Elsevier

Toxicology Letters

Volume 131, Issue 3, 28 May 2002, Pages 147-151
Toxicology Letters

Dermal absorption and disposition of musk ambrette, musk ketone and musk xylene in human subjects

https://doi.org/10.1016/S0378-4274(01)00548-3Get rights and content

Abstract

Musk ambrette, musk ketone and musk xylene have a long history of use as fragrance ingredients, although musk ambrette is no longer used in fragrances. As part of the review of the safety of these uses, it is important to consider the systemic exposure that results from these uses. Since the primary route of exposure to fragrances is on the skin, dermal doses of carbon-14 labelled musk ambrette, musk ketone and musk xylene were applied to the backs (100 cm2) of healthy human volunteers (two to three subjects) at a nominal dose level of 10–20 μg/cm2 and excess material removed at 6 h. Means of 2.0% musk ambrette, 0.5% musk ketone and 0.3% musk xylene were absorbed based on the amounts excreted in urine and faeces during 5 days. Most of the material was excreted in the urine with less than 10% of the amount excreted being found in faeces. No radioactivity was detected in any plasma sample, consistent with low absorption, and no radioactivity was detected (<0.02% dose) in skin strips taken at 120 h. Analysis of urine samples indicated that all three compounds were excreted mainly as single glucuronide conjugates. The aglycones were chromatographically different, but of similar polarity, to the major rat metabolites excreted in bile also as glucuronides.

Introduction

Several nitroaromatics, known as nitromusks are or have been used as fragrance ingredients (Ford, 1998). Three of these, musk ambrette, musk ketone and musk xylene (Fig. 1) were at one time the most important, although musk ambrette was withdrawn from use primarily due to its rare, but confirmed photosensitization effect in humans (Cronin, 1984). At high doses it also causes neurotoxic and reproductive effects in rats (Spencer et al., 1984). Musk ketone and musk xylene do not exhibit these toxic effects and continue to be used as fragrance ingredients. Musk xylene has been shown to cause an increase in hepatocellular adenomas and carcinomas in a 2-year dietary feeding study (Maekawa et al. 1990) although there is evidence that it is a non-genotoxic murine carcinogen. The toxicity profiles of these compounds have been established in rats and as part of this programme the absorption, distribution, metabolism and excretion of dermal doses have been investigated using radiolabelled compounds (Hawkins and Ford, 1999). Means of about 40, 31 and 19% of a single dose (0.5 mg/kg, 11 μg/cm) under occlusion for 6 h of musk ambrette, musk ketone and musk xylene, respectively, were absorbed. The data from these studies were used to obtain approval by an ethical review board for the simulated exposure studies in human volunteers, which are reported here. An evaluation of the systemic human exposure that may result from use of products containing these materials provides critical information for risk assessment, particularly since it is well known that dermal absorption is often considerably lower in humans compared to rats (Wester and Noonan, 1980). It has been reported (Ford, 1998) that the highest use levels of the nitromusks in cosmetic products are found in hydroalcoholic product such as perfumes and colognes. Since such uses result in the highest exposures and since it is assumed that dermal absorption and the resulting systemic exposures will be enhanced by ethanol (Hotchkiss, 1998), a study was designed to determine the systemic availability under conditions simulating the use of such products, e.g. in ethanol on the skin with wash-off 6 h after exposure. The total maximum daily exposure is estimated to be about 10 mg/day therefore a single application of 1–2 mg to an area of about 100 cm used in these investigations was considered to simulate human exposure.

Section snippets

Chemicals

Samples of the non-radiolabelled and carbon-14 uniformly ring-labelled musks were obtained as described by Hawkins and Ford (1999). A sample of O-desmethyl musk ambrette was synthesised at Huntingdon Research Centre by demethylation of 14C-labelled musk ambrette using pyridine hydrochloride.

Subjects

A total of seven healthy adult male volunteers of similar build were enrolled for the studies, which were conducted on three separate occasions. Three subjects participated in the study on musk ambrette, two

Results

The systemic availability as determined based on the excretion of radioactivity in urine and faeces was very low for all three compounds (Table 1). Most of the applied material was recovered from the surface of the skin as well as from the protective gauze at 6 h. Due to the rather low recoveries in two subjects treated with musk ambrette, a third subject was included. The urinary excretion ranged from 1.2 to 3.2% of the applied dose while faecal excretion was much lower at 0.02–0.06%. For musk

Discussion

The results of these investigations highlight the potential value of controlled human volunteer studies in safety evaluation and risk assessment. Studies in rats have shown that at 5 days after administration of dermal doses only 0.4–2.1% of applied material was still in the carcass and tissues (Hawkins and Ford, 1999). Therefore, it is reasonable to conclude that the amount of material measured in excreta provides a good index of the extent of absorption by humans under the conditions of

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