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Phys-chem properties relevant for toxicokinetic assessment

The non-aromatic O-heterocyclic compound Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol (Pyranol, CAS-No. 63500-71-0) is a colorless organic liquid with a floral odor, used as a fragrance substance. The molecular weight of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol l is 172.27 g/mol, the partition coefficient Log Pow is 1.65 and the water solubility was determined to be 23.65 g/L (23 °C). Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol has a vapor pressure of 0.01 hPa at 20 °C. Occupational exposure to Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol may occur through inhalation and dermal contact at workplaces where Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol is produced or used.

Toxicological Profile of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol

In an acute oral toxicity study with rats according to OECD TG 401 and GLP, the LD50-value was determined to be > 2000 mg/kg bw (Huntingdon Research Centre Ltd., 1992a). An acute dermal toxicity study according to OECD TG 402 and GLP revealed a LD50-value of > 2000 mg/kg bw (MB Research Laboratories Inc., 1985). In a primary dermal irritation study with rabbits, conducted according to OECD 404 and GLP, signs of skin irritation were observed; however, these were not relevant for classification and labelling (Huntingdon Research Centre Ltd., 1992b). In a primary eye irritation study according to OECD TG 405 and GLP, Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol caused corneal opacities in all 3 animals accompanied by temporary iritis in one animal and conjunctival irritation in all 3 animals. All reactions had resolved 21 days after instillation (Huntingdon Research Centre Ltd., 1992c). The irritation signs were relevant to classify and label Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol as irritating to eyes (R36). The skin sensitising potential of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol was investigated in the guinea pig maximisation test according to OECD TG 406 and GLP. Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol was considered as non sensitising (Unilever Research UK, 1991). In two bacterial mutagenicity tests (Ames test) and two cytogenetic assays using mammalian cells (chromosome aberration test) no mutagenic or clastogenic effects were noted in the presence and absence of metabolic activation (rodent microsomal S9-fractions) (Unilever Research UK, 1994; Safepharm Laboratories, 2007b; 1988; Huntingdon Research Centre Ltd., 1992d). In an in vitro mammalian cell gene mutation test (HPRT-assay), the substance was not mutagenic (Harlan Cytotest Cell Research GmbH, 2010). Furthermore Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol was not clastogenic or aneugenic in a micronucleus test according to OECD TG 474 and GLP in CD-1 mice (5 animals/sex/dose) (Huntingdon Research Centre Ltd., 1994).

In a repeated dose (28-day) oral toxicity study equivalent to OECD TG 407 and according to GLP, Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol was administered orally (gavage) to groups of 10 rats per dose and sex at 0, 25, 125, or 625 mg/kg bw/d. All animals were dosed once daily, for 4 weeks, until the day before necropsy. No deaths occurred during the whole study period. Administration of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol by gavage at a dose level of 625 mg/kg bw/d was associated with minor changes only. These included salivation associated with dosing, changes in coat condition, marginal reductions in red blood cell values, moderate increases in plasma triglycerides, the presence of ketones in the urine of males only and slightly raised liver weight and adrenal weight (females only). Bodyweight gain and food intake were unaffected by treatment. Since dose levels of 125 and 25 mg/kg bw/d were associated only with increases in plasma triglycerides within the normal range, they can be regarded as no adverse effect levels (Toxicol Laboratories Ltd., 1989a).

Toxicokinetic Analysis of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol

Oral absorption

Administered orally it can be assumed that Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol is well absorbed in the gastrointestinal (GI) tract after dissolving in GI fluids due to its low molecular weight, the relative high water solubility, the moderate Log Pow of 1.65 and the absence of ionisable groups in the Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol molecule at pH values of small intestine. These substance characteristics favor the absorption via passive diffusion, e. g. by passage through aqueous pores or carriage through the epithelial barrier with the bulk passage of water. The systemic effects seen after oral administration demonstrate that Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol is absorbed from the GI tract.

Dermal absorption 

In an in vitro dermal absorption test according to OECD 428 and GLP the penetration of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol (Pyranol) through rat skin was evaluated using 14C-Pyranol (BASF SE, 2013). The diffusion of 14C-Pyranol was assessed by single topical application of target doses of 9500 μg/cm² (pure Pyranol) and 1000 μg/cm² (solution in corn oil) of test substance to split thickness skin preparations mounted on Franz-type diffusion cells (5 diffusion cells for each dose). The mean absorbed doses (receptor fluid, receptor chamber washing) were 14.80 and 36.27 % of dose for skin treated with the high dose and the low dose, respectively. Amounts of the test substance associated with the skin (skin and tape strips 3-6) after the exposure period accounted to 3.12 and 7.51 % of dose for the high dose and the low dose, respectively. These findings correspond to calculated dermal absorption estimates of 17.92% and 43.78% of the applied dose for the high dose (950 mg/mL) and low dose (100 mg/mL), respectively. Mean absorption lag times were 1.27 hours and 0.42 hours for the high and low dose, respectively and demonstrate the presence of a functional barrier in the skin samples used. Taken together, the data clearly demonstrate that Pyranol is absorbed through rat skin under the test conditions used.

Respiratory absorption

Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol is a liquid exhibiting low volatility due to a low vapor pressure (< 0.5 kPa) and a high boiling point (> 150 °C). Therefore only a minimal amount of the substance is available for inhalation. Based on the aforementioned physico-chemical properties (see “oral absorption”), the absorption rate of this Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol fraction is not higher than oral absorption.

Distribution and metabolism

Since the Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol molecule is relative small, relatively highly water soluble and has a moderate Log Pow value, distribution throughout the body is likely to occur after absorption. Based on the partially polar structure and physico-chemical characteristics, particularly the relative high water solubility and moderate Log Pow value below 3, a long biological half-life of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol in tissues is not be expected, thus Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol has no accumulation potential. The metabolism itself is determined by physico-chemical factors like electronic and steric effects within the molecule (Karcher W & Devillers J, 1990). Since Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol contains a functional group (hydroxyl group) in the molecule and is already water soluble, Phase II conjugation reactions at this moiety, i. e. sulfatation and glucuronidation are likely. In addition, these Phase II reactions might occur subsequent to Phase I reactions, e. g. introduction of a OH-group at the tert-butyl moiety via CYP 450 mediated oxidation. In general, metabolism of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol will render the molecule more polar, leading to faster excretion. It is unlikely that metabolism will lead to more toxic products. This assumption is supported by results obtained from both in vitro tests, both in vitro chromosome aberration tests and the in vitro HPRT assay. In all assays no significant increases in toxicity were noted in the presence of a rodent microsomal S9-fraction. This clearly indicates that formation of reactive or more toxic metabolites is unlikely.

Excretion

The relative high water solubility and low molecular weight (< 400) indicate that renal excretion is the most relevant route of systemically available Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol.

Reference

Karcher W & Devillers J (eds.) (1990): Practical Applications of Quantitative Structure-Activity Relationships (QSAR) in Environmental Chemistry and Toxicology. Chemical and Environmental Science Series, Vol. 1.