3-methoxybutan-1-ol

Endpoint summary

Additional information

3-methoxybutan-1-ol (CAS 2517-43-3, EC No 219-741-8) is a colorless liquid with a mild odor. Chemically, it is an branched chain methoxy alcohol. The compound is miscible in water and has a log Pow value of 0,002 (Table 1).

Due to common structures, common metabolism and common toxic effects, branched chain saturated alcohols have been treated as a group by various scientific bodies and regulatory agencies. For example, an Expert Panel put together by the Research Institute for Fragrance Materials (RIFM) recently published “A safety assessment of branched chain saturated alcohols when used as fragrance ingredients” (Belsito et al., 2010), the World Health Organization (WHO) has similarly published a safety assessment of the grouping of “Aliphatic Branched-Chain Saturated and Unsaturated Alcohols, Aldehydes, Acids, and Related Esters” (WHO Food Additive Series:52), and an assessment of “Linear and branched-chain aliphatic, unsaturated, unconjugated alcohols, aldehydes, acids, and related esters (WHO, 1999). The group of saturated alcohols and related esters (and acetyls that are rapidly metabolized to alcohols) is sometimes broken down into primary (EFSA, 2012a), secondary (EFSA, 2016), and tertiary (WHO, 2008) alcohol groups, including their acetyl and ester counterparts that are rapidly metabolized to the alcohols. The metabolism of members of the group of linear and branched-chain alcohols and related esters (and acetyls that are rapidly metabolized to alcohols) can be easily predicted because of their close structural relationship to endogenous substrates and the broad substrate specificities of the relevant enzymes. The prediction that the metabolites would be innocuous is supported by available data on the toxicity of members of this group (WHO. 1999). Although not specifically included in the groupings of primary alcohols (and related esters and acetyls that are rapidly metabolized to alcohols) evaluated by WHO, RIFM, and EFSA for flavorings, fragrances, and feed additives, respectively, 3-methoxybutan-1-ol and its parent and proximate metabolite (i.e., 3-methoxybutyl acetate and 1,3-butanediol) clearly belong to these groupings.

The metabolic pathway for branched chain primary alcohols, including 3-methoxybutan-1-ol and 1,3-butanediol, as outlined by WHO (2010) starts with“…beta oxidative cleavage to yield intermediates of the amino acid and/or fatty acid metabolic pathways. These intermediates are completely metabolized to CO₂via the tricarboxylic acid cycle. As chain length and substitution increase the alcohols and aldehydes undergo a combination of omega-, omega-1 and beta oxidation, and selective dehydrogenation and hydration to yield polar acidic metabolites. Therefore, all of the flavouring agents in this group will eventually be either completely oxidized or oxidized to polar metabolites that are excreted primarily in the urine.”Similarly, a RIFM expert panel (Belsito et al., 2010) concluded that“the major pathway and metabolism and fate are: conjugation of the alcohol group with glucuronic acid, oxidation of the alcohol group, side chain oxidation yielding polar metabolites, which may be conjugated and excreted – or further oxidized to an aldehyde, a carboxylic acid, and to CO₂; and excretion of the unchanged parent compound.”The authors (Belsito et al., 2010) went further to say “In most cases, the metabolism yields innocuous metabolites. Intermediary reactive products of oxidation of primary alcohols are aldehydes, which are toxic and possibly genotoxic, although no relevant genotoxicity was shown with the primary alcohols tested.”

In support of the above, detailed metabolism studies on a methoxyethanol (a primary alcohol) closely structurally-related to 3-methoxybutan-1-ol (Target Substance) have been provided by Sumner et al. (1992, 1995). Those studies showed that the primary metabolic pathway of the alcohol involves conversion to methoxyacetic acid which is either conjugated and directly excreted or (preferentially) conjugated with Coenzyme A and either enters the Krebs cycle and undergoes further catabolism to CO₂or enters the anabolic fatty acid synthesis pathway. Minor metabolic pathways (i.e., less than 15% of total metabolites) include: direct conjugation of the alcohol to glucuronide, direct conjugation of the alcohol to sulfate, or demethylation to the di-alcohol (ethylene glycol) which is ultimately converted to glycine.

References

Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H. Hanifin, J.M., Rogers, A.E., Saurat, H.H., Sipes, I.G., and H. Tagami. 2010. A safety assessment of branched chain saturated alcohols when used as fragrance ingredients. Food and Chem. Toxicol. 48(2010): S1 -S46.

EFSA. 2012a. Scientific Opinion and the safety and efficacy of branched-chain primary aliphatic alcohols/aldehydes/acids, acetals and esters with esters containing branched-chain alcohols and acetals containing branched chain aldehydes (chemical group 2) when used as flavourings for all animal species. Efsa Panel on Additives and Products or Substances used in Animal Feed (FEEDAP). EFSA Journal 2012; 10(10):2927

EFSA. 2016. Safety and efficacy of secondary alicyclic saturated and unsaturated alcohols, ketones, ketals and esters with ketals containing alicyclic alcohols or ketones and esters containing secondary alicyclic alcohols from chemical group 8 when used as flavourings for all animal species. EFSA Journal. EFSA-Q-2010.01108. Adopted 20 April 2016. Doi: 10.2903/j.efsa.2016.4475.

Sumner, S.C.J., Stedman, D.B., Clarke, D.O., Welsch, F. and T.R. Fennell. 1992. Characterization of Urinary Metabolites from [1,2,methoxy-13C]-2-methoxyethanol in Mice Using 13C Nuclear Magnetic Resonance Spectroscopy. Chem. Res. Toxicol. 5: 553-560.

Sumner, S.J., Stedman, D.B., Cheng, SY., Welsch, F. and T.R. Fennel. 1995. Dose Effects on the Excretion of Urinary Metabolites of 2 -[1,2,methoxy-13]Methoxyethanol in Mice. Toxicol Appl. Pharmacol. 134:139-147.

WHO. 1999. Linear and Branched-Chain Aliphatic, Unsaturated, Unconjugated alcohols, Aldehydes, Acids, and Related Esters. Prepared by the Fifty-first meeting of the joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Food Additives Series: 42.

WHO. 2008. Safety Evaluation of Certain Food Additives and Contaminants. WHO Food Additives Series: 59. Prepared by the 68th meeting of the Joint WHO/FAO Expert Committee on Food Additives. Aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally-related substances (addendum). Pages 151-174.

WHO. 2010 (DRAFT). Aliphatic Branched-Chain Saturated and Unsaturated Alcohols, Aldehydes, Acids, and Related Esters. World Health Organization. WHO Food Additives Series: 52.