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Description of key information

2-Butoxyacetic acid is the toxic metabolite of DEGDBE, responsible for the hemolytic effect. Humans are more resistent towards toxicity of 2-butoxyacetic acid. 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetic assessment:

DEGDBE is expected to be readily bioavailable via oral/dermal/inhalation routes.

DEGDBE is expected to undergo extensive metabolism. The presumed metabolites are 2 -(2-butoxyethoxy)acetic acid and 2 -butoxyacetic acid, which is supported by that these ompound are known to induce hemolysis and that clear indications of hemolysis were found in the available toxicity studies. 2 -Butoxyacetic acid is known to be far more potent than 2 -(2-butoxyethoxy)acetic acid.

In the 28 -day oral toxicity study, the urines obtained from DEGDBE treated rats were analyzed for 2 -butoxyacetic acid. No bioaccumulation property can be derived based on the very low values obtained from rats that were allowed to recover.

Study summary:

Rats were treated via gavage with DEGDBE at doses of 0. 25. 100. 250 and 750 mg/kg bw for up to 28 days. The 24 -h urine samples were collected after 8 day and 28 day treatment and after recovery phase of up to 14 days and analyzed for the presumed toxic metabolite 2 -butoxyacetic acid. The obtained values were dose dependent and ranged to 1400±600 mg/L. Comparable values were obtained in the samples of 28 -day treatment, indicating that steady-state of 2 -BAA systemic burden was established within the treatment period. An efficient 2 -butoxyacetic acid clearance could be demonstrated by low levels of 2 -BAA for recovery animals.

Discussion on the results and relevance to other endpoints:

- The study confirms the 2 -butoxyacetic acid as the metabolite of DEGDBE in rats. Together with the known toxicity profile of DEGDBE (hemolysis), it is reasonably to conclude 2 -butoxyacetic acid as the toxic metabolite of DEGDBE and the systemic exposure to 2 -butoxyacetic acid as the mode of action of DEGDBE. Therefore, the read-across appraoch used for endpoints developmental toxicity, repeated dose toxicity and skin sensitization potential is justified.

- Further, the study result is to be used to justify the no need of a 2-generation study, because it is known that 2 -butoxyacetic acid does not induce testicular toxicity. It is not likely that there will be any new effects in the 2 -generation study that were not present in the provided OECD 421 study or in the available developmental toxicity studies on DEGDBE or on its source chemicals.

- The values obtained for rats treated for 8 days and 28 days were comparable, indicating that the steady-state was established in the early phase of the treatment period. Further, the values obtained for the recovery animals are indicative of a very efficient clearace. A significant bioaccumulating potential cannot be derived. The NOAEL obtained in the 28 -day study was 100 mg/kg bw based that there were indications of hemolysis at 250 mg/kg bw. Considering that the effects found at 250 mg/kg bw were actually not associated with adverse health effect , no significant effect after prolonged exposure up to the dose of 100 mg/kg bw can be derived. The provided 28 -day toxicity study is considered to be sufficiently reliable to derive the chronic toxicity.

- The proposed read-across approach includes the use of data on ethyleneglycolbutylether (EGBE). It is well acknowleged that EGBE induce its toxic effects via 2 -butoxyacetic acid and that humans are resistent to 2 -butoxyacetic acid. The existing official reviews on EGBE are of the opinion that there is no significant concern for humans. Likewise, no concern can be derived for DEGDBE.

- Finally, the study results together with all the consideration mentioned above justify the DNEL derivation (no AF for duration exposure; no AF for additional factor for interspecies extrapolation; an AF of 2.5 for interspecies extrapolation).