Reaction mass of cis-1-methyl-1-(4-methylcyclohexyl) ethyl acetate and trans-1-methyl-1-(4-methylcyclohexyl) ethyl acetate and cis- 4-isopropyl-1-methylcyclohexyl acetate and trans-4-isopropyl-1-methylcyclohexyl acetate

Endpoint summary

Description of key information

Menthanyl acetate multiconstituent is bioavailable via oral route. Limited absorption via inhalation and dermal route is anticipated. The substance would cross cellular barriers and would be distributed into fatty tissues. Menthanyl acetate multiconstituent is expected to be rapidly metabolised and mainly excreted in urine therefore no bioaccumulation is anticipated.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There is no reliable and relevant information source in which the toxicokinetic properties (absorption, distribution, metabolism, elimination) of MENTHANYL ACETATE MULTICONSTITUENT were investigated. The expected toxicokinetic behaviour is derived from the physicochemical properties and the results from the available toxicological data following the guide given in the REACH guidance document R.7c:

MENTHANYL ACETATE MULTICONSTITUENT is a multiconstituent whose main constituents have a relatively low molecular weight of 198.3. It is a liquid with a low water solubility of about 16 mg/L and has high lipophilic properties (log Kow = 4.26). Vapour pressure was determined to be about 40 Pa at 20°C. Detailed information can be found in section 4 of MENTHANYL ACETATE MULTICONSTITUENT IUCLID dossier.

 

Absorption:

 

MENTHANYL ACETATE MULTICONSTITUENT being lipophilic (log Kow = 4.26), the rate of uptake into the stratum corneum is expected to be high while the rate of penetration is likely to be limited by the rate of transfer between the stratum corneum and the epidermis. Moreover, it is assumed that the dermal uptake is also limited by the slight water solubility of MENTHANYL ACETATE MULTICONSTITUENT. These assumptions are supported by the absence of systemic effects following single-dose dermal application of MENTHANYL ACETATE MULTICONSTITUENT up to 2000 mg/kg bw which would suggest a limited systemic absorption through cutaneous barriers. Moreover, enhanced skin penetration is not expected since MENTHANYL ACETATE MULTICONSTITUENT is not a skin irritant or corrosive. However, it was found to be skin sensitizing therefore some uptake, even limited, must have occurred. Thus, dermal absorption of MENTHANYL ACETATE MULTICONSTITUENT is expected to be limited but not inexistent.

MENTHANYL ACETATE MULTICONSTITUENT has high log Kow (>4) and it is a small molecule (molecular weight < 200) therefore, it could be absorbed orally by passive diffusion. It is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being lipophilic, it may cross gastrointestinal epithelial barriers even if the absorption may be limited by the inability of the substance to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface. The acute oral gavage toxicity study identified no evidence of systemic toxicity was observed, i.e. neither mortality, nor clinical signs, nor macroscopic effects. Oral bioavailability is confirmed in a combined repeated dose toxicity study with reproduction/developmental toxicity screening test where non-adverse bodyweight gain was reduced at the highest dose group for both sexes. Main phase males from all treatment groups showed an increase in kidney and liver weight both absolute and relative to terminal body weight. A true dose related response however was not evident. Toxicity phase females treated with 5000 ppm showed an increase in liver weight both absolute and relative to terminal body weight. Histopathology revealed adaptive fully reversible microscopic abnormalities in liver (minimal to slight diffuse hepatocellular hypertrophy in main phase males and toxicity phase females at 1500 and 3000 ppm) and thyroid (minimal diffuse follicular cell hypertrophy in main phase males and toxicity phase females at 5000 ppm). These adaptive changes recorded in liver are compatible with metabolism in this detoxifying organ in response to xenobiotic exposure.

Thus, indications of oral uptake of MENTHANYL ACETATE MULTICONSTITUENT at high doses are given while dermal uptake would be more limited.

 

No study by inhalation was performed. However, considering the low vapour pressure (<500 Pa at 20°C), exposure to MENTHANYL ACETATE MULTICONSTITUENT by inhalation is likely to be very limited.

 

Therefore the potential bioavailability of MENTHANYL ACETATE MULTICONSTITUENT can be considered mainly by oral route.

Distribution:

 

MENTHANYL ACETATE MULTICONSTITUENT is a small molecule with low water solubility and high lipophilicity which indicates that it could be widely distributed; based on its lipophilic character, the substance would readily cross cellular barriers or would be distributed into fatty tissues with a low potential to accumulate.

 

Metabolism:

 

No data are available but, in in vitro genotoxicity studies, differences in cytotoxicity were observed with and without metabolic activation: in chromosome aberration test on human lymphocytes, the concentration inducing a 50% decrease in mitotic index was about two times higher in the presence of S-9 than in absence of S-9. Also, in an in vitro gene mutation test on mouse lymphoma L5178Y cells, the highest concentrations analysed, based on cytotoxicity (relative survival), were about two times higher in the presence of S-9 than in absence of S-9. This indicates that MENTHANYL ACETATE MULTICONSTITUENT is metabolised by hepatic microsomal fractions.

Also, in a combined repeated dose toxicity study with reproduction/developmental toxicity screening test, adaptive effects such as increased liver weight and minimal to slight diffuse hepatocellular hypertrophy were observed in males and females at high doses, which is suggestive of metabolisation in this organ.

MENTHANYL ACETATE MULTICONSTITUENT is a cyclic acetate; cyclic acetates are assumed to be rapidly hydrolyzed to the alcohol and the carboxylic acid by carboxylesterases. This hydrolysis can be viewed as a detoxification step. It transforms the poorly water soluble ester into an alcohol, which can subsequently be conjugated and excreted faster than the parent compound. After hydrolysis, acetic acid and primary, secondary or tertiary alcohols can be formed.Primary alcohols can either be conjugated or oxidized via the aldehyde to the corresponding acid. Tertiary alcohols cannot be further oxidized; as for secondary alcohols, conjugation of the alcohol group with glucuronic acid and subsequent elimination is to be expected. The acid metaboliteswould be conjugated with glucuronic acid and excreted mainly in the urine(Belsito et al., 2008).

To summarise, MENTHANYL ACETATE MULTICONSTITUENT is expected to be rapidly metabolized by hydrolysis and oxidation with subsequent conjugation and excretion, primarily as urinary metabolites.

Excretion:

Having a molecular weight lower than 300, MENTHANYL ACETATE MULTICONSTITUENT is expected to be mainly excreted in urine and no more than 5-10% may be excreted in bile. Urinary excretion is supported by metabolism data described above but also by the effects identified in the repeated dose toxicity study with reproduction/developmental toxicity screening test. At 5000 ppm, microscopic changes in kidney (slight focal and unilateral tubular degeneration/regeneration, and minimal focal to multifocal and unilateral to bilateral corticomedullary mineralization) were observed; they are suggestive of excretion via urine of the parent molecule or its metabolites.

Accumulative potential:

 

MENTHANYL ACETATE MULTICONSTITUENT has a low water solubility (< 100 mg/L) and high log Kow (>4) therefore it has affinity to adipose tissues; however, bioaccumulation is not expected to occur, since it is efficiently metabolized to yield oxygenated metabolites that are subsequently conjugated with glucuronic acid and excreted mainly in the urine.

 

References:

Belsito, D., Bickers, D., Bruze, M., Calow, P., Greim, H., Hanifin, J.M., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H., 2008. A toxicologic and dermatologic assessment of cyclic acetates when used as fragrance ingredients. Food Chem. Toxicol. 46 Suppl 12, S1–27.