Review
A safety assessment of branched chain saturated alcohols when used as fragrance ingredients

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Abstract

The Branched Chain Saturated Alcohol (BCSA) group of fragrance ingredients was evaluated for safety. In humans, no evidence of skin irritation was found at concentrations of 2–10%. Undiluted, 11 materials evaluated caused moderate to severe eye irritation. As current end product use levels are between 0.001% and 1.7%, eye irritation is not a concern. The materials have no or low sensitizing potential. For individuals who are already sensitized, an elicitation reaction is possible. Due to lack of UVA/UVB light-absorbing structures, and review of phototoxic/photoallergy data, the BCSA are not expected to elicit phototoxicity or photoallergy. The 15 materials tested have a low order of acute toxicity. Following repeated application, seven BCSA tested were of low systemic toxicity. Studies performed on eight BCSA and three metabolites show no in vivo or in vitro genotoxicity. A valid carcinogenicity study showed that 2-ethyl-1-hexanol is a weak inducer of liver tumors in female mice, however, the relevance of this effect and mode of action to humans is still a matter of debate. The Panel is of the opinion that there are no safety concerns regarding BCSA under the present levels of use and exposure.

Introduction

In 2006 complete literature searches were conducted on the branched chain saturated alcohol group of fragrance ingredients. This document provides a risk assessment of these materials as fragrance ingredients and is a critical evaluation of the pertinent data. The scientific evaluation focuses on dermal exposure, which is considered to be the primary route for fragrance materials. Where relevant, toxicity, metabolism and biological fate data from other exposures have been considered.

The current format includes a group summary evaluation paper and individual Fragrance Material Reviews on discrete chemicals. The group summary is an evaluation of relevant data selected from the large bibliography of studies and reports on the individual chemicals. The selected data were deemed to be relevant based on the currency of protocols, quality of the data, statistical significance and appropriate exposure. These are identified in tabular form in the group summary. Details that are provided in the tables are not always discussed in the text of the group summary. The Fragrance Material Reviews contain a comprehensive summary of all published reports including complete bibliographies (McGinty et al., 2010a, McGinty et al., 2010b, McGinty et al., 2010c, McGinty et al., 2010d, McGinty et al., 2010e, McGinty et al., 2010f, McGinty et al., 2010g, McGinty et al., 2010h, McGinty et al., 2010i, McGinty et al., 2010j, McGinty et al., 2010k, McGinty et al., 2010l, McGinty et al., 2010m, McGinty et al., 2010n, McGinty et al., 2010o, McGinty et al., 2010p, McGinty et al., 2010q).

Section snippets

Rationale for grouping branched chain saturated alcohols together

The group consists of 12 primary, 5 secondary and 3 tertiary alcohols. Of these materials, three have been previously reviewed in RIFM’s Safety Assessment on Terpene Alcohols (Belsito et al., 2008). The names and structures of the materials reviewed are shown in Table 1.1 In

Primary alcohols

When 25 mmoles (2.55 g) of 2-ethyl-1-butanol were administered by gavage to rabbits, 40% of the dose was excreted in the urine as the glucuronide conjugate. The excretion of glucuronide was completed within 24 h (Kamil et al., 1953a). A rabbit was given 3.1 ml (2.55 g) 2-ethyl-1-butanol and the 24-h urine was collected. 2-Ethyl-1-butanol was excreted mainly as diethylacetylglucuronide and a minor amount of methyl n-propyl ketone was also found (Kamil et al., 1953b).

Main metabolites of

Dermal route of exposure

In vitro absorption rates for 2-ethyl-1-hexanol were 0.22 ± 0.09 and 0.038 ± 0.014 mg/cm2/h for rat and human skin, respectively, giving a rat/human ratio of 5.78. The permeability constants were 2.59 ± 1.10 × 10−4 cm/h for rats and 4.54 ± 1.66 × 10−5 cm/h for humans (Barber et al., 1992).

The dermal absorption in the rat was determined to be 5.2% of a dose of 1000 mg 2-ethyl-1-hexanol/kg body weight applied for 6 h; the absorption rate was calculated to be 0.57 mg/cm2/h. The terminal half-life was calculated to

Acute toxicity

Acute dermal toxicity studies have been performed with six primary, three secondary, and three tertiary alcohols, all but one in rabbits. The dermal LD50 values in rabbits and the one in rats are in the range of 1000–>5000 mg/kg body weight. In summary all the compounds are of low acute toxicity by the dermal route (Table 2-1).

Eight primary alcohols, four secondary, and three tertiary alcohols have been tested for oral acute toxicity. The oral LD50 values in rats, mice, and rabbits are in the

Conclusion

The compounds assessed in this group have a close structural relationship, similar metabolism, and toxicity profiles.

Data on metabolism for the compounds under review are available only for the primary alcohols 2-ethyl-1-butanol, 2-ethyl-1-hexanol, isoamyl alcohol, 2-methylbutanol, and for the secondary alcohol 4-methyl-2-pentanol.

The major pathways of metabolism and fate which are common to the primary, secondary and tertiary alcohols in this group are:

  • conjugation of the alcohol group with

Conflict of interest statement

This research was supported by the Research Institute for Fragrance Materials, an independent research institute that is funded by the manufacturers of fragrances and consumer products containing fragrances. The authors are all members of the Expert Panel of the Research Institute for Fragrance Materials, an independent group of experts who evaluate the safety of fragrance materials.

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