Cyclohexanemethanol, 4-(1-methylethyl)-

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Accepted calculation method

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

In vitro model: The metabolism training set contains experimentally observed (documented) in vitro metabolic pathways for 261 parent chemicals of a wide structural diversity, and 1070 observed metabolites compiled into a searchable electronic database. Published data on the metabolism of these chemicals in rodent (mostly rat) liver microsomes and S9 fraction, collected mainly from research publications in scientific journals and, also, from some websites were extracted and introduced into an electronic database. In vivo model: The metabolism training set contains experimentally observed (documented) in vivo metabolic pathways for 647 structurally different parent chemicals, and 4382 observed metabolites compiled into a searchable electronic database. Published data on the in vivo metabolism of these chemicals in rodents (mostly rats) collected mainly from research publications in scientific journals and from some websites were extracted and introduced into an electronic database.

GLP compliance:

no

Radiolabelling:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

other: In Silico rodent metabolic simulator

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

Not applicable: In Silico rodent metabolic simulator

Remarks:

Doses / Concentrations:
Not applicable: In Silico rodent metabolic simulator

No. of animals per sex per dose / concentration:

Not applicable: In Silico rodent metabolic simulator

Control animals:

no

Preliminary studies:

Not applicable: In Silico rodent metabolic simulator

Details on absorption:

Not applicable: In Silico rodent metabolic simulator

Details on distribution in tissues:

Not applicable: In Silico rodent metabolic simulator

Details on excretion:

Not applicable: In Silico rodent metabolic simulator

Metabolites identified:

yes

Details on metabolites:

TIMES in vitro Rat Liver S9 v.06 simulator: Three Phase I metabolites and four Phase II metabolites are generated.
TIMES in vivo Rat Liver S9 v. 03 simulator: Three Phase I metabolites and six Phase II metabolites are generated.

Bioaccessibility (or Bioavailability) testing results:

Not applicable: In Silico rodent metabolic simulator

Table 1. Metabolites generated by In vitro Rat Liver S9 v.06

Generated metabolite (the substance): SMILES	Type of reactions
C(C)(C)(O)C1CCC(CO)CC1	Aliphatic C-oxidation
C(C)(C)C1CCC(C=O)CC1	Aliphatic C-oxidation
C(=O)(O)C1CCC(C(C)C)CC1	Aliphatic C-oxidation
C(=O)(O)C1C(O)C(O)C(O)C(OCC2CCC(C(C)C)CC2)O1	O-Glucoronidation
C(=O)(O)C1C(O)C(O)C(O)C(OC(=O)C2CCC(C(C)C)CC2)O1	O-Glucoronidation
C(C)(C)(O)C1CCC(COC2C(O)C(O)C(O)C(C(=O)O)O2)CC1	O-Glucoronidation
C(C)(C)(C1CCC(CO)CC1)OC1C(O)C(O)C(O)C(C(=O)O)O1	O-Glucoronidation

 

  Table 2. Metabolites generated by In vivo Rat Liver v.03

Generated metabolite (the substance): SMILES	Type of reactions
C(C)(C)(O)C1CCC(CO)CC1	Aliphatic C-oxidation
C(C)(C)C1CCC(C=O)CC1	Aliphatic C-oxidation
C(=O)(O)C1CCC(C(C)C)CC1	Aliphatic C-oxidation
C(=O)(O)C1C(O)C(O)C(O)C(OCC2CCC(C(C)C)CC2)O1	O-Glucoronidation
C(=O)(O)C1C(O)C(O)C(O)C(OC(=O)C2CCC(C(C)C)CC2)O1	O-Glucoronidation
C(C)(C)(O)C1CCC(COC2C(O)C(O)C(O)C(C(=O)O)O2)CC1	O-Glucoronidation
C(C)(C)(C1CCC(CO)CC1)OC1C(O)C(O)C(O)C(C(=O)O)O1	O-Glucoronidation
C(=O)(C1CCC(C(C)C)CC1)NCC(=O)O	Amino Acid conjugation
C(C)(C)C1CCC(COS(=O)(=O)O)CC1	Sulfation

 

Conclusions:

Interpretation of results (migrated information): no data
TIMES in vitro Rat Liver S9 v.06 simulator: Three Phase I metabolites and four Phase II metabolites are generated.
TIMES in vivo Rat Liver S9 v. 03 simulator: Three Phase I metabolites and six Phase II metabolites are generated.

Executive summary:

The metabolism of the substance was predicted using the Tissue Metabolism Simulator (TIMES) tool (Laboratory of Mathematical Chemistry). The results indicate rapid oxidative metabolism for the substance, as follows:

TIMES in vitro Rat Liver S9 v.06 simulator: Three Phase I metabolites and four Phase II metabolites are generated.

TIMES in vivo Rat Liver S9 v. 03 simulator: Three Phase I metabolites and six Phase II metabolites are generated.

The three Phase I metabolites are predicted both in vitro and in vivo to be the results of aliphatic C-oxidation:  

C(C)(C)(O)C1CCC(CO)CC1

C(C)(C)C1CCC(C=O)CC1

C(=O)(O)C1CCC(C(C)C)CC1

Phase II metabolites include O-glucuronidation metabolites.

Expert analysis confirmed that all generated metabolites are credible. Also most of the generated Phase I and O-Glucuronidation metabolites are in coherence with the observed metabolites of the analogue structure of L-menthol (Yamaguchi, et al., 1994; Miyazawa, et al., 2011). The in vivo Sulfation and Amino acid Conjugation Phase II metabolites although not documented are believed to occur by expert judgment.

References 

Miyazawa, M. et al., 2011. Metabolism of (+) and (-) Menthols by CYP2A6 in Human Liver Microsomes. J OLEO SCI, 60(3), pp. 127-132.

Yamaguchi, T., Caldwell, J. & Farmer, P., 1994. Metabolic Fate of [3H]-l-Menthol in the Rat. DRUG METAB DISPOS, 22(4), pp. 616-624.

Reference 2

Endpoint:

basic toxicokinetics

Data waiving:

other justification

Justification for data waiving:

other:

Description of key information

Based on consideration of physicochemical properties (low molecular weight, moderate log Pow, moderate water solubility), the substance would be expected to be absorbed from the gastrointestinal tract; data from toxicology studies confirms absorption after oral dosing. Data also suggest likely absorption following dermal application. No inhalation data for absorption are yet available. Oral, dermal, and inhalation absorption values are thus assumed to be 100%. Given the molecular size, wide distribution of the substance is expected. Data from toxicology studies provides evidence of distribution to a number of organs including the liver, kidney, and testis. Metabolism predicted using in silico methods indicates primarily C-aliphatic oxidation products and glucuronidated metabolites, together with the possibility of oxidative stress under certain conditions. Excretion is expected to be urinary, but might also be faecal following oral dosing. Based on the available data, the substance is not expected to bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In accordance with the section 8.8.1 of Annex VIII in REGULATION (EC) No 1272/2008, the toxicokinetic profile of the substance was derived from all available information collated in the dossier. The physicochemical properties of the substance and the results of toxicity studies together with results from in silico predictions of metabolism were used to assess the toxicokinetics of the substance.

Absorption

Oral absorption: The low molecular weight (i.e., <500 g/mol), moderate water solubility (i.e., 213.7 mg/L) (Firmenich, 2011b), and moderate log Pow value (i.e., between -1 and 4) (Firmenich 2011a) of the substance favours its absorption from the gastrointestinal tract (ECHA, 2012a; Martinez and Amidon, 2002). The systemic effects that have been observed in oral gavage toxicity studies (i.e., repeated dose toxicity studies and a reproductive and developmental toxicity screening study) support that the substance is absorbed from the gastrointestinal tract (Huntingdon Life Sciences 2013a,b,c), although the extent of such absorption cannot be quantified based on the information currently available. Taking into consideration the physicochemical properties of the substance, absorption is expected to be high. Consequently, nearly 100% absorption is assumed.

Dermal absorption: Factors that influence the ability of a compound to penetrate through the stratum corneum and partition into the epidermis include its molecular weight (i.e., poor absorption if molecular weight >500 g/mol), water solubility (i.e., moderate to high dermal uptake between 100 and 10,000 mg/L) and log Pow (i.e., absorption favoured between -1 and 4; values of 2 to 3 are optimal) (ECHA, 2012a). As such, the physicochemical properties of the substance (i.e., MW = 156.27 g/mol; water solubility = 213.7 mg/L; Log Pow = 3.48) favour its absorption through the skin. The observation of lethargy and decreased food and water consumption for up to 4 and 5 days, respectively, following dosing in the acute dermal toxicity study in rabbits (AMR Biological Research, 1979) supports the likelihood of dermal absorption of the substance. However, it should be noted that the extent of such absorption is unclear and that the skin of the animals was shaved and abraded (not intact), which likely aided in absorption. Therefore, no specific conclusions can be made as to the % absorption from this study. Based on the physicochemical properties, dermal absorption of 100% is assumed for the substance in the absence of specific information, although it is acknowledged that absorption may not be complete based on consideration of the molecular weight being >100 g/mol.

Inhalation absorption: Toxicokinetic and toxicological data were not identified for the inhalation route of exposure. The small size of the molecule and its lipophilicity would suggest the potential for absorption. Therefore, as a worst case, 100% absorption can be assumed (ECHA, 2012b).

 

Distribution

Once in the systemic circulation given the small size of the substance, wide distribution would be expected. Based on evidence of effects in several rat tissues and organs in oral toxicology studies (Huntingdon Life Sciences, 2013a,b,c), the substance was considered to have distributed to the liver, the testis, and the kidney.

 

Metabolism

As for many other organic molecules with similar structure (e.g., alicyclic primary alcohols), the substance is expected to be extensively metabolized in the liver following oral administration and is predicted to undergo rapid oxidative metabolism (JECFA, 2003, 2000). When absorbed from the gut, these alcohols are oxidized in the liver to the corresponding carboxylic acids and/or are directly glucuronidated at the primary alcohol group (JECFA, 2000). In silico modelling under in vitro and in vivo conditions has indicated that three metabolites are likely to be produced in the liver via tertiary C-aliphatic oxidation to produce a tertiary/primary diol and C-aliphatic oxidation of the original primary alcohol to produce an aldehyde and then a carboxylic acid (LMC, 2013; OECD Toolbox, 2013; see IUCLID Section 7.1). Figure 1 (see attached document) presents the likely metabolic pathway as predicted for in vivo metabolism. Phase II metabolism is predicted to yield O-glucuronidated conjugates, with the additional possibilities of sulphate and amino acid conjugates (LMC, 2013). The rapid oxidative metabolism of the substance would indicate the possible production of reactive oxygen intermediates and potential situations of oxidative stress under specific conditions, such as overloading of the capacity of the liver to metabolize following usual pathways.

Excretion

Based on the predicted metabolism of the substance, urinary excretion would be expected for the substance, its oxidized forms, and its putative glucuronidated metabolites, consistent with the likely metabolism and excretion described for alicyclic primary alcohols (JECFA, 2003). Following oral dosing, some faecal excretion might also be expected.

Bioaccumulation Potential

Based on the available data and taking into consideration its low molecular weight and other physicochemical properties, the substance is not expected to bioaccumulate.

Summary

In summary, the absorption for the oral route is likely to be close to 100% (between 50% and 100%), and for the dermal and inhalation routes is assumed to be 100%. Bioaccumulation of the substance is not expected.

References

*AMR Biological Research. Determination of acute dermal toxicity (LD50) of 0778/3 in the rabbit. Report No. 120-2993-88. 1979. AMR Biological Research Inc., Princeton, NJ, USA. January 23, 1979.

*ECHA. Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. November 2012 (version 1.1). Guidance for implementation of REACH. European Chemicals Agency.

*Firmenich. Water solubility. 2011a. Firmenich S.A. Process Safety & Analytical Development Laboratory, Geneva, Switzerland. July 11, 2011.

*Firmenich. 957230 Determination of general physico-chemical property: partition coefficient. 2011b. Firmenich S.A., Geneva, Switzerland. June 7, 2011.

*Huntingdon Life Sciences. Mayol: Preliminary toxicity study by oral gavage administration to Crl:CD(SD) rats for 14 days. Report No. HIK0015. 2013a. Huntingdon Life Sciences, Eye, Suffolk, UK. April 10, 2013.

*Huntingdon Life Sciences. Mayol: Toxicity study by oral (gavage) administration to Crl:CD(SD) rats for 4 weeks. Report No. HIK0016. 2013b. Huntingdon Life Sciences, Eye, Suffolk, UK. April 25, 2013.

*Huntingdon Life Sciences. Mayol: Reproductive/developmental toxicity screening study in the CD rat by oral gavage administration. Report No. HIK0019. 2013c. Huntingdon Life Sciences, Eye, Suffolk, UK. November 27, 2013.

*JECFA. Evaluation of Certain Food Additives. Fifty-first report of the Joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series 891. 2000. Available at: http://whqlibdoc.who.int/trs/WHO_TRS_891.pdf.

*JECFA. Alicyclic primary alcohols, aldehydes, acids, and related esters. Safety evaluation of certain food additives / prepared by the fifty-ninth meeting of the Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additive Series: 50. 2003. Available at: http://www.inchem.org/documents/jecfa/jecmono/v50je10.htm.

*LMC. TIMES simulated metabolism of Mayol. Laboratory of Mathematical Chemistry. 2013.

*Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002;42:620-643.

*OECD Toolbox. In silico rat liver metabolism simulator Toolbox plug-in, QSAR TOOLBOX: cyclohexane methanol. OECD QSAR Toolbox for Grouping Chemicals into Categories v3.1.0.21. 2013.