Sebacic acid

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Remarks:

chronic two-year study

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1957

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

no GLP, short documentation, unclear number of animals examined histopathologically, only one dose for females, purity not specified

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1957

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

Albino rats (male/female) were housed individually and fed for two years with the test substance.
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

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: mean weights between 50-60 g
- Housing: individually in floor mesh wired cages
- Diet: basal labaratory diet, ad libitum
- Water: ad libitum

Route of administration:

oral: feed

Vehicle:

other: diet

Duration of treatment / exposure:

2 years

Frequency of treatment:

diet ad libitum

Post exposure period:

no

Dose / conc.:

0.1 other: % (males)

Remarks:

equivalent to approx. 75 mg/kg bw/d nominal in diet

Dose / conc.:

1 other: % (males/females)

Remarks:

equivalent to approx. 750 mg/kg bw/d nominal in diet

Dose / conc.:

3 other: % (males)

Remarks:

equivalent to approx. 2250 mg/kg bw/d nominal in diet

Dose / conc.:

5 other: % (males)

Remarks:

equivalent to approx. 3750 mg/kg bw/d nominal in diet

No. of animals per sex per dose:

19-20 per sex and dose

Control animals:

yes, plain diet

Details on study design:

Post-exposure period: no data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly throughout the study

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly throughout the experimental period

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean weekly diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
- gross autopsy was performed on those animals that died during the course of the experiment

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- weighing: brain, thyroid, lung, heart, liver, spleen, kidneys and adrenals, stomach of approximately half of each group of males; kidneys, spleen, liver and heart of each female

HISTOPATHOLOGY: Yes
- microscopic examination: 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

Statistics:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

- male rats receiving 3 or 5 % test substance: weight gain was significantly reduced compared to the controls
At the end of the study the body weight of males was reduced by 10% and more in the two highest exposure groups.

Food consumption and compound intake (if feeding study):

not specified

Description (incidence and severity):

There was slight, but consistent, reduction in food consumption at 5%.

Gross pathological findings:

no effects observed

Description (incidence and severity):

- no evidence of gross pathology associated with the feeding of the test substance

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Autopsy data for the male animals that died during the course of the two-year feeding program and for the sacrificed rats were analysed for incidence of tumors and/or lung pathology.
Upon autopsy, one female 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.
Details are given below in the section "any other information".

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

Critical effects observed:

no

Autopsy data for the male animals:

(Depicted are animals that died during the course of the 2 -year feeding program or which were sacrificed. A tumor is defined as having a gross evidence of being a new growth present.)

Male group: 0/0.1/1/3/5% test substance

Deaths (N):

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 (N):

lung pathology: 4/7/7/3/4

tumors: 1/2/2/-/-

Executive summary:

The test substance 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. 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.

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

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. 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

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation:
mean weights between 50-60 g
- Housing:
individually in floor mesh wired cages
- Diet: basal labaratory diet, ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:

oral: feed

Details on mating procedure:

no mating

Duration of treatment / exposure:

2 years

Frequency of treatment:

diet ad libitum

Details on study schedule:

2 year cancer study

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.1 other: % (males)

Remarks:

equivalent to approx. 75 mg/kg bw/d nominal in diet

Doses / concentrations 2

Dose / conc.:

1 other: % (males/females)

Remarks:

equivalent to approx. 750 mg/kg bw/d nominal in diet

Doses / concentrations 3

Dose / conc.:

3 other: % (males)

Remarks:

equivalent to approx. 2250 mg/kg bw/d nominal in diet

Doses / concentrations 4

Dose / conc.:

5 other: % (males)

Remarks:

equivalent to approx. 3750 mg/kg bw/d nominal in diet

No. of animals per sex per dose:

19-20 per sex and dose

Control animals:

yes, plain diet

Details on study design:

Post-exposure period: no data

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

- male rats receiving 3 or 5 % test substance: weight gain was significantly reduced compared to the controls
At the end of the study the body weight of males was reduced by 10% and more in the two highest exposure groups.

Food consumption and compound intake (if feeding study):

not specified

Description (incidence and severity):

There was slight, but consistent, reduction in food consumption at 5%.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

- no evidence of an adverse effect on the reproductive organs (testes) up to the highest dose
- soft edematous testes noted at least as frequent in the controls as in the experimental animals

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

Details on results (P0)

- 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:

> 3 750 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

2

Dose descriptor:

NOAEL

Effect level:

> 750 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: non-neoplastic

Target system / organ toxicity (P0)

Critical effects observed:

no

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

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 tumors, ovarian cysts were noted in both control and experimental 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).