% adipic acid were significantly less than the control groups. At necropsy there was no treatment related effect observed. Results of microscopic examination of the organs revealed to be within normal limits in all groups. The NOAEL was 1% for male and female rats (approx. 750 mg/kg bw/day) (Horn et al. 1957). The study does not fully comply with the guidelines for chronic studies because microscopic examination of 15 tissues was done on a representative number of animals for each group, females received only one concentration, the MTD was reached only for males, and the purity of adipic acid is not indicated."

Inhalation

"There is no study with histopathological examination of the nose, the probable target organ after inhalation, available. Systemic effects after repeated inhalation have not been investigated in fully valid studies. However, repeated dose studies with application via the food reveal a low systemic toxicity of adipic acid."

Dermal toxicity:

"No data available"

Human information

Oral toxicity:

"Adipic acid was orally administered to 7 volunteers to investigate excretion of this compound. No symptoms were reported in subacute studies with doses of up to 7 g adipic acid per day administered for up to 10 days (Weitzel 1942 and 1947)."

Inhalation toxicity:

" 7 of 12 workers exposed (for an average of 9.2 years) to various glycols and adipic acid dust particles (concentration 0.47-0.79 mg/m3 [0.08-0.13 ppm], 8 h average value) complained of mucosal irritation (eye, nose, throat). There was no local exhaust ventilation and the workers did not wear respiratory protection. They reported that clouds of adipic acid and other materials were routinely generated during charging of reaction vessels. The investigators suggested that, since the glycol level was kept below 1 ppm, adipic acid was more likely to be the cause of these complaints (Cummings and Roseman 1985). Due to the acidic character of the substance, a local irritation potential is plausible."

Updated relevant information of 2019:

EPA has released the first beta version (version 0.5) of the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The beta version of the iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical  screening data generated by the Toxicity Forecaster (ToxCast) project and the federal  Toxicity Testing in the 21st century (Tox21) collaboration. Adipic acid was tested by ToxCast and/or Tox21 assays [USEPA; ICSS Dashboard  Application; Available from, as of December 8, 2014: http://actor.epa.gov/dashboard/]. Of 16 'intended target families' with all together 523 endpoints only 3 endpoints showed activity. (for further information see IUCLID chapter 7.12)

Justification for classification or non-classification

Adipic acid is of low toxicity after repeated oral uptake; no classification is required according to the EU Regulation no. 1272/2008 (GHS).