Ethanol, 2-methoxy-, manufacture of, by-products from, esters with boric acid

Endpoint summary

Description of key information

The NOAEL in a 28 day rat study was approximately 380 mg B-TTEGME/kg bw/day based upon a toxicity study with Brake fluid up to 1000 mg/kg bw/day. No adverse findings were observed up to highest dose level. The study can be used to define an interim DNEL for hazard characterization until data from the proposed 90d study become available. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

380 mg/kg bw/day

Additional information

The repeated dose toxicity of B-TTEGME was studied by read-across with data from Brake Fluid DOT 4 containing B-TTEGME. Similarity with B-TTEGME was based on a common functional group, common precursors an/or likelihood of common breakdown products and common constituents, as also described in a separated justification document in Section 13.

An oral subacute toxicity study (28 days) was performed with abrake fluidcontaining 38% B-TTEGME,of which ca. 45% was B-TEGME, corresponding with 17% B-TEGME in the tested brake fluid (Shell, 1993a). The test material was administered to rats at doses of 9.5, 57 and 380 mg B-TTEGME/kg bw/day, based upon doses of 25, 150 and 1000 mg brake fluid/kg bw/day. This study was conducted according to OECD 407 guideline and in compliance with GLP, therefore it was considered to be adequate, reliable and relevant. As it was performed with a brake fluid containing 38 % B-TTEGME, it was considered as a support study, and a 90 -day repeated dose toxicity study is proposed (see further). Dosing did not result in treatment related clinical signs, effects on body weight, clinical chemistry, haematology, gross pathology, organ weights and urinalysis. The only finding related to treatment was a very slight hepatocellular centrilobular hypertrophy at histology in males and some females at 380 mg B-TTEGME/kg/day or 1000 mg brake fluid/kg bw/day. Liver weight increases at this high dose compared to controls were approximately 7% in males and 3% in females. Considering the mild nature of the findings, and in the absence of any other relevant treatment related effect, this was not considered to constitute an adverse effect. The NOAEL was therefore considered to be at least 380 mg B-TTEGME/kg bw/day or 1000 mg brake fluid/kg bw/day. The other borated and non-borated glycol ethers and components present in the brake fluids also might have contributed to the findings.

Liver effects such as liver weight increase and histopathological hepatocellular hypertrophy in experimental animals have been described in literature (Andrew, 2005) as frequently observed and adaptive effects, often related to enzyme induction and metabolic breakdown of the products in the liver. A liver weight increase of <10% is generally considered to be non-adverse, while increases of 10% or more are interpreted as being potentially adverse. Liver enlargement associated with an increase in the activity of xenobiotic metabolising enzymes is an adaptation to increased functional load, and is therefore considered to be a physiological rather than a pathological response or adverse effect.

A 3 -month repeated dose toxicity with B-TTEGME was not available, but 90-day oral repeated dose toxicity study with B-TEGME has been proposed by the BGE Consortium. Based on the close structure similarity and similar toxicological profile of both borated glycol ethers, the study with B-TEGME is considered relevant to use from a read across viewpoint. Based upon the data from physicochemical and basic pharmacokinetic assessment, and based upon the 28 -day toxicity study with brake fluid, oral dosingis regarded as the most relevant route of administration for testing. The results of the 90 -day study will be important to decide on further testing or weight of evidence/waiving strategy with regard to reproductive toxicity, as separately described under the other sections (7.8.1 and 7.8.2) and the toxicology testing strategy document (attached).

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

As there are no adverse effects seen up to the doses tested, there is no need for classification. A slight effect was observed in the liver, however this was considered to be a physiological adaptive effect related to metabolism at high dosages.