4-tert-butylphenol

Endpoint summary

Description of key information

The NOAEL for ptBP for repeated-dose toxicity has been determined to be 60 mg/kg body weight/day (the mid-dose) in Sprague-Dawley rats based on the changes in blood parameters observed males at the high-dose level of 200 mg/kg body weight/day in a combined repeated dose and reproductive/developmental toxicity screeening test performed according to OECD guidelines.

In addition an US EPA OPPTS 870.3100 90 day oral toxicity study in rodents was conducted with the read-across substance p-tert-amylphenol (Craig, 2012): NOAEL (based on effects to the stomach) = 200 mg/kg/d.

Additional information on the systemic toxicity of ptBP can be taken from a multigeneration study with ptBP in rats. The NOAEL under the conditions of this test was 70 mg/kg/d.

In a 90d study on a closely related alkylphenol (p-nonylphenol) a NOAEL of 50 mg/kg/d was observed.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

60 mg/kg bw/day

Additional information

The repeated-dose oral toxicity of ptBP was assessed in Sprague-Dawley rats (Ministry of Health & Welfare, Japan, 1996). The study was performed in accordance with OECD Guidelines for the Testing of Chemicals No. 422 and in compliance with GLP, and therefore, was selected as the key study. In this study, 13 male and 13 female rats were orally administered 0 (vehicle control), 20 (low-dose), 60 (mid-dose), or 200 (high-dose) mg/kg body weight/day of ptBP in 0.5% aqueous methyl cellulose (vehicle) by gavage.  Males were administered ptBP over a 6-week period beginning from 14 days prior to mating to 14 days after mating, and females were administered ptBP from 14 days prior to mating to day 4 of lactation. One female rat was found dead on day 43 of the study, with the cause of death attributed to an intubation incident, and therefore, was considered not compound-related. Clinical signs were observed in females belonging to the high-dose group and consisted of stridor associated with dyspnea, which were suspected to be caused by irritation of the respiratory tract during administration. However, histopathological examinations did not reveal signs of irritation of the respiratory tract. No other compound-related clinical signs and no effects on body weights or food consumption were observed in female or male rats. Significant changes in haematology parameters in high-dose males compared to control males included a decrease in red blood cell counts, which was not dose-dependent, and a significant increase in white blood cells counts, which appeared to be dose-dependent. Significant changes in clinical chemistry parameters in males included significant decreases in plasma albumin levels in mid- and high-dose males, which appeared to be dose-dependent and were accompanied by a significant reduction in protein levels at the high-dose level. High-dose males also presented with a significant decrease in plasma potassium concentrations and a significant increase in plasma inorganic phosphate concentrations; however, these changes were not dose-dependent. In contrast, no changes in haematology or clinical chemistry were observed in females. Absolute and relative (to 100 g body weight) organ weights were similar among groups and no compound-related morphological changes were observed upon pathological examination; histopathological findings were observed to occur at the same frequency in control and high-dose groups. The investigators determined that the NOAEL for ptBP for repeated-dose toxicity was 60 mg/kg body weight/day (the mid-dose) in rats based on the respiratory distress observed in females and the changes in blood parameters observed males at the high-dose level of 200 mg/kg body weight/day.

In a 90 day repeated dose study (according to US EPA OPPTS 870.3100), the read-across substance p-tert amylphenol was administered to 20 female and 20 male CD(SD) rats by oral gavage at doses of 50, 200 and 600 mg/kg/day. Minor test related clinical pathology changes (minimal prolongations in prothombin time, mild reductions in glucose, decreases in albumin and moderate increases in urine volume were observed. The changes were not considered adverse as not biologically relevant based on sporadic nature, small magnitude and lack of correlative findings. Decreases were observed with thymus weights in males, but these were not considered adverse as there were no microscopic changes.Test related changes in the stomach (both macroscopic and microscopic) were observed in males and females. The erosion/ulceration of the nonglandular stomach and mucosal hypertrophy of the glandular stomach at 600 mg/kg/day were considered adverse effects. No test article related effects were observed in thyroid assays, bone marrow parameters, estrous cycling or sperm parameters. The NOAEL is 200 mg/kg/d based on the stomach effects.

In addition, the toxicity results discussed in the Toxicity to Reproduction section are relevant to this endpoint.

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for this endpoint, as set out in Regulation (EC) NO. 1272/2008.