Oxirane, reaction products with ammonia, distn. residues

Endpoint summary

Description of key information

Since Amix TE (CAS 68953-70-8) is composed of at least 75 % of TEA (CAS 102-71-6) and the available data for Amix TE are limited, a read-across to TEA was conducted:
In a sub-chronic oral toxicity study with TEA, a NOAEL of 1000 mg/kg bw/day was established, the highest dose tested. In a sub-chronic dermal toxicity study, NOAEL's of 125 and 250 mg/kg bw/day were established for local effects for males and females. Systemic NOAEL's of 125 and 250 mg/kg bw/day were determined for males and females, respectively, based on kidney effects. Similar effects were observed in a sub-chronic dermal study in mice, performed according to the same protocol. In a sub-acute inhalation toxicity study with rats, a NOAEL for systemic effects of 0.5 mg/L was established, the highest dose tested. 0.02 mg/L (the lowest dose tested) was considered to be the NOAEL for local effects in females. Since slight local effects were observed in males, this concentration was determined to be the LOAEL for local effects in males. 

Additional information

Since Amix TE (CAS 68953-70-8) is composed of at least 75 % of TEA (CAS 102-71-6) and the available data for Amix TE are limited, a read-across to TEA was conducted.

In a sub-chronic oral toxicity study with TEA, 20 Cox CD rats/sex/dose were exposed to 0, 250, 500 or 1000 mg/kg bw/day in the diet for 91 days (TSCATS, 1989). Increased feed efficiency was observed in females of the mid-dose group. No significant differences between groups were observed in hematology and organ weights. Gross pathologic and histopathologic examination did not reveal any treatment-related effects. Thus, the NOAEL was established to be 1000 mg/kg bw/day, the highest dose tested.

In a sub-chronic dermal toxicity study, Fischer rats were treated with 0, 125, 250, 500, 1000 or 2000 mg/kg bw/day TEA on the skin, 5 days/week for 90 days (13 weeks). 20 animals/sex/dose were exposed, of which 10 "special" animals were used for periodic urinalysis, hematology, and clinical chemistry determinations; and 10 "base" animals were used for collection of clinical observation data, sperm morphology and vaginal cytology evaluations, necropsy with gross examination and tissue collection, and histopathological examination (Battelle, 1987). No mortality was observed. Topical application of 2000 mg/kg bw resulted in a significant decrease in body weight gain, and grossly visible crusts at the site of application were noted in males and females administered 1000 or 2000 mg/kg bw. Hematologic changes were consistent with the presence of skin inflammation in rats in the 2000 mg/kg groups, and clinical chemistry findings of very mild but generally dose-related increases in serum alanine and aspartate aminotransferase activities were suggestive of liver injury. However, sorbitol dehydrogenase activity, which is generally considered to be a better gauge of liver damage, was not increased, and histopathology revealed no evidence of hepatic injury. Aspartate aminotransferase has a wider tissue distribution than sorbitol dehydrogenase, and increased serum activity could be related to minor injury at another site, such as the muscle, rather than to hepatotoxicity. Additionally, some compounds can cause increases in alanine aminotransferase activity in the liver or serum without causing hepatic injury.

Kidney weights increased with increasing dose in male and female rats. Dosed males had decreased urinary protein excretion which likely reflected a change in renal function or an increase in protein reabsorption, as serum protein concentrations were not affected. Although these findings suggest the possibility of protein droplet accumulation or some other form of renal dysfunction or injury, no evidence of hyaline droplet nephropathy or other histopathologic changes that might account for the weight changes was noted.

Lesions at the site of application ranged from no discernable change, through minimal to mild epidermal thickening (acanthosis), to chronic active inflammation, erosion, and ulceration. The dermis was also thickened with inflammation and fibrosis at the higher doses. There was no histologic evidence to suggest the development of skin sensitization or contact dermatitis. NOAEL's for local effects were determined to be 125 and 250 mg/kg bw/day for males and females, respectively. The NOAEL's for systemic effects were established to be 125 and 500 mg/kg bw/day for males and females, respectively, based on kidney effects.

In a sub-chronic dermal toxicity study using an identical experimental set-up as in the study with rats, mice were exposed to 0, 250, 500, 1000, 2000 or 4000 mg/kg bw/day TEA on the skin (Batelle, 1987). Findings were similar to those in the rat study. All mice survived to the end of the study. Clinical findings were observed only in mice of the 4000 mg/kg group and included scaliness, irritation, and discoloration at the application site for males and females, and skin erosion in one male. The absolute kidney and liver weights of males and females administered 4000 mg/kg were greater than those of the vehicle controls; relative kidney weights of males administered 1000 mg/kg or greater and females in all dosed groups were also greater than those of the vehicle controls. Microscopic examination of the skin of dosed mice indicated acanthosis and inflammation at the site of application. Acanthosis occurred in all dosed groups and in one vehicle control female; the severity increased with increasing dose in males and females. Inflammation was only observed in males and females in the 4000 mg/kg groups and in one female in the 2000 mg/kg group. The NOAEL for local effects was determined to be ≤ 250 mg/kg bw/day. NOAEL's for systemic effects were established to be 1000 and ≤ 250 mg/kg bw/day for males and females, respectively, based on kidney effects.

Repeated inhalation toxicity was investigated in a sub-acute 28-day study performed according to OECD TG 412 (BASF AG, 1993) and under GLP conditions, in which Wistar rats (10/sex/dose) were exposed head/nose only to 0, 0.02, 0.1 or 0.5 mg/L TEA for 6 hours/day and 5 days/week. No mortality was observed. No statistically significant differences between groups were observed in body weight, haematology and clinical chemistry. Differences in grip strength were judged not substance-related because of a lack of concentration- or time-related effect. No other abnormalities were observed during neurofunctional testing. A significant difference in red blood cells was observed in males of the mid-dose group compared to controls, but since this deviation was marginal, not observed in females, and not dose-related, this finding was considered of no toxicological signifance. Local effects were characterized histopathologically by focal inflammatory changes in the submucosa of the larynx, with a concentration-dependent tendency in incidence and severity. No such effects were observed in females of the low dose, whereas minimal to slight effects were seen in males at this dose. Therefore, 0.02 mg/L was considered to be the NOAEL for local effects in females and the LOAEL for males. Since no systemic effects were observed, the systemic NOAEL was established to be 0.5 mg/L, the highest dose tested.

Justification for classification or non-classification

Based on the results of the repeated dose toxicity studies, Amix TE does not need to be classified according to Directive 67/548/EEC and according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.