Dibutyl maleate

Endpoint summary

Additional information

In an industrial setting, dibutyl maleate is synthesized via chemical esterification of n-butanol and maleic acid. Based on the expected metabolism of diesters, butyl hydrogen maleate, maleic acid, maleic anhydride and n-butanol were selected as the most suitable read-across substances for DBM, as they represent metabolic/chemical breakdown products of DBM. Butyl hydrogen maleate is the initial product resulting from the action of esterases in vivo, and can also result from chemical hydrolysis under certain conditions. Butyl hydrogen maleate retains one ester moiety, and re-introduces one of the carboxylic acid moieties that were present in the raw material. Maleic acid results from the complete de-esterification and/or chemical hydrolysis of DBM. Although hydrolysis of DBM (either enzymatic or non-enzymatic) most likely results in the formation of maleic acid as a metabolite, maleic anhydride was included as a potential read-across candidate because of its high reactivity with water, which means that it is rapidly converted to maleic acid in biological systems.

Comparing the target organ and adverse effects of DBM, butyl hydrogen maleate, and maleic anhydride/maleic acid shows that all four substances cause similar adverse effects in the kidneys (i.e. the same pattern of toxicological activity), which corroborates the presence of similar functional groups, which then further supports use of these substances as read across substances because they fulfill the criterion "The similarities may be based on: […] (2) […] or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals;" (REACH Annex XI, Section 1.5.)

Following the progressive hydrolysis of DBM to its parent constituents, reproductive effects, if present, would most likely be related to the maleic acid anion. This is also corroborated by the fact that the remaining metabolite, n-butanol, does not reveal any adverse effects on reproduction and development (Nelson et al., 1989; Ema et al., 2005).

Similar read across evaluations were conducted by U.S. EPA HPV for the diesters category (U.S. EPA, 2008; 2006a) and by EFSA (2012) for the evaluation of flavouring substances including mono- and diesters as it was summarized by the Panel:

 "mono- and diesters included in the present FGE are expected to undergo hydrolysis in humans to yield their corresponding alcohol (linear or branched-chain aliphatic alcohols) and acid components (i.e. alpha-, beta- or gamma-keto or hydroxy acids; or simple aliphatic acids, diacids or triacids), which would be further metabolized and excreted.”.....”The majority of degradation products yielded from the candidate ester hydrolysis are endogenous in mammals and are known to be completely metabolised, through different reactions, depending on their chain length and degree of branching and functional groups."

It is likely that multiple metabolic reactions will occur for some hydrolysis products. The most probable metabolic reactions are the following:

•          Oxidation of alcohol to aldehydes and acids

•          Conjugation of alcohols and acids to glucuronides and sulphates

•          Beta-oxidation of carboxylic acids

•          Omega-oxidation of carboxylic acids”

Therefore, DBM, as a diester from a linear aliphatic alcohol and a dicarboxylic acid, is expected to follow a similar breakdown and excretion pattern, producing the corresponding alcohol and acid. This assumption is supported by performing a metabolism/hydrolysis simulation using QSAR. The predicted metabolites of maleic acid, butyl hydrogen maleate and n-butanol were in agreement with the results starting with the substance of record, DBM, the dibutyl ester of maleic acid.

Comparing the effects of DBM, butyl hydrogen maleate, and maleic anhydride/maleic acid shows that all substances cause similar renal effects (i.e. the same pattern of toxicological activity) and can thus be used as read across substances because they fulfil the criterion "The similarities may be based on: […] (2) […] or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals;" (REACH Annex XI, Section 1.5.) Maleic anhydride can be regarded as suitable for read across, but shows no developmental effects. Thus, it can be concluded that the same predicted outcome would be expected for DBM.

In the case of DBM and butyl hydrogen maleate, reproductive effects, if any, would be related to the maleic acid anion, which is the core structure for DBM, butyl hydrogen maleate, and maleic anhydride. The corresponding linear alcohol n-butanol does not reveal any adverse effects on reproduction and development (Nelson et al., 1989; Ema et al., 2005). Studies conducted with maleic anhydride showed that no adverse reproductive or teratological effects are induced by the maleic anion. Therefore, it is justified to use data from the dossier for maleic anhydride for read-across to DBM.

In summary, because of the systemic toxicity observed in the kidneys with substances with similar chemical core structure such as DBM, butyl hydrogen maleate, and maleic anhydride/maleic acid, in repeated dose studies from 2 to 13 weeks in rats, it is concluded that this group of substances behaves similarly due to the presence of the same maleic acid chemical core structure.

More importantly, the lack of developmental and reproductive toxicity in multi-generation studies with maleic anhydride/maleic acid studies allows the conclusion that there is no reason to expect any adverse developmental and/or reproductive effects in rats expose to DBM except when severe maternal toxicity occurs. The use of toxicity data from maleic anhydride/maleic acid and butyl hydrogen maleate is justified for this read across evaluation.

 

References

EFSA (2012) EFSA Journal 2012; 10(3):2563 "Scientific Opinion on Flavouring Group Evaluation 10, Revision 3 (FGE.10Rev3): Aliphatic primary and secondary saturated and unsaturated alcohols, aldehydes, acetals, carboxylic acids and esters containing an additional oxygenated functional group and lactones from chemical groups 9, 13 and 30", EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF);European Food Safety Authority (EFSA), Parma, Italyhttp://www.efsa.europa.eu/en/efsajournal/pub/2563.htm

Ema M, Hara H, Matsumoto M, Hirose A, Kamata E.(2005) Evaluation of developmental toxicity of 1-butanol given to rats in drinking water throughout pregnancy. Food Chem Toxicol. 2005 Feb; 43(2):325-31.

Nelson BK, Brightwell WS, Robertson SK, Kahn A, Krieg Jr EF, Massari VJ (1989) Behavioral Teratology Investigation of 1-Butanol in Rats. Neurotoxicology and Teratology 11: 313-315.

U.S. EPA HPV (2006a) Comments on Chemical RTK HPV Challenge Submicron Diesters Category. Summary of EPA Comments on the Diesters Category Challenge Submission. Category Definition. Category Justification. Analog Justification. Test Plan. April 26, 2006.

U.S. EPA HPV (2008) Supporting Documents for Risk-Based Prioritization Supporting Documents for Initial Risk-Based Prioritization of High Production Volume Chemicals Diesters Categoryhttp://www.epa.gov/hpvis/rbp/Cat_Diesters_Web_SuppDocs_Sept2008.pdf