Registration Dossier

Administrative data

Description of key information

No data are available on the intermediate but information is available for the major components which indicate low toxicity by the oral, dermal and inhalation routes.  
Following acute exposures to toluene in humans a number of subjective sensations such as headache, dizziness, feeling of intoxication, irritation and sleepiness and decreases in acute neurobehavioural performance are seen. The NOAEC for acute neurobehavioural effects in humans is 50 ppm (188 mg/m3). Following acute inhalation n-hexane can also cause neurobehavioural effects therefore classification will be required for the intermediate. Because of their low viscosities toluene, cyclohexane and ethylbenzene are also considered aspiration hazards.

Key value for chemical safety assessment

Additional information

No data are available on the intermediate but information is available on four major components. 

 

Non Human Data

 

Oral toxicity

Cyclohexane is of low acute toxicity by the oral route, the lowest LC50 value being reported by (HLA, 1982a) with an LC50 >5,000 mg/kg.

 

Acute oral toxicity data on the specific component n-hexane indicate oral LD50 values in rats of > 2000 mg/kg (ATSDR, 1999).

 

The acute oral LD50 of 4-vinylcyclohexene to male rats is 3.08 (2.49-3.81) mL/kg (Smyth et al 1969). Based on a density of 0.8299 g/cm3 (as cited by the US HPV challenge program), the oral LD50 to male rats is 2556 mg/kg.

 

The acute oral toxicity of toluene is considered to be low (LD50> 5000 mg/kg). An LD50 value of 5580 mg/kg is reported by Withey and Hall (1975) and similar oral LD50 values (approximately 5600 mg/kg and 6400 mg/kg for younger and older adult rats, respectively) are reported by Kimura et al (1971).

 

Dermal toxicity

The dermal LD50 of cyclohexane is estimated to be greater than 2,000 mg/kg (HLA, 1982d) with no deaths or systemic symptoms observed. Slight erythema and oedema were noted in some animals.

 

The acute dermal LD50 of 4-vinylcyclohexene to male rabbits is 20 mL/kg (Smyth et al 1969). Based on a density of 0.8299 g/cm3 (as cited in the US EPA HPV challenge program), the rabbit dermal LD50 is 16598 mg/kg.

 

Smyth et al, 1969 report toluene has an acute dermal LD50 value in rats of > 5000 mg/kg.

 

Inhalation toxicity

A 4-hour exposure LC50 in rats of > 9,500 ppm (32,880 mg/m3 or 32.88 mg/L) is reported by HLA (1982b) for cyclohexane. The acute neurotoxicity of cyclohexane is also discussed under the relevant section of this dossier. Also cited in the EU RAR (2004) is a Treon et al. (1943) publication reporting acute inhalation exposure of rabbits. All the animals exposed to 26,000 ppm (89.6 mg/L) died.

 

Acute inhalation toxicity on n-hexane indicates an acute inhalation LC50 value in rats of > 20 mg/L (>20,000 mg/m3) ATSDR (1999).

 

Following a 4 hour exposure period of 8000 ppm 4-vinylcyclohexene, 4 out of 6 rats died (equivalent to 35396 mg/m3 or 35.396 mg/L) (Smyth et al 1969). Whilst no definitive value is available for lethality following short term inhalation exposure, it can be concluded that 4-vinylcyclohexene has low toxicity via the inhalation route.

 

Acute inhalation toxicity on the toluene (BASF, 1980) indicates an acute inhalation LC50 value in rats of > 20 mg/L (>20,000 mg/m3).

 

 

Human information

Acute neurotoxicity data on cyclohexane is available and reported under the relevant sections of this dossier. The NOAEC in a human volunteer study (Lammers et al, 2009) was 250 ppm (860 mg/m3).

 

Data from occupational exposure and/or volunteer studies that provide information on acute exposures that are of value to the risk assessment process are available for toluene:

 

Toluene (Classification: EU – R65, R67; GHS/CLP: Category 1, H304, Cat 3 H336): The acute effects of toluene inhalation exposure include headache, dizziness, feeling of intoxication, irritation and sleepiness and decreases in acute neurobehavioural performance at concentrations ≥ 75 ppm (EU RAR, 2003). A NOAEC of 50 ppm (188 mg/m3) can be determined for acute neurobehavioural effects in humans (Muttray et al, 2005).

 

Minor components with classification for acute toxicity:

 

Xylenes (Classification: EU: R20, 21; GHS/: Category 4 H332; Category 4 H312).

 

Summary

No data are available on this intermediate but data are available for the major components indicating low toxicity by the oral, dermal and inhalation routes. 

However, toluene produces unsteady gait and other indications of neurobehavioural activity at concentrations < 20 mg/L justifying R67/H336. n-Hexane and cyclohexane are also classified R67/H336. Mixed xylenes are considered to be harmful following acute dermal and inhalation exposures (and are classified R20/H332 and R21/H312) but the level in the reaction mass does not trigger classification.

Because of the low viscosities of toluene, cyclohexane and ethylbenzene, and their concentration in the intermediate, labelling for aspiration hazard is mandatory.

 

Additional References:

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

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

US EPA HPV Challenge Program, November 2006. 4-Vinylcyclohexene, CAS 100-40-3

Justification for classification or non-classification

Although there are no studies on the intermediate, there are sufficient data on component substances to indicate they are of low toxicity by the oral, dermal, and inhalation routes with LD50/LC50 values exceeding the values which would warrant classification under Dir 1999/45/EC or Reg (EC) 1272/2008.

 

Data from experimental exposure of human volunteers show that dizziness and sleepiness are experienced at air levels < 20 mg/L of toluene, and similar effects are considered to occur with n-hexane and cyclohexane; the concentration of these components in the intermediate justifies mandatory classification R67 under Dir 1999/45/EC and Category 3 assigned H336 under Reg (EC) 1272/2008.

 

The low viscosity of toluene, cyclohexane and ethylbenzene are such that labelling is required. Because the intermediate contains ≥10% of these substances, classification Xn, R65 "May cause lung damage if swallowed" is mandatory under Dir 1999/45/EC and under Reg (EC) 1272/2008 "Aspiration toxicity Category 1, H304".