Registration Dossier

Administrative data

Description of key information

The available data indicate that mixed xylene should be considered to be irritating to skin, eyes and the respiratory tract.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-guideline study, GLP status not known, animal experimental study, limitations in design and/or reporting but otherwise adequate for assessment.
Qualifier:
equivalent or similar to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
7 day observation period
Principles of method if other than guideline:
0.5 mL of the undiluted compound was applied to an intact and to an abraded site on the backs of six rabbits. The sites were covered with a gauze patch. After a 4 h exposure period the patch and any excess material remaining were removed. 4 h, 24 h, 48 h, 72 h and seven-day scorings of irritation were made using the method of Draize.
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Male rabbits
- Food and water available ad libitum
- Housing: The rabbits were housed individually in hanging wire bottom cages
- no further details

ENVIRONMENTAL CONDITIONS
- In an air-conditioned room where the temperature was maintained at approximately 70°F
- no further details

IN-LIFE DATES: no data
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.5 mL of the undiluted material
Duration of treatment / exposure:
4 h
Observation period:
Up to 7 days
Number of animals:
6
Details on study design:
Rabbits were clipped on the day prior to testing. 0.5 mL of p-xylene was applied to an intact and an abraded site on the backs of six rabbits. ( Epidermal abrasions made with a hypodermic needle). The application sites were covered with a gauze patch and the trunk of each animal was then loosely wrapped in a plastic sheet followed by a wrapping of paper towels. After a 4 h exposure period the wrappings and any excess material remaining were removed. The application sites were scored for irritation (Draize scale) 4 , 24 , 48 and 72 hours and 7 days.
Irritation parameter:
primary dermal irritation index (PDII)
Score:
3
Remarks on result:
other: score is the summation of the average erythema and oedema for 24 and 72 hours divided by 4
Irritant / corrosive response data:
In general, well-defined erythema and barely perceptible to slight oedema were observed throughout the seven-day observation period on intact skin. Similar irritation was observed on abraded application sites.
Other effects:
Primary Irritation Score: 3.0

Interpretation of results:
other: not corrosive
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
CHEVRON PARAXYLENE 99% was not corrosive to the intact skin of the rabbits tested.
Executive summary:

The skin corrosion potential was determined by exposing the intact skin of six rabbits to p-xylene for four hours. The sites of application were not destroyed or changed irreversibly during or after the exposure. CHEVRON PARAXYLENE 99% was considered not to be corrosive to the intact skin of rabbits.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-guideline study, GLP status not known, animal experimental study, limitations in design and/or reporting but otherwise adequate for assessment.
Qualifier:
no guideline followed
Principles of method if other than guideline:
unwashed eye
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
no further details
Vehicle:
not specified
Controls:
not required
Amount / concentration applied:
no data
Duration of treatment / exposure:
1 h (not confirmed)
Observation period (in vivo):
1, 24, 48 and 72 hours, 4 and 7 days post instillation
Number of animals or in vitro replicates:
3 males and 3 females
Details on study design:
no further details
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 1 hour
Score:
6
Max. score:
10
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
Conjunctival redness (vessels definitely injected above normal to more diffuse, deeper crimson red, individual vessels not easily discernible) was noted in all 6 rabbits at 1 h post instillation of o-xylene. Conjunctival chemosis (swelling above normal) and conjunctival discharge (any amount above normal) were noted in 5 rabbits at 1 h post instillation. Phonation at instillation was noted in 4 rabbits. No corneal opacity or iritis was noted in any of the 6 rabbits. All ocular lesions had cleared by Day 7.

Eye Irritation Score Ranges and Means with Standard Deviations

Observation

Hours

Days

1

24

48

72

4

7

Cornea

 

 

 

 

 

 

Mean

0.0

0.0

0.0

0.0

0.0

0.0

S.D.

0.0

0.0

0.0

0.0

0.0

0.0

Range

-

-

-

-

-

-

Iris

 

 

 

 

 

 

Mean

0.0

0.0

0.0

0.0

0.0

0.0

S.D.

0.0

0.0

0.0

0.0

0.0

0.0

Range

-

-

-

-

-

-

Conjunctivae

 

 

 

 

 

 

Mean

6.0

1.7

1.3

1.3

1.0

0.0

S.D.

2.2

0.8

1.6

1.6

1.1

0.0

Range

2-8

0-2

0-4

0-4

0-2

-

Total Score

 

 

 

 

 

 

Mean

6.0

1.7

1.3

1.3

1.0

0.0

S.D.

2.2

0.8

1.6

1.6

1.1

0.0

Range

2-8

0-2

0-4

0-4

0-2

-

Means based on six observations.

Interpretation of results:
slightly irritating
Remarks:
Migrated information not classified Criteria used for interpretation of results: EU
Executive summary:

Conjunctival redness (vessels definitely injected above normal to more diffuse, deeper crimson red, individual vessels not easily discernible) was noted in all 6 rabbits at 1 h post instillation of o-xylene. Conjunctival chemosis (swelling above normal) and conjunctival discharge (any amount above normal) were noted in 5 rabbits at 1 h post instillation. Phonation at instillation was noted in 4 rabbits. No corneal opacity or iritis was noted in any of the 6 rabbits. All ocular lesions had cleared by Day 7.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Mixed xylene (CAS 1330-20-7) comprises individual xylene isomers (m-xylene, o-xylene, p-xylene) and <10% ethyl benzene. The following information is available to characterise the irritation potential of this substance.

Skin irritation/corrosion

Non-human information

Mild-moderate skin irritation was noted in rats and rabbits treated topically with mixed xylene or the xylene isomers. The extent of the irritation appeared to increase with duration of exposure; the most severe dermal irritation ratings were obtained in the longest exposures of 10-days (Hine, 1970).

The effects of short-term occlusive and repeated non-occlusive dermal exposure to m-xylene was investigated in the hairless rat using erythema, transepidermal water loss and skin moisture content as indicators of dermal irritation (Chatterjee, 2005). M-xylene was found to be mildly irritating to skin following single occluded exposure and repeated non-occluded contact and to damage the barrier function of the skin. 

Skin corrosion potential was determined in one study and this study evaluated p-xylene (Chevron Chemical Company, 1973). The intact skin of six rabbits was exposed to p-xylene for four hours. The sites of application were not destroyed or changed irreversibly during or after the exposure and p-xylene was considered not to be corrosive to the intact skin of rabbits.

As reported in the RAR (2008), single exposure ethyl benzene is moderately irritating to the skin of rabbits. Repeated exposure results in erythema and oedema with superficial necrosis giving a "chapped" appearance and exfoliation of large patches of skin.

 

Human information

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.

Eye irritation/corrosion

Non-human information

Moderate eye irritation was observed in rabbits treated with mixed xylene. Primary irritation studies in rabbits using the washed and unwashed eye (HLA, 1983) demonstrated transient eye irritation (conjunctival redness and oedema) following exposure to o-xylene.  No corneal effects were reported in either study.

Ethyl benzene caused irritation in the eyes of rabbits and guinea pigs (latter exposed to 5000 and 10000 ppm of ethyl benzene vapour) (RAR, 2008). 

Human information

No obvious irritation of the eye was reported in volunteer studies where individuals were exposed to 442 mg/m3 mixed xylene for 15-30 minutes (SCOEL, 1992; Carpenter, 1975; Hastings, 1984).

High concentrations of ethyl benzene vapours are irritating to mucous membranes of the eyes (RAR, 2008).

Respiratory irritation

Non-human information

A respiratory tract irritancy study in mice (HLA, 1983a) reported that exposure to o-xylene at a nominal concentration of 9480 mg/m3 via air inhalation resulted in very slight to slight depressions in respiratory rates indicative of very slight to slight respiratory irritation. For p-xylene at a nominal concentration of 11580 mg/m3, slight to severe depressions in respiratory rates indicative of slight to severe respiratory irritation were reported (HLA, 1983b).

A sensory irritation study in mice (De Ceaurriz, 1981) reported a decrease in respiratory rate during a 5 minute period of exposure of mice to the vapour of o-xylene with an RD50 value of 6370 mg/m3.

For ethyl benzene RD50 values of 1432 or 4060 ppm (6215 to 17620 mg/m3) for sensory irritation were determined in different strains of mice (RAR, 2008).

Human information

Mild irritation of the upper respiratory tract was reported in volunteer studies where individuals were exposed to 442 mg/m3 xylene for 15-30 minutes (Carpenter, 1975; Hastings, 1984).

No symptoms of nose or throat irritation have been reported in volunteers exposed to mixed xylene up to 400 ppm (UK HSC, 2001).

The RAR (2008) reports that high concentrations of ethyl benzene vapours are irritating to the nose and respiratory tract.

Reference

UK HSC (2001): European Commission Directive 2000/39/EC establishing a First List of Indicative Occupational Exposure Limit Values at European Community 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: Consultative Document


Justification for selection of skin irritation / corrosion endpoint:
Mild-moderate skin irritation was reported in rats and rabbits treated topically with mixed xylene or xylene isomers. The extent of the irritation appeared to increase with duration of exposure, however the severity of the response did not appear sufficient to require classification.
Note: Although xylene isomers (including mixed xylene) are classified H315 - Skin irritant Cat 2 according to the CLP regulation, the rationale for this is not clear since the available data indicate a potential to cause no more than mild-moderate skin irritation.

Justification for selection of eye irritation endpoint:
Xylene isomers (including mixed xylene) are considered to be irritating to the eyes and warrant classification H319 - Eye irritant Cat 2.

Effects on skin irritation/corrosion: moderately irritating

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Mixed xylenes are classified as skin irritants under Annex VI of the CLP regulation and therefore H315 (skin irritant Cat 2) applies under CLP.

 

Mixed xylenes are considered to be irritating to the eyes and warrant classification as Cat 2 (H319): induces reversible eye irritation (conjunctival redness and oedema) under CLP.

 

Mixed xylenes are considered to be irritating to the respiratory system based on the occurrence of reversible irritant effects in animal studies and should therefore be classified Category 3 (H335) for specific target organ toxicity - single exposure (STOT-SE) under CLP.

 

According to the RAR (2008) and transitional measures, ethylbenzene warrants classification for irritation to the skin, eyes and respiratory tract (Xi, R36/37/38). Classification under DSD is no longer applicable.