Cyclohexylamine

Endpoint summary

Description of key information

Based on the chronic studies discussed above and the available comprehensive reviews of the available subacute and subchronic data (Bopp et al., 1986, NL Health Council 2010, MAK 2006) it can be concluded, that the NOAEL for repeated dose toxicity after oral ingestion is 15 mg/kg bw/day in rats. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

15 mg/kg bw/day

Study duration:

chronic

Species:

rat

Additional information

There are more than 20 subacute, subchronic or chronic studies reported in the literature. Comprehensive reviews are available that discuss all available data (Bopp et al., 1986, NL Health Council 2010, MAK 2006). Since the data are overall consistent chronic studies are regarded as the most valuable studies for risk assessment these studies are discussed into more detail in this chapter.

Groups of 48 male and female Wistar rats received 600, 2000, 6000 ppm cyclohexylamine hydrochloride in the diet for 2 years. The average intake of cyclohexylamine hydrochloride during the experiment by males was 24, 82, 300 mg/kg bw/day and by females was 35, 120, 440 mg/kg bw/day. These doses correspond to 18, 60, 219 mg/kg bw/day cyclohexylamine for males and 26, 88, 321 mg/kg bw/days cyclohexylamine for females (Gaunt et al., 1976).

Parameters investigated included: mortality and clinical signs, food and water intake, weight development, hematological parameters, clinical chemical parameters, urinary parameters, organ weights, gross and histopathological examination.

Mortality was lower in the treated groups than in the control groups. No treatment related increase in any tumor was reported in any dose group. In all dose groups, body weight gain, food and water intake were reduced.

In the high dose group hematologic parameters (haemoglobin, packed cell volume, reticolocylte counts, total leucozytes, neutrofils, lymphocytes) and chlinical chemistry (serum urea concentration, serum albumine level, LDH) and urine analysis were affected. Absolute and/or relative organ weights were altered (e.g. heart, liver, spleen, kidney, stomach, small intestine, caecum, adrenals, pituitary, thyroid, brain). In males, absolute testes weights were decreased, while in females gonadal weights were increased. Histological changes were reported in the lung (aveoli with foamy macrophages), the kidney (mild glomerulonephrosis) and testes (bilateral athrophy, tubules with reduced activity, deposites in tubules).

In the mid dose group, the main findings are hemathologic alterations (haemoglobin, total leucozytes), clinical chemistry (serum urea concentrations and serum albumin levels) and organ weights (e.g. heart, liver, spleen, kidney, stomach, small intestine, caecum, adrenals, thyroid, brain). In males, absolute testes weights were decreased, while in females relative gonadal weights were increased. Histological investigations indicate lesions in the testes (tubules with few or no spermatids).

At the low dose body weight gain was reduced by approx. 10%. Observations on hematologic and clinical-chemistry parameters were observed but gave no consistent picture (MAK 2006). Absolute and relative organ weights were affected (abs. weight: heart, liver, kidney; rel. weight: brain).

Overall, due to the slight effects observed at the low-dose group no NOAEL was observed in this study and the low dose group is considered to be the LOAEL of 18 mg/kg bw/day.

In a multigeneration study, weanling rats (FDRL, 30/sex/group) were given diets containing cyclohexylamine hydrochloride resulting in cyclohexylamine doses of 0, 15, 50 or 150 mg/kg bw/day, for 2 years (Oser et al 1976).

Treatment had no influence on the mortality rate. No difference in tumor incidence was found between treated and control groups.

There was a dose dependent and statistically significant decrease in mean terminal body weights at doses of 50 mg/kg bw/day and above in females and 100 mg/kg bw/day and above for males. Data on absolute and relative organ weights and on histological findings were summarized but no statistical analysis was presented. With a few exceptions, all absolute organ weights were decreased in all exposure groups while the relative weights were either higher or similar when compared to those in controls. Since there was no clear dose-response relationship this effect is assumed to result from the reduction in body weight gain. Upon microscopic examination, no clear dose-response was found for any parameter. There was increased incidences in calcification of the kidney (5/24, 11/35, 10/27, 8/41 vs 2/33 in controls), mucosal thickening of the bladder (9/58, 13/56, 9/56, 13/56 vs 8/57), testical atrophy (6/15, 9/13, 3/10, 12/20 vs 5/19), and abnormal germinal epithelium in the high dose group (0/15, 1/13, 1/10, 3/20 vs 0/19). No effects were seen in hematological, clinical chemistry, and urine-analysis parameters.

Overall a NOAEL of 15 mg/kg bw/day can be established from this study.

In a carcinogenicity study in rats with insufficient documentation groups rats (25/sex/group) were given doses of 0, 0.15, 1.5 or 15 mg cyclohexylamine sulphate /kg-bw/day for 2 years. Slight depression of weight gain was reported in the high does males during the first year. No significant difference was reported for food intake, mortality, blood chemistry and heamotological parameters. A bladder tumor was found in one out of eight male survivors in the high-dose group. There were no treatment-related changes in any of the other organs examined (Price et al. 1970).

In a chronic study with mice (ASH-CSI; 48 males and 50 females/group) animals were dosed with 300, 1000 or 3000 mg cyclohexylamine hydrochloride per kg diet for 80 weeks. This concentration is equivalent to approx. 29, 102 or 292 mg cyclohexylamine/kg bw/day (assuming 20 mg bw and 3 g feed per day; MAK 2006).

No statistically significant increase in any tumor incidence was reported. Mortality was not affected. In females, no effect was reported on body weight or organ weight. In male animals of the mid- and high-dose groups, body weight gain differed from controls; in the low-dose group differences were observed only occasionally (wk 1, 12, 26). Other effects observed were limited to the high-dose group and indicated changes in haematology (netrophils, lymphocytes) in males and histology of the liver and lungs in females. No abnormalities were found in the testis.

Based on the effects on bw a NOAEL of 29 mg/kg bw/day can be concluded in this chronic study in mice.

Bopp et al. 1986 reviewed a study in which Beagles dogs (n=3/sex/group) were given daily oral capsules of cyclohexylamine sulphate (0, 0.15,1.5 or 15 mg/kg bw/day. No effects were observed in growth, behavior, heamatology, serum chemistry, urine-analysis or hepathic or renal function tests. One male and one female from each group were sacrificed after one year. Organ weight and histopathology were unaffected in these animals. After about 4 years, the doses were increased to 50, 100 or 150 mg/kg bw/day. Animals lost weight after dose increase (dose groups not reported), but subsequently slowly regained weight. Clinical pathology tests were not affected and no histopathological changes were attributed to the treatment. The study was terminated at the end of the 9.5 year period.

Justification for classification or non-classification

According to the EU classification criteria 67/548/EWG Annex 1 and EU regulation no. 790/2009 (GHS) Annex 1 the compound is not classified. No further classification is proposed.