Registration Dossier

Administrative data

Description of key information

In animal studies xylene isomers (including mixed xylene) 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.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 523 mg/kg bw
Quality of whole database:
Multiple studies conducted in rats and mice consistently demonstrate that the oral LD50 for xylene isomers (including mixed xylene) exceeds 2000 mg/kg bw.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
27 124 mg/m³
Quality of whole database:
Multiple studies conducted in rats and mice consistently demonstrate that the inhalation LC50 for xylene isomers (including mixed xylene) exceeds 20,000 mg/m3.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
12 126 mg/kg bw
Quality of whole database:
The available data indicate that the dermal LD50 in rabbits exceeds 2000 mg/kg bw.

Additional information

The multi-constituent substances covered by this registration comprise individual xylene isomers (m-xylene, o-xylene, p-xylene) and ethyl benzene (>10% - <20%). The following information is available to characterise their acute health hazards.

Acute toxicity: oral

Non-human information

Acute oral data is available for mixed xylene, xylene isomers and ethyl benzene.

The acute oral LD50 of mixed xylene (containing 17% ethyl benzene) in rats is 3523 mg/kg. This information is derived from what is considered to be the key study (NTP, 1986) as this is the most recent study with the lowest reported LD50 value.

Xylene is of low toxicity via the oral route. The LD50 values for xylene isomers (including mixed xylene) 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 ethyl benzene is low with LD values above 2000 mg/kg.An oral LD50 of 3500 mg/kg was determined for rats (male/female) (RAR 2008).

Human information

No relevant information sourced for mixed xylene, xylene or ethyl benzene.

Acute toxicity: inhalation

Non-human information

An LC50 value of 27,571 mg/ m3 was obtained for male rats exposed to mixed xylene (composition undefined) for 4 hours (Hine, 1970).

Considering xylene isomers, an LC50 of 27,124 mg/m3 has 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/m3 is a combined value for males and females; the LC50 for males was 25,713 mg/m3 and for females, 28,570 mg/m3.

Ethyl benzene is harmful by inhalation, with the LC50 in rats reported as 17,600 mg/m3after the guideline exposure period of 4 hours (RAR, 2008).

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 ethyl benzene (RAR, 2008).

Acute toxicity: dermal

Non-human information

The data for mixed xylene (composition undefined) supports the conclusion that the LD50 would be >2000 mg/kg bw, with an LD50 of >4600 mg/kg bw reported (Hine & Zuidema, 1970).

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 ethyl benzene has been reported as being tested with rabbits and revealed a dermal LD50 of 15500 mg/kg (RAR, 2008).

Human information

No human information is available.


Justification for selection of acute toxicity – oral endpoint
For mixed xylene an acute oral LD50 in rats of 3,523 mg/kg is derived from NTP (1986). This is the most recent investigation available and provides the lowest oral LD50 value for xylene isomers (including mixed xylene). The oral LD50 of ethyl benzene in rats is 3500 mg/kg (RAR, 2008).

Justification for selection of acute toxicity – inhalation endpoint
For p-xylene an acute inhalation LC50 in rats of 27,124 mg/m3 is available (HLE, 1986). This is the most recent investigation available and provides the lowest inhalation LC50 value for a 4-hr exposure period. For mixed xylene, an LC50 of 27,571 mg/m3 has been reported (Hine and Zuidema, 1970). A 4 hr LC50 of 17,600 mg/m3 has been reported for ethyl benzene in rats (RAR, 2008).
Note: Although xylene isomers (including mixed xylenes) are classified H332 - Harmful if inhaled according to the CLP regulation, the rationale for this is not clear since the available LC50 values are clearly greater than 20,000 mg/m3. Ethyl benzene is also classified H332 according to the CLP regulation.

Justification for selection of acute toxicity – dermal endpoint
A dermal LD50 in rabbits of 12,126 mg/kg bw is derived for m-xylene from Smyth et al. (1962) while an LD50 of >4200 mg/kg bw is reported for mixed xylene (Hine and Zuidema, 1970). The dermal LD50 of ethyl benzene in rabbits is 15,500 mg/kg bw (RAR, 2008).
Note: Although xylene isomers (including mixed xylene) are classified H312 - Harmful in contact with skin according to the CLP regulation, the rationale for this is not clear since the LD50 is clearly above 2,000 mg/kg bw.

Justification for classification or non-classification

Although xylene (including mixed xyxlene and xylene isomers) 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.

Ethyl benzene is classified as Harmful by inhalation in Annex I of Dir 67/548/EEC and in Annex VI of the CLP regulation.

No classification is warranted for acute toxicity via oral route under DSD or CLP for either xylenes or ethyl benzene.

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.

Ethyl benzene is not classified for acute toxicity via the dermal route.

Aspiration 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.