Registration Dossier

Administrative data

Description of key information

The key studies chosen for this endpoint are two subchronic oral toxicity studies via the diet, of duration 18 weeks (Reyna, 1987) and 14 weeks (Saitoh, 1994) at similar dose levels and a subacute dermal toxicity study (Daly, 1985). Supporting studies are an 18-week oral gavage study using only two dose levels, both too high to provide a no-effect level (Laham, 1985) and a 14-day subacute oral study (Komsta, 1989).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
20 mg/kg bw/day

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day

Additional information

Oral Toxicity

 Reyna, 1987 (Rel. 1)
In a subchronic oral toxicity study, TBEP was administered in the diet to Sprague-Dawley rats at 300, 3000 and 10,000 ppm (approximately equivalent to 0.02, 0.20 and 0.60 ml/kg bw/day, i.e. 20.4, 204 and 612 mg/kg bw/day). for 18-weeks.

There were no ophthalmic lesions attributable to ingestion of TBEP. All treatment group rats gained weight comparable to the controls. During the first week both sexes of the high and intermediate dose groups consumed less diet than controls. Throughout the remaining period all treatment groups consumed amounts of diet similar to the controls. One high dose female died during the study however the death was not attributed to exposure to TBEP. The only haematological and clinical chemistry changes were increased platelet counts (10,000 ppm both sexes) and increased serum gamma glutamyl transpeptidase and a depressed plasma cholinesterase in the 3000 and 10,000 ppm groups. Increased liver weight (both absolute and relative in both sexes) was found in the 10,000 ppm dose group. Microscopic examination revealed mild periportal hepatocellular hypertrophy and periportal vacuolisation in males only at 3000 and 10,000 ppm. The liver was therefore the only target organ in this study, with treatment-related effects at the high dose level of 10,000 ppm and minimal effects at the mid-dose level of 3000 ppm.

 Based upon the results of this study the NOEL is considered to be at least 300 ppm TBEP in the diet (equivalent to approximately 20.4 mg/kg bw/day), for both sexes. The LOAEL is 3000 ppm (204 mg/kg bw/day) based on mild liver effects.

 

 Saitoh, 1994 (Rel. 2)
In a study to evaluate the toxicity of TBEP to Wistar rats on repeated exposure, rats were fed a diet containing 0.03, 0.3 or 3.0% TBEP for 5 or 14 weeks. Body weight gain was suppressed in all rats in the top dose groups (3.0%). Serum cholinesterase activity was significantly decreased in both sexes in the 0.3 and 3.0% groups and serum gamma glutamyl transferase was significantly increased in both sexes in the top dose group after both 5 and 14-weeks of exposure. Serum amylase levels were also increased in males (0.3 and 3.0 % groups) and in females (3%). The target organ in this study was the liver; absolute and relative liver weights in both sexes were significantly increased in the top dose group (3.0%) after both 5 and 14-weeks of treatment. Histopathological examination showed only male rats in the top dose group (3.0%) to exhibit moderate periportal hepatocyte swelling after 14-weeks.

 The authors concluded that the NOEL for the dietary study was 0.03 % diet (male rat: 20 mg/kg bw/day; female rat: 22mg/kg by/day), and LOAEL of 3.0% (200 mg/kg bw/day) based on mild liver effects.

 

 Laham, 1985 (Rel. 2)
In a study of the subchronic oral toxicity of TBEP, rats were dosed with 0.25 or 0.5 ml/kg (255 and 509 mg/kg bw/day) of undiluted TBEP. During the first week of the study 2 high-dose female rats showed evidence of muscular weakness and ataxia which disappeared by week 5. All TBEP-treated animals appeared less active than controls during the study and one female died during week 13. After the 7th week all rats showed clinical signs of toxicity attributed to exposure to TBEP which included difficulties in breathing in several rats in both low and high dose groups, although the low dose rats were less affected. High dose group rats had tremors followed by piloerection, lachrimation and increased urination. There was no significant difference in body weights between exposed and control groups or between high dose and low dose rats. There were no haematological changes observed in treated rats when compared to controls. Biochemical changes which were statistically significant included elevated levels of Mg in both dosed groups and high amylase and GGT levels in rats dosed with 0.5 ml/kg in females. Raised level of BUN (high dose only), decreased glucose (low dose only), decreased uric acid (both doses), dose-related decreased in red cell AChE and reduction in(high dose only) were reported in males. There was a statistically significant increase in both liver and kidney weights (high dose females), a significant increase in liver weight in low dose females and similar increase for high dose males when expressed as percent body weight. Gross pathological examination revealed a slight enlargement of the liver of most high dose rats. The major observation was in relation to the heart of male test animals, showing increased multiple foci of mononuclear cell infiltration, haemorrhage and/or myocardial fibre degeneration. The cardiac changes were considered by the authors to be due to TBEP accelerating the development of focal myocarditis, a systemic toxic effect commonly found in ageing SD rats.

 No NOAEL was established in this study. The LOAEL was 255 mg/kg bw/day, based on increased liver weight in females and decrease in red blood cell AChE plus cardiac lesions in males.

  

Komsta, 1989 (Rel. 2)

In a 14-day study in rats at 1, 10 and 100 mg/kg bw/day TBEP did not demonstrate any significant toxic effects (Komsta, 1989).

  In a 28-day study in rats at using diets containing 500, 2000, 7500 and 15000 ppm TBEP (approximately 50, 750 and 1500 mg/kg bw/day) reported by Monsanto (1985a), no clinical signs of neurotoxicity were reported and no TBEP-related effects were observed at necropsy.

Conclusion

 The available studies are considered acceptable to fulfil this endpoint and provide adequate information for risk assessment. There are no indications of toxicity requiring evaluation in a longer study, therefore no chronic toxicity study is proposed. The NOAEL of 300 ppm (approximately 20 mg/kg bw/day) from both dietary studies, of 18 weeks (Reyna, 1987) and 14 weeks (Saitoh, 1994) has been taken for repeat exposure risk assessment.

 

Dermal Toxicity

 Daly, 1985 (Rel. 1)

In a dermal subacute study, rabbits were exposed to 10, 100 and 1000 mg/kg TBEP on 21 consecutive days. There were no deaths and no adverse clinical signs of toxicity. No adverse systemic toxicity was observed following dosing at any dose level. Local irritation (moderate erythema), oedema, atonia and desquamation occurred in a dose-related manner and severity and increased with time. Microscopic observations of treated skin from high dose animals included squamous cell hyperplasia, hyperkeratosis, hair follicles distended with keratin and surface accumulation of keratin and erosions/ulcers. No such observations were seen in control males and only infrequently in control females.

The NOAEL for systemic toxicity was 1000 mg/kg bw/day, however no NOAEL for local effects could be established.

Justification for classification or non-classification

The guidance values for classification of a substance as harmful on repeated exposure by the oral route according to the criteria of Annex VI Directive 67/748/EEC(R48/22) relate to severe effects reported at 50 mg/kg bw/day or below in a 90-day study. The equivalent guidance values for classification according to EU/GHS criteria (STOT Category 2) relate to effects reported at 10-100 mg/kg bw/day in a 90-day study. For TBEP, the no-effect level in 18-week and 14-week oral dietary studies (Reyna et al, 1987; Saitoh, 1994) was 300 ppm (approximately equivalent to 20 mg/kg bw/day). Only mild effects on the liver were reported at the LOAEL of 3000 ppm (approximately equivalent to 200 mg/kg bw/day). In an oral gavage study of 18 weeks duration, no NOAEL was established but the LOAEL was 0.25 ml/kg bw/day (255 mg/kg bw/day) based on haematology/clinical chemistry and exacerbation of cardiac lesions. Oral studies of neurotoxicity of similar duration are reported in section 7.9.1. None of the reported studies indicates toxicity which would lead to classification. No systemic toxicity was reported in a subacute dermal toxicity study (Daly, 1985).

TBEP is not classified for repeat-dose toxicity according to the criteria of Annex VI Directive 67/748/EEC or UN/EU GHS.