Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Skin sensitisation

The skin sensitisation potential of cyclohexane was investigated in two GLP-compliant studies using a modified Buehler test method in accordance with OECD guideline 406 (Moore, 1996a,b).

In the first study, 9 males and 11 females were induced with 10% cyclohexane in ethanol and challenged with 10% cyclohexane in acetone. In the second study, 20 guinea pigs (10 per sex) were dermally induced with 20% cyclohexane in ethanol and challenged with 10% cyclohexane in ethanol. Both tests included concurrent negative (vehicle) and positive controls (1-chloro-2,4-dinitrobenzene, 0.1% in 50% ethanol: 0.9% saline at induction and 0.07% in acetone at challenge).

In the first study, induction treatment resulted in no redness (14/20 animals) to very faint redness on some tested animals (6/20 animals). Very faint redness was seen 24 h after challenge in 1/20 animals of the test group and no reactions were observed in any animal at 48 h post-challenge.

During the induction phase of the second study, responses ranged from no redness (3/20 animals) and faint redness (2/20 animals) to necrosis (15/20) in the test group. Twenty-four hours after challenge application, very faint redness was observed on the skin of 5/20 test animals. No dermal effects were observed 48 h after challenge. It cannot be excluded that the severe dermal reactions during the induction phase could have confounded the challenge results.

No skin reactions were observed in negative control animals in either study. The incidence of sensitisation among the positive control animals was 8/10 and 7/10 in the first and second study, respectively.

In both studies, the incidence of sensitisation in cyclohexane-induced and -challenged animals was 0/20. While the first study provides the most reliable results (Moore, 1996a), the weight of evidence from both studies clearly indicates that cyclohexane was not skin sensitising in the Buehler test.

Justification for read-across approach

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests", which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, cyclohexane (CAS No. 110-82-7) is selected as reference substance for assessment of ecotoxicological and toxicological endpoints, for which no methylcyclohexane data are available.

Similarity is based on:

(1) common functional group: Methylcyclohexane and cyclohexane share a 6-membered saturated alicyclic ring as a common molecular structure and are therefore allocated to the group of monocyclic hydrocarbons (cycloalkanes);

(2) common precursors and likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals: Methylcyclohexane and cyclohexane do not share a common precursor; however, both substances are produced by hydrogenation of the corresponding aromatic compounds toluene (see Section Manufacture and Use) and benzene (EC-ECB, 2004), respectively, which are in turn structurally similar substances. In general, methylcyclohexane and cyclohexane are likely to undergo the same chemical reactions characteristic of cycloalkanes, e.g. combustion to CO2 and H2O and halogenation (Breitmeier and Jung, 2005). The assessment of toxicokinetic behaviour indicates that both substances share a common main metabolic pathway, namely mono- and dihydroxylation of the alicyclic ring resulting in the respective isomers of methylcyclohexanol/-diol and cyclohexanol/-diol, followed by conjugation to the corresponding glucuronides (see Toxicokinetics); and

(3) constant pattern in the changing of the potency of the properties between substances: For methylcyclohexane and cyclohexane, the constant pattern is characterized by similarities in the potency of properties.

- Physicochemical properties:

Both substances show overall similar physico-chemical properties, being liquids, moderately volatile, lipophilic and slightly soluble in water. (see Section 4, Physical and chemical properties and EC-ECB, 2004).

- Environmental fate and ecotoxicological profile:

Methylcyclohexane and cyclohexane show similar properties in environmental fate and ecotoxicological profile: both substances are volatile, not bioaccumulative and show corresponding adsorption values (see section 5, Environmental fate and pathways and EC-ECB, 2004). Furthermore the available experimental data demonstrate that both substances exhibit a similar ecotoxicity profile. Both are acute very toxic to aquatic organisms (see Section 6, Aquatic toxicity and EC-ECB, 2004) with invertebrates and/or algae being the most sensitive organism groups. The available data on algae indicate a chronic toxicity potential with NOErC being 0.067 mg/L for methylcyclohexane and 0.94 mg/L for cyclohexane, resulting in chronic classification for both substances.

- Toxicological profile:

Methylcyclohexane and cyclohexane show similar toxicokinetic behaviour (see Section 7.1, Toxicokinetics). For those toxicological endpoints, for which both substances have been tested, similar levels of toxicity have been observed. Thus, both substances are of low acute toxicity via the oral and inhalation route, but fulfil the classification criteria for Aspiration toxicity (Category 1) and Narcotic effects (STOT-SE 3) according to Regulation (EC) No 1272/2008. Both substances were not skin and eye irritating in experimental studies, but are classified for Skin irritation (Category 2), mainly based on their defatting properties. Methylcyclohexane and cyclohexane have been extensively studied for repeated dose toxicity mainly via inhalation. For methylcyclohexane, the lowest chronic NOAEC for systemic effects is 400 ppm (1600 mg/m³) in rats, while for cyclohexane the most reliable subchronic systemic NOAEC in rats and mice is 2000 ppm (6880 mg/m³). Applying a time-extrapolation factor of 3 (ECHA, 2010), the chronic NOAEC for cyclohexane would be 667 ppm (2293 g/m³), which would be in the same order of magnitude as for methylcyclohexane. Both substances have been tested negative for mutagenicity in vitro.

Conclusion:

In order to avoid the need to test methylcyclohexane for every endpoint for which information gaps are identified, the read-across approach is applied for the assessment of environmental and human health hazards. Thus, environmental and human health effects are predicted where applicable from adequate and reliable data for cyclohexane by interpolation to methylcyclohexane in accordance with Annex XI, Item 1.5 of Regulation (EC) No 1907/2006.

A detailed justification for the read-across approach is provided in the technical dossier (see IUCLID Section 13).

References

Breitmaier, E. and Jung, G. (2005). Organische Chemie. Grundlagen , Stoffklassen, Reaktionen, Konzepte, Molekülstruktur. 5th ed. Georg Thieme Verlag, Stuttgart.

ECHA (2010). Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health. Source: European Chemicals Agency, http://echa.europa.eu/

EUROPEAN COMMISSION - European Chemicals Bureau (EC-ECB) (2004). European Union Risk Assessment Report: Cyclohexane; CAS No: 110-82-7; EINECS No: 203-806-2. European Chemical Bureau - Institute for Health and Consumer Protection.


Migrated from Short description of key information:
Skin sensitisation: not sensitising (OECD 406, GLP, Buehler test, read-across from cyclohexane)

Justification for selection of skin sensitisation endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

This information is not available.


Justification for selection of respiratory sensitisation endpoint:
Study not required according to Annex VII-X of Regulation (EC) No 1907/2006.

Justification for classification or non-classification

Based on read-across from the structurally similar reference substance cyclohexane, the available data on skin sensitisation do not meet the criteria for classification according to Regulation (EC) No 1272/2008 or Directive 67/548/EC, and are therefore conclusive but not sufficient for classification.

There is no information available on respiratory sensitisation.