5-amino-o-cresol

Endpoint summary

Description of key information

According to the results of the in vivo key studies (Acceptable study followed basic scientific principle, Klimisch 2). The NOAEL No Observed Adverse Effect Level was defined at 180 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

180 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

By gavage during 90 days: a first study was performed with similar OECD guideline 408. Males and females rats were treated daily by oral gavage with the registered test item for 13 weeks with  diluted in 0.1% gelatin 25000 swelling. Doses used were 0, 300, 900 and 2700 mg/kg bw/day. Mortality and clinical signs were recorded at least once daily; body weights, water and food consumption were recorded weekly during the treatment period. Clinical laboratory investigations (haematology, blood/clinical biochemistry) as well as urinalysis were carried out before the start of administration and twice during the treatment period. All animals were subjected to a detailed necropsy. However, there was a deviation: animals were treated only 5 days per week instead of 7. The main toxic effects in this study were local irritation on the stomach mucosa, hepatotoxicity and toxic effects on the red blood cells, and a transient effects on the general behaviour immediately after application in the beginning of the study. Although of less severity, some of these effects were observed at the lowest dose level. Hence, particularly due to the effect observed at the low dose level (organ weight changes), no NOAEL can be derived. The LOAEL was defined as 300 mg/kg bw/day. (Hofer, 1978-1979).

A secondary gavage study during 90 days with the same method was performed at lowest doses to investigate a non-effect dose. This study focused on three effects observed in the precedent assay: (1)disturbed general condition with central nervous symproms immediately after the administration (2) decrease in the number of red blood cells (decrease of hematocrit) and (3) increased relative liver weight. No toxicity was observed during the treatment period at all the tested doses. The NOAEL (No observed adverse effect level) was defined as 180 mg/kg bw/day. (Hofer, 1978-1979).

One relevant in vivo study was performed in order to evaluate the potential toxicity of the registered substance during repeated exposure by oral route (feeding studies). Sprague Dawley rats were exposed continuously to test item mixed in diet at 0.21% in diet (equivalent to 180.9 and 205.88 mg/kg bw/day in males and females respectively), 0.95% in diet (equivalent to 818.35 and 931.37 mg/kg bw/day in males and females respectively) and 2.95% in diet equivalent to 2541.2 and 2892.16 mg/kg bw/day in males and females respectively). They were exposed for 90 days. All animals were observed once daily for mortality/morbidity and once weekly for signs of pharmacological or toxicological effects. Body weights and food consumption were recorded once weekly. Following blood collection from animals via cardiac puncture, the animals were subjected to necropsy and gross pathology. Tissues from all major organs of control and high dose groups were collected and evaluated histopathologically. In addition, liver, urinary bladder, thyroid, kidneys and all gross lesions from mid and low dose group animals were also examined microscopically.

In this 90 days study,with the exception of visibly enlarged thyroids in the animals treated with 1.0 and 3.0%, there were no consistent external or internal abnormalities or gross lesions observed in treated animals that could be related to treatment. Microscopic examination of the organs revealed test material dose related changes in the thyroid glands in the animals treated at all dose levels. The changes noted were a combination of mild to moderate follicular cell hyperplasia, misshapen follicles, and small follicles. The appearance of these glands was similar to that of a "sporadic microfollicular goiter”.

This effect is caused by an increase in the cell size of the columnar epithelium surrounding the follicles in the thyroid. Centrilobular hepatocytomegaly was noted in livers of several test animals (1 male and 1 female at the low dose, 2 males at mid dose and in 4 males and 3 females in the high dose group) and may reflect the site of metabolism of the drug. The few changes in other tissues were distributed among test and control rats and were considered spontaneous incidental lesions.

Justification for classification or non-classification

The NOAEL = 180 mg/kg bw/d