Cyclohexane, oxidized, aq. ext.

Endpoint summary

Description of key information

There are no repeated dose toxicity studies available on Cyclohexane, oxidized, aquous extract (COP Acid), but a well-documented chronic study on the primary component, adipic acid, is considered a reliable read-across.  In this 2-year oral study, adipic acid was of low repeated dose toxicity, however it was not tested according to modern standards. The NOAEL was 1% for male rats (approx. 750 mg/kg bw/day) and higher doses (3 and 5%) caused body weight retardation with no indication of specific target organ toxicity. The NOAEL for female rats was 1% (approx. 750 mg/kg bw/day), the highest dose tested in females. In humans no symptoms were reported after oral administration of up to 7 g adipic acid per day for up to 10 days to 7 volunteers to investigate compound excretion.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

750 mg/kg bw/day

Study duration:

chronic

Species:

rat

Additional information

There are no repeated dose toxicity data available for Cyclohexane, oxidized, aquous extract (COP Acid) but a well-documented chronic study on the primary component, adipic acid, is considered a reliable read-across.

Read Across (Adipic Acid):

Hazards identified by OECD/ICCA high production volume chemicals program in 2004:

Animal data:

Oral toxicity:

"In a limited three-weeks feeding study four rats were dosed with food containing 2% adipic acid (approximately 1500 mg/kg bw/day) no differences were observed compared to control animals in general behavior, liver size, peroxisome proliferation, hepatic activities of catalase and carnitine acetyltransferase, and no hypolipidemia was seen (Moody and Reddy 1978).

Groups of 8 to 10 male rats received neutralized adipic acid (0, 50, 100, 200 and 400 mg/day, approximately 0, 833, 1666, 3333, 6666 mg/kg bw/day) in a protein deficient diet for 19 weeks. After 7 weeks and (probably) at the end of the experiment, rats were killed and examined grossly. Weight gain and general behaviour were recorded and histopathology of liver, kidneys and intestine was performed. Rats fed with 400 mg/day showed lower weight after 19 weeks. No obvious symptoms were observed. Several unexplained intercurrent deaths in control and dose groups occurred, and only 5-7 animals survived 19 weeks. Only at 400 mg/day slight effects were seen on liver and irritation of intestine. The NOAEL is 3333 mg/kg bw (Lang and Bartsch 1953). The study is very limited in its reliability because only kidneys, liver and intestine have been examined histopathologically.

Groups of 13-15 male and female rats received adipic acid (neutralized with NaOH) in a standard diet (0, 400, 800 mg/day, approximately 0, 5000, 10000 mg/kg bw/day) for 33 weeks. Weight gain and general behavior were recorded. After 8, 23 and 25 weeks, rats were killed and histopathology of liver, kidneys and intestine was performed. The administration of 400 mg/day of adipic acid had no effect on weight gain and general behavior of the animals. Ten out of 14 rats fed with 800 mg/day died during the first 4 weeks. The surviving animals showed retarded weight gain, appeared unkempt and apathetic and suffered from heavy diarrhea during the first three weeks. They recovered by the fifth week, and after 33 weeks, the weights of the high-dose rats were the same as that of the 400 mg/day group. Histopathology: slight effects were seen on liver and irritation of intestine at 400 mg/day. No NOAEL was obtained in this study (Lang and Bartsch 1953). The study bis very limited in its reliability because only kidneys, liver and intestine have been examined histopathologically.

In a two-years feeding study rats were fed with food containing different amounts of adipic acid. 20 male rats per group received food containing 0, 0.1, 1, 3 and 5 % of adipic acid (0, approximately 75, 750, 2250, and 3750 mg/kg bw/day), respectively, and 10 or 19 female rats per group received food containing 0 or 1% (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 to be within normal limits in all groups. 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."

Inhalation:

"There is no study with histopathological examination of the nose, the probable target organ after inhalation, available. Systemic effects after repeated inhalation have not been investigated in fully valid studies. However, repeated dose studies with application via the food (see below) reveal a low systemic toxicity of adipic acid."

Dermal toxicity:

"No data available"

Human information:

Oral toxicity:

"Adipic acid was orally administered to 7 volunteers to investigate excretion of this compound. No symptoms were reported in subacute studies with doses of up to 7 g adipic acid per day administered for up to 10 days (Weitzel 1942 and 1947)."

Inhalation toxicity:

" 7 of 12 workers exposed (for an average of 9.2 years) to various glycols and adipic acid dust particles (concentration 0.47-0.79 mg/m3 [0.08-0.13 ppm], 8 h average value) complained of mucosal irritation (eye, nose, throat). There was no local exhaust ventilation and the workers did not wear respiratory protection. They reported that clouds of adipic acid and other materials were routinely generated during charging of reaction vessels. The investigators suggested that, since the glycol level was kept below 1 ppm, adipic acid was more likely to be the cause of these complaints (Cummings and Roseman 1985). Due to the acidic character of the substance, a local irritation potential is plausible."

Updated relevant information:

None

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Well documented chronic feeding study.

Justification for classification or non-classification

Adipic acid is of low toxicity after repeated oral application; no classification is required according to the EU classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).