Adipic acid, compound with hexane-1,6-diamine (1:1)

Carcinogenicity

Description of key information

No experimental data are available for carcinogenicity of AH-Salt.
A 2-year feeding study with adipic acid gave no evidence of increased tumor incidences in rats (Horn et al, 1957; for details see section Repeated dose toxicity).
Cell transformation
In vitro cell transformation tests with AH-salt (analytical purity 100%) in cultured BALB 3T3 cells revealed no morphological transformation both in the absence and presence of a rat liver metabolic activation system (BASF AG, 1980, see section Genetic toxicity in vitro). The highest concentration was not cytotoxic. The positive control substances, as expected, caused statistically significant increased incidences of morphologically transformed foci. The acceptance criteria for the validity of the tests were fulfilled.

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

Young albino rats (50 – 60 g) were fed basal diet containing adipic acid. Body weights, food consumption and general appearance condition were recorded weekly. Gross autopsy was performed on animals that died during the experiment. After 2 years, the surviving rats were weighed, sacrificed and examined for gross and microscopic pathology. Organ weights were determined and tissue of different organs was examined microscopically.

GLP compliance:

no

Remarks:

pre GLP-study

Species:

rat

Strain:

not specified

Details on species / strain selection:

common rodent species

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
young male and female albino rats
- Source: Carworth Farm
- Weight at study initiation: ca. 60 g (males); ca. 50 g (females)
- Housing: individually in cages with wire mesh floors
- Diet: ad libitum
- Water: ad libitum
No further data.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

2 years

Frequency of treatment:

continuously in the diet

Dose / conc.:

0.1 other: % in diet

Remarks:

males; approximately 50 - 100 mg/kg bw/d

Dose / conc.:

1 other: % in diet

Remarks:

males and females; approximately 500 - 1000 mg/kg bw/d

Dose / conc.:

3 other: % in diet

Remarks:

males; approximately 1500 - 3000 mg/kg bw/d

Dose / conc.:

5 other: % in diet

Remarks:

males; approximately 2500 - 5000 mg/kg bw/d

No. of animals per sex per dose:

20 males per group (control group; 0.1%, 1%, 3%, 5% dose groups);
10 females (control group);
19 females (1% dose group)

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly observations were made of the general appearance and condition of each
animal

BODY WEIGHT: Yes
- Time schedule for examinations: at weekly intervals during the course of the study

FOOD CONSUMPTION: Yes
- Time schedule: at weekly intervals during the course of the study

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

After 2 years on the respective diets, the surviving rats were weighed, sacrificed by a blow on the head, and examined for gross and microscopic pathology. The brain, thyroid, lungs, heart, liver, spleen, kidneys, adrenals, stomach, and testes of approximately half of each group of males were weighed. The kidneys, spleen, liver, and heart of each female were weighed. Microscopic examination of the following tissues were done on 4 representative number of animals of each group: thyroid, lungs, heart, liver, spleen, kidneys, adrenals, stomach, small intestine, large intestine, pancreas, bone marrow, testes or ovaries, and uterus.

Statistics:

no

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Males: Throughout the study, the following clinical signs were observed among all groups, including controls: wheezing, blood-tinged crust about the noses and eyes, and body sores. The incidence of these findings did not appear to be significantly different among the groups although a lower incidence of signs indicative of respiratory infection and body sores occurrent in the 5% dose group.
Females: Clinical signs noted in control and test groups included blood-tinged crust about the eyes and noses, unthriftness, and body sores.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Males: The percent survival for each test group was higher than for the control group.
Females: Mortality in the treated group was similar to control. One experimental rat and two control animals died during the final 6 months.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Males: There were no body weight differences throughout the 2-year period in rats treated with 0.1 or 1% adipic acid. During the rapid growth period, the weight gains of the 3.0 and 5.0% adipic acid groups were significantly less than the control groups. At the end of the study the body weight of males was reduced by 10% and more in the two highest exposure groups.
Females: There were no significant differences in body weight gains.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Males: There was slight, but consistent, reduction in food consumption at 5%.
Females: There were no significant differences in food consumption.

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Males: When the surviving males were sacrificed at the end of the study, there was no significant differences in organ weights.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Males: The incidence of lung pathology and tumor growth appeared to be equally distributed among all groups, including the controls.
Females: There were no pathologic findings.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Males: When the surviving males were sacrificed at the end of the study, there was no significant differences in microscopic examination.
Females: There were no pathologic findings.

Dose descriptor:

NOAEL

Effect level:

500 - 1 000 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

body weight and weight gain

Remarks on result:

other: The actual dose received corresponds to 1 % in the diet and was calculated using the food consumption.

Critical effects observed:

not specified

Executive summary:

Rats were fed either the basal laboratory diet, or the diet to which adipic acid was added. Groups of 20 males received diets containing the test substance at 0 (control), 0.1, 1, 3, and 5% in the diet; 10 and 20 females received the test substance at 0 (control) and 1% in the diet, respectively. After 2 years, surviving rats were killed and examined grossly. The weights of selected organs were recorded, and microscopic examination of selected tissues was done on a representative numberof animals from each group.

Male rats: The percent survival for each test group was higher than for thecontrol group. There were no body weight differences throughout the 2-year period in rats treated with 0.1 or 1% adipic acid. During the rapid growth period, the weight gains of the 3.0 and 5.0% adipic acid groups were significantly less than the control groups. At the end of the study the body weight of males was reduced by 10% and more in the twohighest exposure groups. There was slight, but consistent, reduction in food consumption at 5%, Throughout the study, clinical signs were observed among all groups including controls. The incidence of these findings did not appear to be significantly different among the groups although a lower incidence of signs indicative of respiratory infection and body sores occurred in the 5% dose group. The incidence of lung pathology and tumor growth appeared to be equally distributed among all groups, including the controls. When the surviving males were sacrificed at the end of the study, there was no significant differences in organ weights or microscopic examination.
Female rats: There were no significant differences in body weight gains or food consumption. Clinical signs were noted in the control and the test group.There was no microscopic pathology.

The NOAEL was 1% in the diet (ca. 500 - 1000 mg/kg bw/d).

Endpoint conclusion

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

chronic

Species:

rat

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

There is no need to classify AH-Salt for carcinogenicity according to the Directive 67/548/EC or GHS or EU GHS criteria (Regulation (EC) N° 1907/2006).

Additional information

No experimental data considering carcinogenic activity are available for AH salt. However, the substance was not genotoxic in several in vitro and in vivo test systems and did not induce morphological transformation in cultured mammalian cells in the presence and absence of metabolic activation. In addition, a 2-year feeding study with one of the components of AH salt, adipic acid, gave no evidence of a carcinogenic activity, and both components of AH-salt, adipic acid and 1,6-diaminohexane, gave negative results in genotoxicity tests. Overall, the data available do not imply an increased risk of carcinogenic activity of AH salt. Therefore, a carcinogenic activity of AH salt has not to be considered probable, and additional testing of AH salt has not to be regarded necessary.