Adipic acid

Carcinogenicity

Description of key information

Adipic acid was not carcinogenic in a limited two-years feeding study where male rats were fed with up to 5% (3750 mg/kg bw/day) and female rats with 1% (750 mg/kg bw/day) adipic acid.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: 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, short description of the results, low number of animals, few organs examined, unclear number of animals examined histopathologically, only one dose for 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. 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 exposure:

test item mixed with basal diet

Duration of treatment / exposure:

2 years

Frequency of treatment:

diet ad libitum

Post exposure period:

no

Remarks:

Doses / Concentrations:
male rats: 0, 0.1, 1, 3, and 5%; (ca. 75, 750, 2250, 3750 mg/kg bw/day)
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
female rats: 0, 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

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.

Mortality:

mortality observed, non-treatment-related

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 for other groups, 0.1, 1% male and 1% female, 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):

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:

> 3 750 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no caricnogenic effect up to the highest dose tested

Dose descriptor:

NOAEL

Effect level:

> 750 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no carcinogenic effect up to the highest dose tested

During the rapid growth of the 2-year feeding studies,
weight gains for the male rats receiving 3 or 5% adipic acid was  

significantly less than the controls. Growth for other groups, 0, 0.1, 1%  

male and 0, 1% female, was comparable to that of the respective controls.  

At the end of the study the body weight of males was reduced by 10% and  

more in the two highest exposure groups. There was slight, but  

consistent, reduction in food consumption at 5%. There was no evidence of  

gross pathology associated with the feeding of adipic acid (see chapter  

Repeated Dose Toxicity).

Results males (control, 0.1, 1, 3, 5% adipic acid; 20 male
animals/group):
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. 

Only tumors presenting gross evidence of being a new growth  were scored.

Male group: 0/0.1/1/3/5%
Deaths:
total deaths                  12/7/5/4/5
lung pathology              7/3/1/3/-
tumors                         3/2/2/-/4
other causes                   3/3/2/1/1

Sacrificed:
lung pathology                   4/7/7/3/4
tumors                           1/2/2/-/-

Results females (10 control animals and 19 animals dosed
with 1% adipic acid):
The results of microscopic examination appeared to be within normal  

limits. One experimental and two control animals died during the final  

six months. Upon autopsy, one control rat and one experimental rat were  

found to have tumors.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: the incidence of tumors observed in the adipic
acid treated groups was as frequent as in the control
groups.

Executive summary:

Adipic acid was not carcinogenic in a two-years feeding study where groups of twenty male rats were dosed with food containing 0, 0.1, 1, 3 and 5 % adipic acid (approx. 0, 75, 750, 2250, 3750 mg/kg bw/day), and female rats were dosed with 0 (n = 10) and 1 % (n = 19) adipic acid (approx. 0, 750 mg/kg bw/day), respectively. Animals that died during the study and survivors were analyzed for incidences of tumor growth and lung pathology. The incidences of tumors observed in the adipic acid treated groups were as frequent as in the control groups (Horn et al. 1957). The study does not comply with the current guidelines for carcinogenicity studies because the number of animals used was low, microscopic examination of only 15 tissues was done only on a representative number of animals for each group, only one concentration was tested for females, the MTD for females was not reached, and the purity of adipic acid is not indicated.

Endpoint conclusion

Dose descriptor:

NOAEL

750 mg/kg bw/day

Justification for classification or non-classification

Adipic acid is not carcinogenic; no classification is required according to the EU classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).

Additional information

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

"Adipic acid was not carcinogenic in the previously described two-years feeding study (see chapter 3.1.5: Repeated Dose Toxicity) where groups of twenty male rats were dosed with food containing 0, 0.1, 1, 3 and 5 % adipic acid (approx. 0, 75, 750, 2250, 3750 mg/kg bw/day), and female rats were dosed with 0 (n=10) and 1% (n=19) adipic acid (approx. 0, 750, mg/kg bw/day), respectively. Animals that died during the study and survivors were analyzed for incidences of tumor growth and lung pathology. The incidences of tumors observed in the adipic acid treated groups were as frequent as in the control groups (Horn et al. 1957). The study does not fully comply with the guidelines for carcinogenicity studies because the number of animals used was low, microscopic examination of only 15 tissues was done only on a representative number of animals for each group, only one concentration was tested for females, the MTD for females was not reached, and the purity of adipic acid is not indicated."

Updated relevant information:

None