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Administrative data

Description of key information

Data are available for the read-across substance TAME. A NOAEC of 250 ppm (1060 mg/m3) is selected for inhalation exposure based on the organ (liver, adrenals and kidneys) weight increases seen in the 90 day study with male and female F-344 rats.
For the oral route, a NOAEL of 125 mg/kg bw/day is selected based on an increased adrenal (absolute and relative) and kidney (relative) weight at the higher doses in male rats in the 28 days study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
1 060 mg/m³

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 repeated dose toxicity of the substance ‘C5-6 branched alkylmethyl-ethers’ with sufficient certainty.

Regarding the oral route, a subacute toxicity with rats is available for TAME. Five male and five female Sprague-Dawley rats were administered 0, 125, 500 or 1000 mg/kg bw TAME in corn oil by gavage (Daughtrey et al., 1995a). The dose was given once daily, 7 days a week for a period of 29 days. The critical effects observed were an increased adrenal (absolute and relative) and kidney (relative) weight at 500 and 1000 mg/kg bw in males. The organ weight increases in the kidney and adrenals were not accompanied by any histopathological changes. The liver weights were not statistically significantly affected. The NOAEL was set at 125 mg/kg bw/day.

For inhalation repeated dose toxicity, two 90 days studies are available for TAME, one with rats and one with mice (Huntingdon Life Sciences, 1997a/b). In addition, a subacute toxicity study with rats is available (IIT Research Institute, 1992). The 90 days studies are considered key (longer exposure duration, lower NOAEC). In these studies the exposure concentrations were 250, 1500 and 2500 / 3500 ppm (1060, 6360, 10600 / 14840 mg/m3).

 

In mice, the critical effect was an increase in the labeling index of hepatocytes in high- and mid-exposure males and females and low-exposure females. There was microscopic evidence of centrilobular, hepatocellular hypertrophy in high- and mid-exposure males and females. Based on these findings, the NOAEC for male mice exposed to TAME was 250 ppm (1060 mg/m3); a NOAEC for female mice was not established by the study authors. However, given the absence of dose-response in the female liver proliferation findings and their transient nature, the EU concluded in their risk assessment report that the NOAEC can be set at 250 ppm (1060 mg/m3) for both males and females.

In rats, effects critical for setting the NOAEC were (relative) organ weights increases in male and female liver, adrenals and kidney. Increased weights in the absolute and relative adrenal weights in the 3500 and 1500 ppm males and females and 250 ppm males were explained by the investigators as a response to stress due to the exposure to the test material. They did not consider this a direct effect of the test material because there were no microscopic lesions in the adrenals. Only male rats showed α-2µ-syndrome-related cell proliferation of the kidney tubules, which could have attributed to the weight change in male kidneys at 3500 ppm. The increase in the female kidney weights at 3500 and 1500 ppm could not be explained by any toxicological phenomenon. After the 4-week recovery period, the high dose males and females had increased kidney to body weights, although the absolute and kidney to brain weights were comparable to control values.

The investigators set the NOAEC to 250 ppm (1060 mg/m3) for females based on the increased liver and kidney weights at 1500 ppm. Based on the liver weight increase at all dose groups, no NOAEC can be set for males. While liver weight increase is a typical form of adaptation and could be seen as non-adverse, it is more difficult to account for the adrenal or especially the kidney weight increases simply as adaptive. It is debatable whether, e.g., the adrenal organ weight increases with no adverse changes in microscopy or blood values can be discounted as “indirect” or “stress-related”. However, although there was an 8% increase in kidney/brain weight and a 10% increase in adrenal/brain weight in males at 250 ppm, this level was not qualified as a LOAEC by the EU (conclusion from the EU risk assessment report). The weight increases were statistically significant only when presented as absolute weight or organ/brain weight values. Since the body weight of the low dose males also increased (+9%), a factor that may have played a contributing or confounding role, and since there was no histopathological damage present in these animals, the exposure level of 250 ppm (1060 mg/m3) was considered as a NOAEC.

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 repeated dose toxicity.

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