Cyclohexane, oxidized, aq. ext.

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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, only one dose for females, purity not specified.

Data source

Reference

Reference Type:

publication

Title:

Safety of adipic acid as compared with citric and tartaric acid.

Author:

Horn HJ, Holland EG, Hazleton LW

Year:

1957

Bibliographic source:

Agricult. Food Chem. 5, 759-762.

Materials and methods

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

Test material

Test material information

Constituent 1

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:

rat

Strain:

other: Carworth Farm strain

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: diet

Duration of treatment / exposure:

2 years

Frequency of treatment:

diet ad libitum

Doses / concentrations

Remarks:

Doses / Concentrations:
0.1, 1, 3 and 5 % (approx. 75, 750, 2250, 3750 mg/kg bw)
Basis:
nominal in diet

No. of animals per sex per dose:

19-20 males or females per group

Control animals:

other: basal laboratory diet

Results and discussion

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male/female

Basis for effect level:

other: no significant adverse effects were detected at the highest dose level for males and females combined

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

The highest dose level for females was taken as an indication of the minimum NOAEL

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Males: The percent survival for each test group was higher than for the control group. 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 male controls. Growth for other groups, 0.1, 1% male and 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%.

 

Compound % in Diet	Sex m/f	Number of Rats Start/Finish	Avg. Body Weight initial/final [g]
0	m	20/8	59/440
0	f	20/8	40/321
0.1	m	20/13	61/417
1	m	20/15	63/437
1	f	19/17	48/304
3	m	20/16	61/400
5	m	20/15	57/360

 

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.

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. 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. 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. 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.

 

Applicant's summary and conclusion

Executive summary:

In a two-year study, groups of 20 male rats were given 0, 0.1, 1, 3 and 5 % of adipic acid in the diet (equivalent to doses of 0, approximately 75, 750, 2250 and 3750 mg/kg bw/day). Groups of 10 or 19 female rats received food containing 0 or 1 % adipic acid (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 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 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.