Dipotassium adipate

Repeated dose toxicity: oral

Administrative data

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, 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.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Report date:

1957

Materials and methods

Test guideline

Qualifier:

no guideline followed

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

Limit test:

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

Test material form:

not specified

Details on test material:

Test substance: purity not specified

Test animals

Species:

rat

Strain:

other: Carworth Farm strain

Sex:

male/female

Details on test animals or test system and environmental conditions:

/

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: diet

Details on oral exposure:

/

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

/

Duration of treatment / exposure:

2 years

Frequency of treatment:

diet ad libitum

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
75 mg/kg bw
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
750 mg/kg bw
Basis:
nominal in diet

Doses / concentrations 3

Remarks:

Doses / Concentrations:
2250 mg/kg bw
Basis:
nominal in diet

Doses / concentrations 4

Remarks:

Doses / Concentrations:
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

Details on study design:

/

Positive control:

/

Examinations

Observations and examinations performed and frequency:

/

Sacrifice and pathology:

/

Other examinations:

/

Statistics:

/

Results and discussion

Results of examinations

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

/

Effect levels

Dose descriptor:

NOAEL

Effect level:

750 mg/kg bw/day (nominal)

Based on:

not specified

Sex:

male/female

Basis for effect level:

other: /

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 Sex No. of rats Average body [%] in diet m/f start/finish weight initial/final [g] 0 m 20/8 59/440 0 f 10/8 49/321 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.