Registration Dossier

Administrative data

Description of key information

Toluene is irritating to skin and eyes in animals however classification is required only with respect to 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:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study, no restrictions, fully adequate for assessment.
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products Inc, Denver, Pennsylvania, USA
- Age at study initiation: approximately 13 weeks
- Weight at study initiation: 2-3 kg
- Housing: individual in suspended stainless steel cages.
- Diet (e.g. ad libitum): Purina Rabbit Chow HF (pellets) ad libitum
- Water (e.g. ad libitum): ad libitum via automatic system
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 65-70°F (approx 18-21°C)
- Humidity: 40-88%
- Air changes (per hr): no data
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 12 July 1988 To: 19 July 1988
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.5 mL
Duration of treatment / exposure:
4 h
Observation period:
7 days
Number of animals:
7
Details on study design:
TEST SITE
- Area of exposure: right dorsal side
- % coverage: no information
- Type of wrap if used: gauze patch held loosely in contact with the skin by means of a semi-occlusive dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was removed using distilled water and paper towels
- Time after start of exposure: 4 hours

SCORING SYSTEM: Observations were according to the Draize method
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
1.8
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: very slight to moderate to severe erythema in all 7 animals 24, 48 and 72 hours
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
1.1
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: very slight oedema in 5 animals at 24 hours. Very slight to slight oedema in all 7 animals at 48 and 72 hours.
Irritant / corrosive response data:
The incidence and severity of irritation increased as the study progressed, and by 72 hours all animals exhibited erythema, ranging from very slight to severe, and slight oedema. On day 7, erythema ranged from well-defined to severe for all animals, and oedema ranged from very slight to slight for 5 animals. The mean score for erythema was 2.43 at 72 hours and on day 7. The inflammation persisted in all test animals at the end of the observation time (individual scores for erythema on day 7 were 2, 2, 2, 4, 2, 3, and 2).

Mean scores for skin irritation

45 min

24 h

48 h

72 h

7 days

Mean (24, 48, and 72h scores)

Erythema

0.14

1.14

1.86

2.43

2.43

1.81

Oedema

1.00

0.71

1.14

1.43

0.86

1.10

 

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Toluene is moderately skin irritating.
Executive summary:

The skin irritation potential of toluene was assessed in 7 rabbits according to EU method B4. 0.5 mL of neat toluene was applied under semi-occlusive dressings for 4 hour and irritation responses noted for up to 7 days.

Erythema was seen in all 7 animals from 24 hours and persisted in all animals on day 7. Oedema was seen in all 7 animals from 24 or 48 hours and was still present in 5 animals on day 7. A mean erythema score exceeding 2 was observed which persisted for more than 24 hours (from 72 hours to 7 days) and persisted in all test animals at the end of the observation time (individual scores for erythema on day 7 were 2, 2, 2, 4, 2, 3, and 2).

Toluene is considered to be irritating to rabbit skin and warrants Category 2, H315, under GHS / CLP.

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:
experimental study
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
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:
slightly 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 GHS / CLP.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

LOA is currently reviewing the human and animal data supporting Human Health for Toluene. It is expected to be completed by Q4 2020.

The irritation potential of toluene was reviewed and reported in the EU RAR (2003). No additional relevant animal data has been sourced in the updated literature review.

Skin

Non-human information

In the key study identified, the skin irritation potential of toluene was assessed in 7 rabbits according to EU method B4 (Exxon, 1988). Toluene caused significant inflammation of the skin as a mean erythema score exceeding 2 was observed which persisted for more than 24 hours. In addition, the inflammation persisted in all test animals at the end of the observation time (individual scores for erythema on day 7 were 2, 2, 2, 4, 2, 3, and 2). In a supporting study (Guillot et al, 1982a) skin irritation potential was assessed using four different methods. The most relevant method used a group of six rabbits and semi-occlusive dressings, although a French scoring system was used and therefore results are not readily interpreted. Toluene was classified as a slight irritant (PCI 2.13). The results are consistent with the Exxon study and indicate that toluene is irritating to skin.

Human information

No data 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.”

Eye

Non-human information

In the key study, ocular irritation potential of toluene was evaluated in a study performed according to OECD Guideline 405, and of GLP quality (Exxon, 1995). Ocular lesions (redness, chemosis) occurred within 72 hours after exposure and persisted for at least 24 hours. However, the mean score (24, 48 and 72 hours) for redness of the conjunctivae and chemosis did not exceed values of 2.5 and 2, respectively. Sugai et al (1990) also assessed eye irritation potential. Although the report does not contain irritation scores it is reported that "corneal involvement or irritation that persists for more than 24 hours but recovers within 21 days" was seen. A third study (Guillot et al, 1982b) used a non-standard scoring system (mean ocular irritation index) that does not allow classification according to the EU system. However the conclusion that toluene was irritating to the eye with or without rinsing after 30 seconds is consistent with the results of other studies.

Human information

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 (192 mg/m3) toluene is a NOAEC for eye irritation in humans.


Justification for selection of skin irritation / corrosion endpoint:
The available key and supporting studies indicate that toluene is irritating to the skin. Other information indicates that it possesses defatting properties

Justification for selection of eye irritation endpoint:
The available key and supporting studies indicate that toluene is slightly irritating to the eye but not to an extent that warrants classification

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: slightly irritating

Justification for classification or non-classification

The results of animal studies show that toluene is irritating to the skin of rabbits. It is also reported that toluene has defatting properties. It is proposed that the appropriate classification is Category 2, H315, under GHS / CLP.

Toluene is slightly irritating to the eyes in both animal and human studies, but not to an extent that warrants classification.

Toluene can cause irritation to the respiratory tract in animals at very high concentrations. The irritant effect of lower concentrations has not been examined and no classification for respiratory irritation is proposed.