reaction products of acetic anhydride and adipic acid

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

Remarks:

other: chronic two-year study

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

1957

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

No GLP, short documentation, unclear number of animals examined histopathologically, only one dose for females, purity not specified. Read-across justification: The available toxicological data for the target and source substances is outlined in the data matrix (Annex I). The toxicological properties of the target substance are related mainly to acetic acid/acetate since the anhydride components of the substance are hydrolytically unstable. When the target substance comes in contact with water or moisture a complete hydrolysis will take place to form no other hydrolysis products than acetic acid/acetate and adipic acid. Thus, the use of data from acetic acid and adipic acid is justified to evaluate toxicological properties of the target substance. Furthermore, data from acetic anhydride is used in the assessment. Experimental data obtained with the source substances indicate that the substances has low oral (LD50 > 1780 – 3310 mg/kg bw) and inhalation (LC50 1680 - 7700 mg/m3) acute toxicity. Furthermore, the acetic acid and acetic anhydride are irritating to skin at concentration < 25% and corrosive to skin at ≥ 25%. Acetic anhydride and acetic acid are not tested for sensitisation due corrosive properties; adipic acid did not show any evidence of sensitising in an animal study. The source substances did not show positive response in genetic toxicity studies available. Repeated toxicity studies via oral route conducted for acetic acid showed NOAEL values ≥ 210 mg kg bw/day and via inhalation route for acetic anhydride 4.2 mg/m3.. Reproduction toxicity studies conducted for acetic acid did not show any adverse effects on reproduction at the highest concentration tested (1600 mg/kg bw/day).

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. 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

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:

adipic 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

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 cancer study

Doses / concentrations

Remarks:

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

No. of animals per sex per dose:

19-20 per sex and dose

Control animals:

yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

eight gains for the male rats receiving 3 or 5% adipic acid was significantly less than the controls.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

eight gains for the male rats receiving 3 or 5% adipic acid was significantly less than the controls.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

histopathologic examination of the testes, ovaries and uterus revealed no evidence of an adverse effect on the reproductive organs.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

750 mg/kg bw/day (actual dose received)

Sex:

female

2

Dose descriptor:

NOAEL

Effect level:

3 750 mg/kg bw/day (actual dose received)

Sex:

male

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In an 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).

Executive summary:

Studies on fertility are not available. In the 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 tested doses (3750 mg/kg bw/day in males, 750 mg/kg bw/day in females). Soft edematous testes were observed at least as frequent in the controls as in the adipic acid dosed animals. Two of the surviving control female animals and one of the experimental females had ovarian