Registration Dossier

Administrative data

Description of key information

No data are available on the intermediate but information is available for the main components indicate some degree of skin and eye irritation. Whilst 4-vinylcyclohexane is minimally irritating to skin and eyes, cyclohexane is considered to be a skin irritant and is slightly irritant to the eyes.  Available data for toluene and n-hexane provide some evidence of skin and eye irritation with controlled exposures to liquid test substances although the severity varies widely. Data available on the minor components indicate ethylbenzene, styrene and xylenes are skin and eye irritants. Ethylbenzene and xylenes are also considered to be respiratory irritants. 

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Non human data

Skin irritation

Data on the specific component n-hexane indicate some irritation following dermal contact with effects sufficiently severe to warrant classification (ATSDR, 1999).

 

There are two skin irritation studies on cyclohexane (HLA, 1982e; Jacobs and Martens, 1987). The first study gave a primary irritation score of zero at 24 h and 72 h, the second study gave a mean erythema score of 1.93 calculated over the 24 h and 72 h post-application period. In this study the erythematous reaction reached maximum severity at 5 days post-application with a gradual increase in dermal reaction for a further 144 h observation time. Overall, it was concluded (EU RAR, 2004) that the irritation reactions were significant and still present at the end of the study. In addition, a 14 -day repeated dermal application study in rabbits on uncovered skin has been reported (Treon et al., 1943a). An initial erythematous response, gradually progressing to skin hardening, fissuring and bleeding with continued application was reported (EU RAR, 2004), with healing of the lesions within one week once application of cyclohexane had ceased.

 

4 -vinylcyclohexene applied undiluted to rabbit skin was no more than a moderate irritant to the skin (Smyth, 1962).

 

Toluene caused significant inflammation of the skin as a mean erythema score exceeding 2 was observed which persisted for more than 24 hours (Exxon, 1988). Furthermore, the inflammation persisted in all test animals at the end of the observation time. Guillot et al, 1982 classified toluene as a slight irritant (PCI 2.13). The results are consistent with the Exxon study and indicate that toluene is irritating to skin.

 

 

Eye irritation

Data on n-hexane indicate that instillation of liquid test substance into the eye may induce some evidence of eye irritation but not of a severity that warrants classification (ATSDR, 1999).

 

Washed and unwashed primary eye irritation studies in rabbits are available on cyclohexane (HLA, 1982f&g). In the unwashed study, all ocular lesions cleared within 24 hours.

 

4-vinylcyclohexene was minimally irritating to rabbit eyes (2 on a 0-10 scale of necrosis) following a single application (Smyth, 1962).

 

Ocular lesions (redness, chemosis) occurred within 72 hours after exposure to toluene which persisted for at least 24 hours (Exxon, 1995). However, the mean score (24, 48 and 72 hours) for redness of the conjunctivae and chemosis did not exceed values of 2.5 and 2, respectively. Sugai et al (1990) reported that "corneal involvement or irritation that persists for more than 24 hours but recovers within 21 days". The level of irritation was not of a severity to trigger classification.

 

Respiratory irritation

Acute inhalation exposure to cyclohexane at a nominal concentration of 32, 880 mg/m3 of air did not appear to produce upper airway irritation in mice (HLA (1982c).

See also data on the minor components below.

 

 

Human information

Very little information has been reported on the irritation effects of cyclohexane in humans. In a human volunteer study (Lammers et al, 2009) the maximum exposure concentration was 250 ppm (860 mg/m3). The study reported slight signs of irritation of the eye and throat were noted more frequently at 250 ppm (860 mg/m3) than at 25 ppm (86 mg/m3). These findings which could be treatment related were 'subjective'.

 

Data cited in the EU RAR (2004) from an UK HSE review of cyclohexane, indicates application of undiluted liquid cyclohexane to human skin for 1 hour produced erythema and weal formation.

 

No data on skin irritation have been found on toluene. The EU RAR (2003) stated “it is well known that toluene has a degreasing effect on the skin. After repeated exposures, toxic contact dermatitis may develop. ” There are no data from direct exposure of human eyes to liquid toluene. A number of human experimental studies in volunteers have investigated reports of eye “irritation” resulting from exposures to toluene in ambient air. These studies indicate that toluene produces subjective sensations of eye irritation at concentrations ≥ 75 ppm (EU, 2003a). Muttray et al (2005) exposed twenty healthy men to a constant level of 50 ppm toluene. Acute symptoms related to eye irritation were assessed with the Swedish Performance Evaluation System (SPES) self-assessment questionnaire, once before and 3 times during exposure. Values obtained during exposure were related to pre-exposure values. There was no effect of toluene exposure on "irritation to the eye", "watering eyes" or "blurred vision”. 50 ppm (188 mg/m3) toluene is a NOAEC for eye irritation in humans.

 

Summary of information on irritation potential:

 

Based on the data summarised above, 4-vinylcyclohexene does not trigger classification.

 

In relation to skin irritation, the although the animal studies gave results slight below the limits of classification, the RAR (2004) concluded that the irritant properties of cyclohexane were delayed and persisted until the end of observation period (16 days). Since defatting properties are also expected, it was concluded that cyclohexane be classified Xi, R38 under according to Dir 67/548/EEC, corresponding to GHS/CLP Category 2 H315. Liquid cyclohexane is a slight irritant to the eyes in animal experiments, but not to the extent which warrants any classification. Although cyclohexane vapour exhibited slight respiratory irritant properties in mice, these effects were slight and insufficient to warrant classification. There is no evidence of any significant eye or respiratory tract irritation in humans which would warrant classification

 

There are sufficient data on toluene and n-hexane to indicate that they produce evidence of skin and eye irritation in animals although the response varies and is not always of a severity to warrant classification for eye irritation. Toluene can cause irritation to the respiratory tract in animals at very high concentrations. The irritant effect of lower concentrations has not been examined and no classification for respiratory irritation is proposed.

Toluene and n-hexane carry the following classification: EU -Harmful Xi, R38; GHS/CLP - Category 2 H315.

 

Minor components with classification for irritation

 

Xylene (Classification: EU -Harmful Xi, R38; Annex VI Harmonised GHS/CLP- Category 2 H315; Self classification: EU -Harmful Xi, R36, R37, R38; GHS/CLP- Category 2 H319, Category 3 H335, Category 2 H315): There is little human information available but the ATSDR (2007) reports that dermal exposure of humans to xylene causes skin irritation, dryness and scaling of the skin, and vasodilation. Mild irritation of the eye and upper respiratory tract was reported in volunteer studies where individuals were exposed to 442 mg/m3 (SCOEL,1992) for 15-30 minutes (Carpenter, 1975; Hastings, 1984). No symptoms of nose or throat irritation have been reported in volunteers exposed to mixed xylenes up to 400 ppm (UK, 2001).

 

Ethylbenzene (Classification: EU -Harmful Xi, R36, R37, R38; GHS/CLP- Category 2 H319, Category 3 H335, Category 2 H315) caused irritation in the eyes of rabbits and guinea-pigs and after single exposure the chemical is moderately irritating to the skin of rabbits (EU RAR, 2008a). RD50 values of 1432 or 4060 ppm (6215 to 17620 mg/m3) for sensory irritation were determined in different strains of mice (EU, 2008).

 

Data on styrene (Classification: EU -Harmful Xi, R36, R38; GHS/CLP- Category 2 H319, Category 2 H315) indicate some irritation following dermal and eye contact with effects sufficiently severe to warrant classification.

 

Additional references

ATSDR (1999). Toxicological Profile for n-Hexane. http: //www. atsdr. cdc. gov/toxprofiles/tp113. html

ATSDR (2007). Toxicological profile for xylene. US Dept Health and Human Services.

EU RAR (2003). European Union Risk Assessment Report for Toluene. EC Joint Research Centre http: //ecb. jrc. ec. europa. eu/DOCUMENTS/Existing- Chemicals/RISK_ASSESSMENT/REPORT/toluenereport032. pdf

EU RAR (2004)

European Union Risk Assessment Report: Cyclohexane. EC Joint Research Centrehttp://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/SUMMARY/cyclohexanesum031.pdf

EU (2008a). Draft Risk Assessment Report for Ethylbenzene. http://echa.europa.eu/doc/trd_substances/ethylbenzene/rar/trd_rar_germany_ethylbenzene.pdf

SCOEL (1992). Recommendation from the scientific expert group on occupational exposure limits for xylenes.

UK HSC (2001). UK HSC Consultation Document on EC Directive 2000/39/EC establishing a first list of indicative occupational exposure limit values at EC level in implementation of council directive 98/24/EC on the protection of the health and safety of workers from the risks related to chemical agents at work. UK Health and Safety Commission. Available from www.hse.gov.uk/condocs.

 

 


Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Although there are no studies on the intermediate itself, there are sufficient data on the components present. Classification with respect to skin irritation is required for any complex substances and intermediates that have a combined total concentration of irritating components ≥10% (CLP) or ≥20% (DPD). Based on the existing data and the concentrations indicated in the intermediate, the following classification is mandatory: Xi, R38 according to Dir 1999/45/EC and Category 2, H315 according to Reg (EC) 1272/2008.

 

The minor components styrene, ethylbenzene and xylenes are classified as irritating to the eye. Complex substances and intermediates containing ≥10% as a total concentration should be labelled for eye irritation “Causes serious eye irritation” Category 2 H319 under Reg (EC) 1272/2008. As the total concentration of these minor components does not exceed ≥20%, the intermediate does not require labelling according to Dir 1999/45/EC.

 

Whilst ethyl benzene and xylenes are themselves classified as irritating to the respiratory tract, the combined concentration does not exceed 10%; hence classification is not triggered for the intermediate.