Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

Based on the considerations described in the document "Read-across substantiation C5-6 branched alkylmethyl-ethers” (incl. the supporting references Tuppurainen et al., 2007 and Niska et al., 2008), it can be concluded that the available information of TAME can be used to predict the fertility effects of the substance ‘C5-6 branched alkylmethyl-ethers’ with sufficient certainty.

A well-conducted two-generation reproductive toxicity study regarding TAME with 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 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 NOAEC for parental toxicity was 250 ppm (1060 mg/m3). Toxicity to offspring was seen at 1500 ppm leading to a NOAEC of 250 ppm (1060 mg/m3) for developmental effects.

Short description of key information:
Data are available for the read-across substance TAME. TAME did not cause effects on fertility. The NOAEC for parental toxicity is 250 ppm (1060 mg/m3), for effects on fertility 3000 ppm (12720 mg/m3, the highest concentration tested) and for offspring toxicity 250 ppm (1060 mg/m3).

Effects on developmental toxicity

Description of key information
Data are available for the read-across substance TAME. In the rat developmental toxicity weight reductions were observed in litters at 3500 ppm (14840 mg/m3) (NOAEC for developmental toxicity: 1500 ppm (6360 mg/m3), maternal NOAEC: 250 ppm (1060 mg/m3)).
Toxicity to offspring in the 2-generation study with rats (NOAEC of 250 ppm (1060 mg/m3)) was also observed at concentrations at which also maternal toxicity was observed (maternal NOAEC: 250 ppm (1060 mg/m3)).
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; rats: 1500 and 3000 ppm), while the signs of toxicity were less obvious in the intermediate dose for mice (1500 ppm).
Additional information

Based on the considerations described in the document "Read-across substantiation C5-6 branched alkylmethyl-ethers” (incl. the supporting references Tuppurainen et al., 2007 and Niska et al., 2008), it can be concluded that the available information of TAME can be used to predict the developmental toxicity of the substance ‘C5-6 branched alkylmethyl-ethers’ with sufficient certainty.

In the developmental toxicity study regarding TAME with rats (CIIT, 1997a), maternal toxicity was present at 1500 and 3500 ppm and it was manifested as reduction of body weight, reduction of weight gain and various clinical signs, especially at the top dose group. The NOAEC for maternal toxicity is therefore set at 250 ppm (1060 mg/m3). Based on the weight reductions seen in the litters at 3500 ppm and the absence of embryo-foetal effects at 250 or 1500 ppm doses, 1500 ppm (6360 mg/m3) is chosen as the NOAEC for developmental toxicity in Sprague-Dawley rats.

In the two-generation reproductive toxicity study regarding TAME with rats, toxicity to offspring was seen at 1500 ppm leading to a NOAEC of 250 ppm (1060 mg/m3) for developmental effects. The NOAEC for parental toxicity was 250 ppm (1060 mg/m3) in this study.

 

In the developmental toxicity study regarding TAME with mice (CIIT, 1997b), malformations (cleft palate) were observed at 1500 and 3500 ppm. Regarding maternal toxicity, four dams died during the first four days of exposure in the 3500 ppm dose group. At 1500 and 3500 ppm, maternal liver absolute and relative weights were significantly increased. The toxicity noted at 1500 ppm (11% relative liver weight increase) is likely to represent a slight adaptation of the liver rather than representing significant maternal toxicity, which would account for the foetal malformations. Based on the 90 day study, it is likely that the animals were lethargic and prostrate during exposure at 1500 ppm, which could have contributed to maternal stress. However, no clear mechanism could be attributed to cleft palate seen in mice. Nevertheless, the available data are not considered sufficient for classification of TAME for developmental toxicity. The NOAEC for developmental effects is set to 250 ppm (1060 mg/m3) based on the malformations (cleft palate) seen at 1500 (6360) and at a higher incidence at 3500 ppm (14840 mg/m3) in mice.

Overall, the lowest NOAECs for developmental toxicity of the above studies are comparable with the NOAEC for repeated dose toxicity (250 ppm (1060 mg/m3)) which is taken as starting point for the DNEL derivation.

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 of TAME is not necessary for reproductive and developmental toxicity.

Based on the proposed read-across approach, this non-classification does also apply for C5-6 branched alkylmethyl-ethers.