Registration Dossier

Diss Factsheets

Administrative data

Description of key information

In animal studies xylene isomers, ethylbenzene and mixed xylenes exhibit low acute toxicity by oral and dermal routes with the reported LD50 values all exceeding 2000 mg/kg bw. Mixed xylene is considered harmful by inhalation.

In humans critical effects of xylenes are irritation and CNS effects, with the overall NOAEC inhalation for the latter effect being 300 mg/m3.

Data on the components benzene, toluene and styrene indicate that no classification is warranted on the basis of acute lethality following exposure via oral, dermal or inhalation routes. Although toluene produces unsteady gait and other indications of neurobehavioural activity at concentrations < 20 mg/L the levels in mixed xylenes are not sufficient to warrant classification.

Key value for chemical safety assessment

Additional information

Mixed xylene (CAS 1330-20-7) comprises individual xylene isomers (m-xylene, o-xylene, p-xylene) and ethylbenzene. Data for these substances and the specific component substances benzene, toluene and styrene have been included as supporting information.

Acute toxicity: oral

Non-human information

Acute oral data is available for individual xylene isomers, ethylbenzene and for mixed xylenes Xylene is of low toxicity via the oral route. The LD50 values for xylene isomers (including mixed xylenes) range from 3523 to 8400 mg/kg (NTP, 1986; Hine & Zuidema, 1970; Wolf et al., 1956; Smyth et al., 1962). The acute oral toxicity of ethylbenzene is low with LD values above 2000 mg/kg. An oral LD50 of 3500 mg/kg was determined for rats (male/female) (RAR 2008). For mixed xylenes (containing 17% ethylbenzene) the acute oral LD50 in rats of 3523 mg/kg is derived from what is considered to be the key study (NTP, 1986) as the most recent with the lowest reported LD50 value. Acute oral LD50 values of >2000 mg/kg, approx. 5000 mg/kg and >5000 mg/kg have been reported for benzene (Kimura et al., 1971; Withey and Hall, 1975), styrene (EU, 2008) and toluene (Withey and Hall, 1975), respectively.

Human information

No relevant information sourced for xylene or ethylbenzene.  

Acute toxicity: inhalation

Non-human information

Considering xylene isomers, an LC50 of 27,124 mg/m3has been derived for p-xylene from what is considered to be the key study (HLE, 1986). This study provides the lowest reported LC50 value for a guideline exposure period of 4 hours. This is a GLP compliant study and the most recently conducted. The LC50 value of 27,124 mg/m3is a combined value for males and females; the LC50 for males was 25,713 mg/m3and for females, 28,570 mg/m3. Ethylbenzene is harmful by inhalation, with the LC50 in rats reported as 17,600 mg/m3after the guideline exposure period of 4 hours (RAR, 2008). An LC50 value of 27,571 mg/ m3was obtained for male rats exposed to mixed xylenes (composition undefined) for 4 hours (Hine, 1970).

Acute inhalation LC50 values of 44,500 mg/m3, 11,810 mg/ m3 and >20,000 mg/ m3 have been reported for benzene (Drew and Fouts, 1974), styrene (EU, 2008) and toluene BASF, 1980), respectively.

Human information

Mild eye and upper tract respiratory tract irritation has been reported (see 5.3 below). Neurological and physiological symptoms have been reported in workers exposed to xylene, but this is mainly resulting from exposure to solvent mixtures and therefore difficult to attribute directly to xylene.The lowest NOAEC reported for CNS effects which is considered reliable is for p-xylene at 70 ppm (Anshelm Olson, 1985).This value is consistent both with the SCOEL review and reviews (e. g. UK HSC, 2001) supporting the existing IOELV for the xylene isomers.

There are no specific human data for ethylbenzene (RAR, 2008).

Styrene exposure has been associated with CNS effects in humans. CNS depression, measured by psychomotor tests was noted after exposure to 376 ppm for 1 hour but no significant effects were observed at 216 ppm (Stewart 1968).

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). Acute toxicity: dermal

Non-human information

A dermal LD50 in rabbits of 12,126 mg/kg is derived for m-xylene from what is considered to be the key study (Smyth, 1962) as the lowest reported LD50 value. The acute dermal toxicity of ethylbenzene has been reported as being tested with rabbits and revealed a dermal LD50 of 15500 mg/kg (RAR, 2008). The data for mixed xylenes (composition undefined) also support the conclusion that the LD50 would be >2000 mg/kg bw with an LD50 of >4600 mg/kg bw reported (Hine & Zuidema, 1970). Acute dermal LD50 values of >8,260 mg/kg and >5,000 mg/kg have been reported for benzene (Roudabush at al., 1965) and toluene (Smythe et al., 1969), respectively. No information is available on the acute dermal LD50 of styrene (EU, 2008).

Human information

No relevant information sourced for xylene or ethylbenzene.

Justification for classification or non-classification

INHALATION Although mixed xylene (considering the xylene isomers and ethylbenzene) is classified as Xn, R20 Harmful by inhalation under Annex I of Dir 67/548/EEC, the rationale for this is not clear since the LC50 is clearly above 20,000 mg/m3and classification would appear not to be justified. Corresponding classification under CLP is of H332 Harmful if inhaled.

Ethylbenzene is classified as Harmful by inhalation in Annex I of Dir 67/548/EEC and in Annex VI of the CLP regulation.Styrene and toluene are both classified as Xn R20corresponding to H332 Harmful if inhaled under CLP

ORAL No classification is warranted for acute toxicity via oral route under DSD or CLP for either mixed xylenes, ethylbenzene or any of the specific component substances..

DERMAL Although xylene (all isomers) is currently classified under DSD Xn, R21 Harmful in contact with skin under Annex I of Dir 67/548/EEC, the rationale for this is not clear since the LC50 is clearly above 2,000 mg/kg bw and classification would appear not to be justified. Corresponding classification under CLP is H312 Harmful in contact with skin.

Ethylbenzene and the specific components benzene, tolueneand styrene are not classified for acute toxicity via the dermal route.

ASPIRATION This is a known hazard of hydrocarbons and classification is based on the physical characteristics of mixed xylene as a kinematic viscosity is considered to be below the cut off values for DSD of 7mm2/s and for CLP of 20.5 mm2/s for hydrocarbons and therefore classification as Xn; R65 Harmful: May cause lung damage if swallowed under DSD and under CLP, Cat 1 H304 May be fatal if swallowed and enters airways is warranted.

Toluene is classified as R67 Vapours may cause dizziness or drowsiness. However mixed xylenes contain toluene below the trigger level of 20 % toluene which would warrant classification under DPD or CLP.