Toluene

Endpoint summary

Description of key information

Toluene is of low acute toxicity by the oral (LD50 > 5000 mg/kg), dermal (LD50> 5000 mg/kg) and inhalation (4 hour LC50 >20 mg/L) routes.  In humans a number of subjective sensations such as headache, dizziness, feeling of intoxication, irritation and sleepiness and decreases in acute neurobehavioural performance are seen following acute exposure = 75 ppm.  The NOAEC of 50 ppm (192 mg/m3) for acute neurobehavioural effects in humans is taken into account in the risk characterisation of acute neurotoxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-guideline, non-GLP, animal experimental study, published in peer-reviewed literature. Pre-dates implementation of GLP and guideline but otherwise acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

yes

Remarks:

only male rats used

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Sprague-Dawley Cobb

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Canadian Breeding Farms, St. Constante, Quebec, Canada
- Weight at study initiation: 150-200 g
- Fasting period before study: overnight prior to dosing
- Housing: individually
- Diet: rat pelleted diet ad libitum
- Water: ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- no data

IN-LIFE DATES: no data

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

Dose levels selected based on the results of a pilot study

Doses:

5 dose levels; 4000, 4560, 5200, 5930, or 6760 mg/kg

No. of animals per sex per dose:

20 males

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: observed three times daily, weighed prior to the day of dosing
- Necropsy of survivors performed: yes

Statistics:

LD50's were estimated by the method of probit analysis. The analysis included a goodness of fit test to ensure that the probit model was applicable.

Sex:

male

Dose descriptor:

LD50

Effect level:

5 580 mg/kg bw

95% CL:

5 300 - 5 910

Remarks on result:

other: death within 36 hours of dosing and neurotoxic effects at high doses

Mortality:

The majority of deaths occurred 24-36 hours after dosing

Clinical signs:

other: Rats dosed at high levels with toluene exhibited hind-limb paralysis and petechial bleeding, especially from the urinary tract, eyes and nose

Gross pathology:

Epithelial cells of the stomach lining were stripped and mild acute gastritis was observed in the glandular portion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The LD50 of toluene, calculated by probit analysis, was 5580 mg/kg to male rats.

Executive summary:

The acute oral LD50 was determined to be >5000 mg/kg using groups of 20 males rats. Toluene is of low oral toxicity and does not warrant classification under Dir 67/548/EEC or GHS.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

The available data provide information that is adequate for the purpose of hazard assessment

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

other: Recommendation from the Scientific Committee on Occupational Exposure Limits

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Science position underpinning EU occupational exposure limit for toluene

Qualifier:

no guideline required

Principles of method if other than guideline:

Scientific review of underlying human neurological effects data, in support of Dir 2006/15/EC

GLP compliance:

no

Test type:

other: regulatory review

Limit test:

yes

Species:

other: human

Route of administration:

inhalation: vapour

Sex:

male/female

Dose descriptor:

other: STEL (15 min)

Effect level:

100 ppm

Based on:

test mat.

Remarks on result:

other: SCOEL concluded that an IOELV-STEL of 100 ppm (384 mg/m3) would protect against both short-term neurological effects and short-term local effects

The critical health effect underpinning the IOELV-STEL for toluene was human neurological changes reported at high exposures, with data supporting a NOAEC of 80 ppm (300 mg/m3) for 4.5 hr. Toxicokinetic information indicated that since the steady-state level of toluene in blood was achieved after exposures of around 25 min of exposure, a 15 min exposure to 100 ppm (384 mg/m3) would not lead to adverse health effects. In addition, while high concentrations of toluene vapour have been associated with symptoms of eye and upper respiratory tract irritation in human volunteers exposed to 75-100 ppm (286 – 383 mg/m3) for several hours, SCOEL concluded that an IOELV-STEL designed to minimise acute neurological effects would also mitigate the possibility of other short-term adverse effects.

Executive summary:

The critical health effect underpinning the IOELV-STEL for toluene was human neurological changes reported at high exposures, with data supporting a NOAEC of 80 ppm (300 mg/m3) for 4.5 hr. Toxicokinetic information indicated that since the steady-state level of toluene in blood was achieved after exposures of around 25 min of exposure, a 15 min exposure to 100 ppm (384 mg/m3) would not lead to adverse health effects. In addition, while high concentrations of toluene vapour have been associated with symptoms of eye and upper respiratory tract irritation in human volunteers exposed to 75-100 ppm (286 – 383 mg/m3) for several hours, SCOEL concluded that an IOELV-STEL designed to minimise acute neurological effects would also mitigate the possibility of other short-term adverse effects.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

384 mg/m³ air

Quality of whole database:

The available data provide information that is adequate for the purpose of hazard assessment

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study pre-dates GLP and guideline development and has limitations in design and reporting but otherwise acceptable for assessment.

Principles of method if other than guideline:

Study investigated mortality in groups of 4 male rabbits exposed for 24 hours. No further details are provided but gives adequate relative guide to LD50.

GLP compliance:

no

Test type:

other:

Limit test:

no

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.5 to 3.5 kg

No other data provided

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24 hours

Doses:

- no data

No. of animals per sex per dose:

4 males

Control animals:

not specified

Sex:

male

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

95% CL:

9.63 - 20.77

Remarks on result:

other: LD50 quoted as 14.1 mL/kg (12267 mg/kg using density of 0.87)

LD50 quoted as 14.1 mL/kg (9.63 -20.77)

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 value of 14.1 mL/kg (9.63-20.77), corresponding to 12267 g/kg (8.38-18.07).

Executive summary:

Acute dermal toxicity in the rabbit was found to be low (LD50 >5000 mg/kg). Toluene does not warrant classification under GHS / CLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

The available data provide information that is adequate for the purpose of hazard assessment

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

Non-human information

Acute toxicity: oral

The acute oral toxicity of toluene is considered to be low (LD₅₀> 5000 mg/kg). Withey and Hall (1975) performed what is considered to be the key study using a method which resembles that of EU guideline B1 (Acute toxicity (oral)). Groups of 20 male rats, were fasted overnight, dosed with 4000, 4560, 5200, 5930, or 6760 mg/kg of toluene and observed three times daily for at least 7 days after dosing. Rats dosed at high levels with toluene exhibited hind-limb paralysis and petechial bleeding, especially from the urinary tract, eyes and nose. The LD₅₀ was calculated to be 5580 mg/kg. Similar oral LD₅₀values (approximately 5600 mg/kg and 6400 mg/kg for younger and older adult rats, respectively) were reported by Kimura et al (1971).

Acute toxicity: inhalation

Acute 4 hour inhalation toxicity was investigated in groups of 10 male and female rats (BASF, 1980). Exposure concentrations were 6.08, 20.00, 23.98, 38.87 and 61.80 mg/L. The LC50 was calculated to be > 20 mg/L (28.1 mg/L in males and females; 25.7 mg/L in males and 30 mg/L in females). According to the EU RAR (2003), animals showed watery discharge from eyes and nose, unrest, increased respiration, rocking gait, narcosis, startling movements and hyperaemia of the ears and extremities. In the highest exposure group, salivation was observed. In the group exposed to 6.08 mg/L of toluene, no adverse clinical signs were observed. All surviving rats appeared normal after 3 days following the exposure.

Acute toxicity: dermal

A single acute dermal toxicity study on toluene in the rabbit has been found (Smyth et al, 1969). Fur was removed from the entire trunk by clipping and the dose held in contact with the skin for 24 hours (retained by impervious plastic film). The 4 animals per group were immobilised during the contact period, after which the film was removed and the rabbits caged for a 14 day observation period. The LD₅₀ value was reported to be 14.1 mL/kg, corresponding to 12267 mg/kg (using a density of 0.87). No information on clinical signs or mortality pattern was provided.

Human information

The acute effects of toluene inhalation exposure have been investigated in a number of human experimental studies in volunteers. These studies indicate that toluene produces a number of subjective sensations such as headache, dizziness, feeling of intoxication, irritation and sleepiness and decreases in acute neurobehavioural performance at concentrations = 75 ppm (EU RAR, 2003). Muttray et al (2005) exposed twenty healthy men to a constant level of 50 ppm toluene. The Pupillographic Sleepiness Test (PST) was performed before and after 4.5 hours of exposure. Acute symptoms were assessed with the Swedish Performance Evaluation System (SPES) self-assessment questionnaire, once before and 3 times during exposure. There was no effect of toluene exposure on PST or tiredness but scores for unpleasant smell and irritation to the throat were increased.

When reviewing critical health effects underpinning an indicative occupational exposure limit (IOELV) for toluene, SCOEL noted that while human neurological changes were reported at high exposures the data supported a NOAEC of 80 ppm (300 mg/m3) for 4.5 hr. Since toxicokinetic information indicated that steady-state levels of toluene in blood were achieved after exposures of around 25 min of exposure, SCOEL concluded that a 15 min exposure to 100 ppm (384 mg/m3) would not lead to acute neurological effects. Furthermore, the IOELV-STEL was likely to protect against other short-term (subjective, irritative) effects.

Justification for selection of acute toxicity – oral endpoint
The available key and supporting studies indicate that the acute oral toxicity of toluene is low (LD50 >5000 mg/kg)

Justification for selection of acute toxicity – inhalation endpoint
The available animal data indicate that the acute inhalation toxicity of toluene is low (LC50 >20000 mg/m3). Information supporting the IOELV indicates that no adverse neurological effects are expected following short-term (15 min) exposure to 100 ppm (384 mg/m3) toluene. CNS depression is apparent at higher exposures.

Justification for selection of acute toxicity – dermal endpoint
The available data indicate that the acute dermal toxicity of toluene is low (LD50 >12000 mg/kg)

Justification for classification or non-classification

Toluene is of low acute toxicity by the oral, dermal, and inhalation routes with LD50/LC50 values exceeding the doses which would warrant classification under GHS / CLP.

Since data from experimental exposure of human volunteers show that dizziness and sleepiness are experienced at air levels < 20 mg/L for 4h and rocking gait and narcosis were observed in rats in the BASF study at this same concentration then toluene justifies classification as STOT-SE 3 (H336) under GHS / CLP.

The low viscosity of toluene (dynamic viscosity of 0.56 mPa s at 25°C and a surface tension of 27.93 nM at 25°C) justifies classification under GHS / CLP, Aspiration toxicity Category 1 assigned H304.