Registration Dossier

Administrative data

Description of key information

There are no skin and eye irritation data are available on any of the streams within this category (CAS Numbers; 102110-14-5, 64741-84-0, 64742-49-0, 68476-55-1,92128-65-9). However there are data on constituents present in some streams which indicate that Aliphatics and Cyclics C5 and Higher streams should be considered to be irritating to skin and eyes and that classification is appropriate with respect to the skin.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion, other
Remarks:
In Vivo
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline compliant study, GLP status unknown, limitations in reporting but otherwise acceptable.
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
not specified
Species:
rabbit
Type of coverage:
other: under exposure chamber
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
Neat, 0.5 mL, to an area of 6cm2
Duration of treatment / exposure:
4 hours
Observation period:
144 h (i.e. 6 days) after end of application
Number of animals:
6
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24/48/72 h
Score:
> 2
Reversibility:
no data
Remarks on result:
other: erythema score 3.00 at 144 h
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24/48/72
Score:
0
Reversibility:
fully reversible
Remarks on result:
other: oedema only seen at 1 h

Mean scores (Draize et al 1944):

Time after end of application

1 h

24 h

48 h

72 h

144 h

Mean score for erythema

1.00

2.00

2.20

2.40

3.00

Mean score for edema

2.20

0.00

0.00

0.00

0.00

 

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Benzene is considered to be irritating to rabbit skin (mean over 24/48/72 h for erythema >2)
Executive summary:

The irritation potential of benzene was assessed on the skins of six shaved rabbits exposed to neat benzene for 4 hours, using an exposure chamber of 6 cm2. One hour after exposure oedema grade 2 and erythema grade 1 were documented. No oedema, but mean scores of 2.0/2.2/2.4 for erythema were recorded at 24, 48, and 72 hours after the end of exposure. Erythema increased to a mean of grade 3 at 6 days.

It is concluded that benzene is irritating to rabbit skin and should be classified as Xi, R38. Under CLP it is proposed that the appropriate classification is Category 2, H315.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation, other
Remarks:
In Vivo
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study available as unpublished report, no restrictions, fully adequate for assessment.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: HRP, Inc, Denver, PA, USA
- Age at study initiation: males approx 12-13 weeks, females approx 11-12 weeks
- Weight at study initiation: 2.24-2.95 kg
- Housing: single housed in suspended stainless steel and wire mesh cages
- Diet: Agway certified diet RCA Rabbit (pellets) ad libitum
- Water: ad libitum via automatic system
- Acclimation period: at least 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: approx 18-21°C
- Humidity: 40-60%
- Air changes (per hr): no information
- Photoperiod: 12 hrs dark /12 hrs light

IN-LIFE DATES: From: 4 October 1994 To: 11 October 1994
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 mL
Duration of treatment / exposure:
Single application
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
6 (4 male and 2 female)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): NA - eyes were unwashed.

SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: 2% sodium fluorescein under UV light
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: no corneal effects
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Remarks on result:
other: mild iritis in 3 animals at 1 hour only
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
1.4
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: scores of 2 or 3 in all animals at 24 hours, 1 or 2 in all animals at 48 hours and 1 in 4 animals at 72 hours
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.4
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: minimal chemosis in 5 animals at 24 hour and persisting until 48 hours in 2 animals
Irritant / corrosive response data:
There were no corneal effects and iridial effects were limited to 3 animals at the 1 hour observation only. At 1 hour conjunctival redness, chemosis, and discharge were observed in all animals. Redness was observed in all animals at 24 and 48 hours and in four animals at 72 hours. Chemosis was observed in five animals at 24 hours and two animals at 48 hours. Discharge was observed in four animals at 24 hours. In addition, dye retention of the nictitating membrane was observed in three animals at 24 hours and one at 48 hours. All conjunctival effects had recovered by day 7.


Other effects:
Clinical signs were not observed in any animal and all animals survived to study termination

Mean ocular irritation scores for each observation interval

 

1 hour

24 hour

48 hour

72 hour

7 day

Corneal opacity

0

0

0

0

0

Iritis

0.5

0

0

0

0

Conjunctival redness

3.00

2.17

1.50

0.67

0

Chemosis

3.33

0.83

0.33

0

0

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Toluene is not irritating to the rabbit eye.
Executive summary:

The eye irritation potential of toluene was evaluated following a single 0.1 mL instillation to the right eye of 6 New Zealand White rabbits. The treated eyes of all animals remained unwashed. Observations for signs of ocular irritation and toxicity were made at 1, 24, 48, and 72 hours post-instillation and on Day 7.

There were no corneal effects and iridial responses were limited to three animals at 1 hour. Toluene elicited conjunctival irritation in all animals from 1 hour which persisted until 72 hours in 4 animals but was fully recovered by day 7.

Toluene is slightly irritating to the rabbit eye but no classification is warranted under Dir 67/548/EEC or GHS.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Non-human information

There are no specific skin or eye irritation studies on any of the streams. Data on the specific components benzene (Jacobs, 1991), toluene (Exxon, 1988), n-hexane and pentane indicate some irritation following dermal contact with effects sufficiently severe for all except pentane to warrant labelling. Eye irritation data on the specific components benzene, toluene ((Exxon, 1995), pentane indicate that instillation of liquid test substance into the eye induces some evidence of eye irritation. For benzene the effects are sufficient to warrant labelling (Wolf et al, 1956).

The irritation potential of benzene was assessed on the skins of six shaved rabbits exposed to neat benzene for 4 hours, using an exposure chamber of 6 cm2(Jacobs. 1991). One hour after exposure oedema grade 2 and erythema grade 1 were documented. No oedema, but mean scores of 2.0/2.2/2.4 for erythema were recorded at 24, 48, and 72 hours after the end of exposure. Erythema increased to a mean of grade 3 at 6 days. A second study (Wolf et al, 1956) examined skin irritation potential of benzene following repeated applications. Undiluted benzene was applied 10 -20 times over 2-4 weeks to the ear and shaved abdomen of white rabbits (abdomen bandaged). Perceptible to definite erythema, oedema and superficial necrosis were documented. These effects resulted in a "chapped" appearance and exfoliation of large patches of skin. Although the design and reporting are not compliant with regulatory guidelines the results are consistent with benzene being irritating to rabbit skin.

Human information

There is no specific human information concerning skin or eye irritation on any of the streams or on the majority of specific components identified as present in some streams. Specific information are available for benzene and toluene:

Benzene (Classification: EU - Irritating Xi, R36, R38; GHS/CLP - Category 2 H319, Category 2 H315): Liquid benzene on direct contact with the skin may cause erythema and blistering. Skin contact with benzene removes fat from the tissue which may result in the development of a dry, scaly dermatitis if exposure is repeated or prolonged. High concentrations of benzene vapours are irritating to the mucous membranes of the eyes, nose and respiratory tract (EU RAR, 2008).

Toluene (Classification: EU - Irritating Xi, R38; GHS/CLP - Category 2 H315): No data on skin irritation have been found. 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 RAR, 2003). In a recent study, 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.

Cyclohexane (Classification: Category 2 H315): Cyclohexane is classified as having a potential to cause skin irritation according to CLP.

Heptane (Classification: Category 2 H315): Heptane is classified as having a potential to cause skin irritation according to CLP.

References

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 (2008). European Union Risk Assessment Report for Benzene. EC Joint Research Centre. http: //ecb. jrc. ec. europa. eu/documents/Existing-chemicals/RISK_ASSESSMENT/REPORT/benzenereport063. pdf.


Justification for selection of skin irritation / corrosion endpoint:
Information on the marker substances present indicates a potential for irritation following dermal contact with effects sufficiently severe to warrant classification. Results obtained for the key component benzene are considered indicative of the overall effects of these streams on the skin.

Justification for selection of eye irritation endpoint:
Information on the marker substances present indicate a potential for irritation following eye contact with effects sufficiently severe to warrant classification. Results obtained for the key component toluene are considered indicative of the overall effects of these streams on the eye.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: slightly irritating

Justification for classification or non-classification

Although there are no studies on the streams identified for this category there are sufficient data on component substances to indicate that Aliphatics and Cyclics C5 and Higher streams are irritating to the skin and should be classified Category 2, H315 according to Reg (EC) 1272/2008. Streams that contain >10% benzene will be required to be labelled for eye irritation, Category 2, H319 under Reg (EC) 1272/2008.