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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
612 mg/kg bw/day
Additional information

In a subchronic oral toxicity study (Reyna, 1987), 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 effects on bodyweight, or organ weights other than the liver. No effects were observed on either male or female reproductive organs. Based upon the results of this study the NOEL for fertility is 10000 ppm (approximately 612 mg/kg bw/day).

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%). There were no effects on either male or female reproductive organs. Based upon the results of this study the NOEL for fertility is 3000 ppm (approximately 200 mg/kg bw/day).

In a study of the subchronic oral toxicity of TBEP by gavage (Laham, 1985), rats were dosed with 0.25 or 0.5 ml/kg (255 and 509 mg/kg bw/day) of undiluted TBEP. During the latter part of the study, 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 effects on either male or female reproductive organs. The NOEL for fertility was 509 mg/kg bw/day.

 Neither these key and supporting studies, nor other oral and dermal studies of shorter duration gave any alert for effects on male or female fertility and the developmental toxicity studies described below showed no evidence of developmental toxicity. A reproductive toxicity study is therefore considered to be of low priority and the screening for reproductive/developmental toxicity study OECD guideline 421 has not been performed.

Short description of key information: 

No specific studies on reproduction (fertility) are available. Data on effects on reproductive organs have been assessed from the key studies for subchronic oral toxicity studies via the diet, of duration 18 weeks (Reyna, 1987, Rel. 1) and 14 weeks (Saitoh, 1994, Rel. 2), with supporting data from an 18-week gavage study (Laham, 1985, Rel. 2).

Effects on developmental toxicity

Description of key information

The key studies chosen for developmental toxicity are a range-finding developmental toxicity study (Schardein, 1985, Rel. 2) and the peer-reviewed summary of the full developmental toxicity study (Monsanto, 1985, Rel. 2).

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 500 mg/kg bw/day
Additional information

The developmental toxicity of TBEP has been studied in rats.

 

In a range-finding developmental toxicity study, TBEP was administered by gavage in corn oil to groups of 5 mated Charles River CD female rats at dose levels of 0, 25, 250,and 2000 mg/kg bw/day on days 6 to 15 of gestation. At doses up to 1000 mg/kg bw/day, all rats survived. Two animals died or were sacrificed in the high dose group. Maternal toxicity (reduced righting reflex, hypoactivity, lethargy, ataxia and stained anogenital haircoat) was observed in the animals receiving 500 to 2000 mg/kg bw/day. Maternal weight gain was normal in animals receiving 1000 mg/kg bw/day or less. The treatment had no effect at any dose level on foetal resorption, foetal viability, postimplantation loss and total implantations.

 

The report of the full developmental toxicity study is not available, however the principal data have been summarised in two peer-reviewed publications (IPCS, 2000; ECETOC, 1992). TBEP was administered by gavage in corn oil to three groups of 25 mated Charles River CD female rats at dose levels of 250, 500 and 1500 mg/kg bw/day on days 6 to 15 of gestation. A fourth group served as a vehicle control. Maternal weight gain was depressed only in the high-dose group. The treatment had no effect at any dose level on foetal resorption, foetal viability, post-implantation loss, total implantations or incidence of foetal malformations.

The combination of the full range-finding study report and the peer-reviewed publication are considered adequate to cover the requirements for this endpoint. There was no indication in either study that TBEP induced any kind of embryo-foetal toxicity even at maternally toxic dose levels. The NOEL (development) was 1500 mg/kg/day.

Justification for classification or non-classification

The guidance for classification of a substance as toxic for reproduction, Category 3 according to the criteria ofAnnex VI Directive 67/748/EECor as suspected human reproductive toxicant Category 2 according to GHS criteria indicate that the substance should cause a strong suspicion of impaired fertility or of developmental toxicity other than general effects secondary to maternal toxicity in animal studies.

TBEP did not cause any adverse effects on male or female reproductive organs in repeated dose toxicity studies of up to 18 weeks at doses causing general toxicity. TBEP did not cause any embryofoetal toxicity in a developmental toxicity study according to OECD 414.

TBEP is therefore not classified for reproductive toxicity according to the criteria of Annex VI Directive 67/748/EECor UN/EU GHS.

Additional information