Bicyclo[3.1.1]hept-2-ene-2-ethanol, 6,6-dimethyl-, 2-acetate, (1R,5S)-

Endpoint summary

Description of key information

Nopyl acetate 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. Nopyl acetate is expected to be rapidly metabolised and mainly excreted in urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No data on toxicokinetic properties of nopyl acetate (absorption, distribution, metabolism, elimination) are available in the literature. In accordance with REACH guidance document R.7c, the expected toxicokinetic behaviour of nopyl acetate is derived from its physicochemical properties and the available toxicological data.

Nopyl acetate is a monoconstituent substance having a relatively low molecular weight of 208. It is a liquid with a low water solubility of about 19 mg/L and high lipophilic properties (log Pow = 4.24). Vapour pressure was determined to be about 1.33 Pa at 20°C. Detailed information can be found in section 4 of nopyl acetate IUCLID dossier.

 

Absorption:

Nopyl acetate being lipophilic (log Kow = 4.24), 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 nopyl acetate. These assumptions are supported by the absence of systemic effects following single-dose dermal application of nopyl acetate up to 2000 mg/kg bw which would suggest a limited systemic absorption through cutaneous barriers. Moreover, enhanced skin penetration is not expected since nopyl acetate 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 nopyl acetate is expected to be limited but not inexistent.

Nopyl acetate has high log Kow (> 4) and it is a small molecule (molecular weight around 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 only slight evidence of systemic toxicity, i.e. neither mortality nor macroscopic effects, however, females were somnolent and exhibiting laboured breathing but only at very high and lethal doses (5 and 10 mL/kg bw). Oral bioavailability is confirmed in a combined repeated dose toxicity study with reproduction/developmental toxicity screening test where bodyweight gain was reduced at the highest dose group for both sexes. Macroscopic observations at necropsy showed an increase in kidney and liver weight both absolute and relative to terminal body weight in males. Females of the high dose group also showed an increase in liver weight both absolute and relative to terminal body weight. Histopathology revealed fully reversible microscopic abnormalities in liver (minimal to slight diffuse hepatocellular hypertrophy in males and females). 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 nopyl acetate at high doses are given while dermal uptake would be more limited.

 

No study by inhalation was performed. However, considering the low vapour pressure of nopyl acetate (< 500 Pa), exposure to this substance by inhalation is likely to be very limited.

 

Therefore the potential bioavailability of nopyl acetate can be considered mainly by oral route.

 

Distribution:

Nopyl acetate 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 (see Accumulation potential below).

 

Metabolism:

No data are available on the metabolism of nopyl acetate. However, in in vitro genotoxicity studies, differences in cytotoxicity were observed with and without metabolic activation: in Ames test, nopyl acetate concentrations leading to cytotoxicity were higher in presence of metabolic activation than without metabolic activation; in chromosome aberration test on human lymphocytes, the concentration inducing about 50% decrease in mitotic index was about two times higher in the presence of S9 than in absence of S9. This indicates that nopyl acetate is metabolised by hepatic microsomal fractions.

Moreover, 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 metabolism in the liver.

Furthermore, nopyl acetate is a bicyclic 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. As hydrolysis by carboxylesterases might be less efficient for esters with bulky alcohols, it can be expected that the rate of acetate hydrolysis would be lower with bicyclic alcohols than monocyclic alcohols. However, esters with bulky alcohol moieties are nevertheless cleaved efficiently by human carboxylesterase hCE-2. 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 metabolites would be conjugated with glucuronic acid and excreted mainly in the urine (Belsito et al., 2008).

To summarise, nopyl acetate 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, nopyl acetate 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 3000 and 9000 ppm, partly reversible changes in kidney (tubular degeneration/regeneration, hyaline droplets and granular casts) were observed in main phase and recovery males. Although these effects are specific to male rat, they are suggestive of excretion via urine of the parent molecule or its metabolites.

 

Accumulative potential:

Nopyl acetate 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.

Ishida, T., Toyota, M., Asakawa, Y., 1989. Terpenoid biotransformation in mammals. V. Metabolism of (+)-citronellal, (+-)-7-hydroxycitronellal, citral, (-)-perillaldehyde, (-)-myrtenal, cuminaldehyde, thujone, and (+-)-carvone in rabbits. Xenobiotica 19, 843–855.

Alicyclic Primary Alcohols, Aldehydes, Acids, and Related Esters,WHO Food Additives Series 50