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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
12 720 mg/m³
Species:
rat
Additional information
The reproductive toxicity of TAEE was studied in a GLP-compliant OECD 422 guideline study in which male and female rats received 0, 100, 375 or 750 mg/kg bw/day by oral gavage in corn oil (Covance Laboratories Ltd, 2009d). Males were dosed for up to 8 weeks, females for approximately 6 weeks. The NOAEL for systemic (parental) toxicity was 100 mg/kg bw/day based on increased ALT activity in females and significant increased relative liver weights accompanied by diffuse enlargement of the hepatocytes without the normal zonal pattern in males at mid- and high-dose levels, and increased adrenal weights in both sexes at the high dose level (see section on repeated dose toxicity). Regarding effects on fertility, there was no effect of treatment on fertility (mating index, pregnancy rate, implantations, gestational length etc). Qualitative testis staging did not indicate any abnormalities in the integrity of the various cell types present within the different stages of the spermatogenic cycle and hence there was no effect of treatment on spermatogenesis. The NOAEL for reproductive toxicity was 750 mg/kg bw/day, the highest dose tested.

 

The negative result regarding effects on fertility in this OECD 422 investigation is supported by the two-generation studies for the structural analogues TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane).

TAME:

A well-conducted two-generation reproductive toxicity study (in accordance with US EPA guidelines and GLP compliant) with Sprague Dawley rats is available (CIIT, 1998). In that study, statistically significant changes in abnormal sperm counts were reported at 1500 ppm and 3000 ppm. These changes were however within the ranges of historical controls. Moreover they did not affect the reproductive parameters. Therefore the NOAEC for effects on fertility is set to 3000 ppm (12720 mg/m3), the highest concentration tested. The NOAEC for parental toxicity was 250 ppm (1060 mg/m3) based onchanges in liver, adrenal and kidney weights, reduction in body weight and general signs of toxicity to the central nervous system, such as ataxia.

ETBE:

A two-generation reproductive toxicity study by the oral route in Sprague-Dawley rats, performed according to OECD Guideline 416 and under GLP (CIT, 2004a), did not show any effect on mating, fertility, gestation, fecundity or delivery or sperm parameters. No effects were observed on the progeny from delivery until weaning. Therefore, the NOAEL for effects on fertility is 1000 mg/kg bw/day, the highest does tested. The NOAEL for adult toxicity was 250 mg/kg bw/day based on a statistically significant reduction in body weight gain in F0 males, an increased absolute and relative kidney weight in F0 and F1 males and increased absolute and relative liver weights in F1 males at 500 mg/kg bw/day.


Short description of key information:
The available data do not indicate that TAEE causes effects on fertility.

Effects on developmental toxicity

Description of key information
The available data do not indicate that TAEE causes developmental toxicity.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 060 mg/m³
Additional information

The developmental toxicity of TAEE was studied in a GLP-compliant OECD 422 guideline study in which male and female rats received 0, 100, 375 or 750 mg/kg bw/day by oral gavage in corn oil (Covance Laboratories Ltd, 2009d). Males were dosed for up to 8 weeks, females for approx. 6 weeks. The NOAEL for systemic (parental) toxicity was 100 mg/kg bw/day based on the increased ALT activity in females and significantly increased relative liver weights accompanied by diffuse enlargement of the hepatocytes without the normal zonal pattern in males at mid- and high-dose levels, and increased adrenal weights in both sexes at the high dose level (see section on repeated dose toxicity). Regarding developmental toxicity, there was no effect of treatment on pup parameters (pup numbers, litter size, survival to PND 4, body weights etc). The NOAEL for developmental toxicity was 750 mg/kg bw/day, the highest dose tested.

For the structural analogues TAME (2-methoxy-2-methylbutane) and ETBE (2-ethoxy-2-methylpropane), developmental toxicity studies are available.

TAME:

A developmental toxicity study with rats and a study with mice, both performed according to EPA guidelines and under GLP, were available (CIIT, 1997a,b). In rats, developmental toxicity effects were reported at concentrations at which also maternal toxicity was observed. In mice, malformations (cleft palate) at 1500 ppm and 3500 ppm (NOAEC of 250 ppm (1060 mg/m3)) were observed. There was clear maternal toxicity in the high dose animals (mice: 3500 ppm), while the signs of toxicity were less obvious in the intermediate dose for mice (1500 ppm). The available data do not trigger classification for developmental toxicity. Overall, the lowest NOAECs for developmental toxicity of the above studies is comparable with the NOAEC for repeated dose toxicity (250 ppm (1060 mg/m3)) which is taken as starting point for the DNEL derivation of TAEE.

ETBE:

Prenatal developmental toxicity by the oral route was studied in Sprague-Dawley rats.The study was performed in agreement with OECD guideline 414 and under GLP (CIT, 2004b).The study did not show developmental effects. The NOAEL for developmental toxicity was 1000 mg/kg bw/day (the highest dose tested) and the NOAEL for maternal toxicity was 500 mg/kg bw/day (decreased maternal body weight gain).

Justification for classification or non-classification

In accordance with Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification is not necessary for effects on fertility and developmental toxicity.