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Description of key information

There are data for repeat exposure to one low benzene naphtha streams representing the inhalation route of exposure and a related stream representing the dermal route.  These do not indicate any specific target organ toxicity which would warrant classification.  However, there are substantial data on the repeated dose toxicity of toluene which demonstrates significant target organ toxicity and, when present at concentrations greater than or equal to 10%, this component substance will influence classification due to mammalian toxicity effects.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Near guideline, GLP animal experimental study, available as published report, fully adequate for assessment
Qualifier:
equivalent or similar to
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
Cited as Directive 87/302/EEC, part B, p. 8
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI., USA
- Age at study initiation: approx. 6-7 weeks
- Housing: 5 per cage in polycarbonate cages with hardwood bedding
- Diet: IH 07 Rat and Mouse Ration (Zeigler Bros., Inc., Gardners, PA) ad libitum
- Water: ad libitum
- Acclimation period: 18days

ENVIRONMENTAL CONDITIONS:
- Temperature: mean temperature 72.4°F (~22.4°C), range 63-82°F (~17-28°C)
- Humidity: mean humidity 59.8%, range 44-82%
- Air changes (per hr): not reported
- Photoperiod: 12hrs dark / 12hrs light

IN-LIFE DATES: Not reported
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Toluene was dissolved in corn oil. Solutions at 20 mg/kg were stable for at least 2 weeks at room temperature

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 31.2, 62.5, 126, 250 and 500 mg/mL
- Amount of vehicle (if gavage): dose volume of 10 mL/kg
- Lot/batch no. (if required): no data
- Purity: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose mixtures were analysed several times during the 13-week studies and found to be within 10% of the target concentrations
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily, 5 days/ week
Remarks:
Doses / Concentrations:
312, 625, 1250, 2500, 5000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes
Details on study design:
Post-exposure period: none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes (for dead and moribund animals)
- Time schedule: twice/day

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: beginning of the study and weekly

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to termination
- Anaesthetic used for blood collection: no data
- Animals fasted: yes
- How many animals: all
- Parameters examined: eosinophils, haematocrit, haemoglobin, lymphocytes, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, mean cell volume, methaemoglobin, monocytes, platelets, erythrocytes, reticulocytes, segmented neutrophils, leukocytes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to termination
- Animals fasted: yes
- How many animals: all
- Parameters examined: blood urea nitrogen (BUN), albumin, calcium, lactate dehydrogenase, inorganic phosphorus, total protein.

URINALYSIS: Yes
- Time schedule for collection of urine: overnight prior to termination
- Animals fasted: yes
- How many animals: all
- Metabolism cage used for collection: yes
- Parameters examined: No data
Sacrifice and pathology:
Necropsy was performed on all animals.
Tissues examined in control, 2500 and 5000 mg/kg/day groups: adrenal glands, aorta, brain, caecum, colon, duodenum, oesophagus, heart, ileum, jejunum, kidneys, liver, lungs, and bronchi, mammary gland, mesenteric lymph nodes, nasal cavity and turbinates, pancreas, parathyroid glands, pituitary gland, preputial or clitoral glands, prostate/testes or ovaries/uterus, rectum, salivary glands, spinal cord, spleen, sternebrae, including marrow, stomach, thymus, thyroid gland, tissue masses, trachea, urinary bladder and gross lesions. Tissues examined in other groups were: brain, kidneys, liver, and urinary bladder.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY
All rats in the 5000 mg/kg group died within the first week. In the 2500 mg/kg group 8 males and one female died before termination of the study. Clinical signs included prostration, hypoactivity, ataxia, piloerection, lachrymation, and excessive salivation in the 5000 and 2500 mg/kg groups.

BODY WEIGHT AND WEIGHT GAIN
The final mean body weight of males that received 2500 mg/kg was 19% lower than that of vehicle controls.

HAEMATOLOGY, CLINICAL CHEMISTRY AND URINALYSIS
A there were no treatment related effects in the haematological and serum chemical analyses or urinalyses.

ORGAN WEIGHTS
Absolute and relative kidney weight was increased in males at 625 mg/kg and higher, and in females at 1,250 mg/kg and higher. The differences in absolute and relative liver weights for female rats that received 2500 or 1250 mg/kg (22-62% relative liver weight increase) and for males that received 1250 or 625 mg/kg (8-78% relative liver weight increase) were statistically significant. Statistically significant increases were also seen in absolute and relative heart weight for male and female rats at 2500 and females at 1250 mg/kg. Absolute, but not relative brain weight was reduced in both sexes at 2500 mg/kg.

HISTOPATHOLOGY
Neuropathological changes in the brain, consisting of neuronal cell necrosis in the dentate gyrus and Ammons horn of the hippocampus, was seen in male and female rats that received 2500 or 1250 mg/kg. In addition to the hippocampal lesions, necrosis and/or mineralisation were present in the granular layer of the cerebellar cortex. Haemorrhage was present in the mucosa, submucosa, or muscularis of the urinary bladder of males and females of the two highest dose groups. A dose of 312 mg/kg/kg did not cause any effects.
Key result
Dose descriptor:
NOAEL
Effect level:
625 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: neuropathology (neuronal cell necrosis in hippocampus)
Key result
Dose descriptor:
LOAEL
Effect level:
1 250 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: adverse clinical signs, differences in brain, liver, kidney and heart weight and neuropathology (neuronal cell necrosis in hippocampus).
Critical effects observed:
not specified
Conclusions:
NOAEL considered to be 625 mg/kg/day. Increased relative weights of liver and kidney are interpreted as toxicologically insignificant differences in liver and kidney weight unaccompanied by histological findings.
Executive summary:

Groups of 10 male and 10 female F344N rats received 0, 312, 625, 1250, 2500, or 5000 mg toluene/kg in corn oil by gavage for 13 weeks. All rats in the 5000 mg/kg group died within the first week. In the 2500 mg/kg group 8 males and one female died before termination of the study. The final mean body weight of males that received 2500 mg/kg was 19% lower than that of vehicle controls. Clinical signs included prostration, hypoactivity, ataxia, piloerection, lachrymation, and excessive salivation in the 5000 and 2500 mg/kg groups. Absolute and relative kidney weight was increased in males at 625 mg/kg and higher, and in females at 1,250 mg/kg and higher.

The differences in absolute and relative liver weights for female rats that received 2500 or 1250 mg/kg (22-62% relative liver weight increase) and for males that received 1250 or 625 mg/kg (8-78% relative liver weight increase) were statistically significant. Statistically significant increases were also seen in absolute and relative heart weight for male and female rats at 2500 and females at 1250 mg/kg. Absolute, but not relative brain weight was reduced in both sexes at 2500 mg/kg. There were no treatment related effects in the haematological and serum chemical analyses or urinalyses. Neuropathological changes in the brain, consisting of neuronal cell necrosis in the dentate gyrus and Ammons horn of the hippocampus, was seen in male and female rats that received 2500 or 1250 mg/kg. In addition to the hippocampal lesions, necrosis and/or mineralisation were present in the granular layer of the cerebellar cortex. Haemorrhage was present in the mucosa, submucosa, or muscularis of the urinary bladder of males and females of the two highest dose groups. A dose of 312 mg/kg/kg did not cause any effects.

The NOAEL for repeat dose oral toxicity is considered to be 625 mg/kg. At this dose increased absolute and relative liver and kidney weight (up to 46% increase in relative kidney weight, up to 78% increase in relative liver weight) were unaccompanied by histopathological findings were present. Therefore, the increased relative weights of liver and kidney are interpreted as toxicologically non-significant signs of metabolic activity related to exposure.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
625 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Adequate information is available on the marker substance toluene to characterise the long-term hazards of these streams after ingestion.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
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, notable limitations in design, but contributing to weight of evidence.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
- only 5/sex/group examined for chronic toxicity at 1 year
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: Fischer-344 rats [CDF(F-344)/CrIBr]
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA., USA
- Age at study initiation: approx. 6-7 weeks
- Housing: group housed, sexes separately, 10/cage in stainless steel suspended cages
- Diet: standard laboratory diet (Wayne Lab-Blox F6, Allied Mills Inc., Chicago, IL., USA) ad libitum (except during exposure)
- Water: ad libitum
- Acclimation period: quarantined for at least 10 days

ENVIRONMENTAL CONDITIONS: No details reported

IN-LIFE DATES: Not reported
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: rectangular stainless steel and glass chambers (nominal volume 8.0 m3)
- Source and rate of air: absolute and charcoal filtered air separate from the room air supply
- Temperature, humidity, pressure in air chamber: temperature 22°C / relative humidity 50%. The inhalation chambers containing toluene were maintained at slight sub-atmospheric pressure (0.1 in - 0.5 in H2O). Control chambers were under slight positive pressure (0.1 in - 0.5 in H20).
- Air flow rate: approx. 2000 L/min
- Generation: toluene vapour was generated by bubbling clean dry air (dew point -40°C) through liquid toluene. The rate of vapour generation was regulated by controlling airflow into the generator flask.

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
- Samples taken from breathing zone: not reported
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The time weighted average concentration of toluene for each exposure group was 0.0, 30.1, 99.7, 299.0 ppm for target concentrations of 0, 30, 100 and 300 ppm, respectively.
Duration of treatment / exposure:
6 h/day
Frequency of treatment:
5 days/week, up to 24 months (interim kills at 6, 12 and 18 months)
Remarks:
Doses / Concentrations:
0, 30, 100, 300 ppm
Basis:
other: target concentration
Remarks:
Doses / Concentrations:
0, 30.1, 99.7, 299.0 ppm
Basis:
other: time weighted average concentration
Remarks:
Doses / Concentrations:
0, 113, 377 or 1131 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
120
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes (for dead and moribund animals)
- Time schedule: once/day non-exposure days, twice/day exposure days

DETAILED CLINICAL OBSERVATIONS: Yes (including palpation and measurement of tissue masses)
- Time schedule: every 2 weeks

BODY WEIGHT: Yes
- Time schedule for examinations: beginning of the study (week 0), weekly for the first 6 months, every other week from 6 to 24 months and immediately prior to sacrifice

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to sacrifice
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6, 12, 18 and 24 months (prior to termination)
- Anaesthetic used for blood collection: no data
- Animals fasted: yes
- How many animals: selected (no further detail reported)
- Parameters examined: haemoglobin concentrations, haematocrits, total erythrocyte counts and total and differential leukocyte count. Mean corpuscular volumes, mean corpuscular haemoglobins, and mean corpuscular haemoglobin concentrations were calculated.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6, 12, 18 and 24 (months prior to termination)
- Animals fasted: yes
- How many animals: selected (no further detail reported)
- Parameters examined: blood urea nitrogen (BUN), serum glutamic pyruvic transaminase (SGPT) activity, and serum alkaline phosphatase (SAP) activity

URINALYSIS: Yes
- Time schedule for collection of urine: 16 hour period prior to blood collection (at 6, 12, 18 and 24 months)
- Metabolism cages used for collection of urine: yes
- Animals fasted: yes
- Parameters examined: appearance, specific gravity, protein, pH, ketones, glucose and microscopic particles
Sacrifice and pathology:
SACRIFICE AND GROSS PATHOLOGY: Animals killed at each interval, and all survivors at 24 months, were exsanguinated following carbon dioxide anaesthesia. Each was examined grossly and the brain, heart, kidneys, liver, lungs and gonads weighed.

HISTOPATHOLOGY: The following tissues were examined histopathologically: brain, spinal cord, peripheral nerve, pituitary, parathyroid, salivary gland, heart, lungs, spleen, liver, pancreas, oesophagus, adrenals, lymph nodes, kidneys, bladder, prostate, ovaries, uterus, fallopian tubes, stomach, small intestine, large intestine, skeletal muscle, thymus, skin, mammary gland, bone marrow, adipose tissue, aorta, ear canal, nasal turbinate, trachea, tibial and plantar nerves, lumbar, sacral and dorsal ganglia, proximal and distal hind limb, eyes and testes.
Statistics:
Analysis of variance (Kruskal-Wallis test for ratios): absolute body weight, total body weight change (surviving animals), organ weights, organ weight/body weight and organ weight/brain weight ratios. Other techniques for multiple comparisons: Tukey's for equal-sized groups, Scheffe's for groups of unequal sizes. Tests for homogeneity of variance, transformed (natural logarithm) as needed, and analysis of variance were used for haematology data.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
There were 140 unscheduled deaths (14.6% of 960 animals) over the 2-year course of the study. The distribution of spontaneous deaths among the treatment groups was not significantly different from controls.

There were no differences between control and toluene exposed groups with regard to clinical observations, blood chemistry analyses, urinalysis, ophthalmology, gross or histopathological findings.

The males in the toluene treatment groups were significantly heavier than the control males throughout the study although there was no clear cut dose response relationship. A similar finding was noted for the females but the effect disappeared during the final weeks of the study. Neither observation was considered to be adverse.

Female rats exposed to 100 and 300 ppm of toluene for 24 months had slightly, but significantly, reduced haematocrits and for the 300 ppm group only the mean corpuscular haemoglobin concentration was slightly, but significantly, increased. Other haematology parameters were not significantly different from controls.
Key result
Dose descriptor:
NOAEC
Remarks:
chronic toxicity
Effect level:
300 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: no toxicologically significant effects at highest dose tested (300 ppm)
Key result
Dose descriptor:
NOAEC
Effect level:
1 131 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: no toxicologically significant effects at highest dose tested (1131 mg/m3)
Critical effects observed:
not specified

All statistically significant differences from control were considered to be of no toxicological significance.

Conclusions:
Toluene does not cause adverse effects in the rat following inhalation exposure to 300 ppm for up to 24 months. The NOAEC for chronic systemic or local toxicity in this study was 300 ppm (1131 mg/m3).
Executive summary:

Chronic toxicity of inhaled toluene was assessed in Fischer-344 rats exposed to 0, 30, 100 or 300 ppm 6 h/day, 5 days/week for 6, 12 or 18 months. There were no toxicologically significant effects on bodyweight, clinical signs, ophthalmoscopy, haematology, blood and urine clinical chemistry, organ weights or gross and microscopic pathology. The NOAEC for chronic systemic and local toxicity from this study was 300 ppm (1131 mg/m3) for an exposure duration of 18 months.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
1 131 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
Adequate information is available on the marker substance toluene to characterise the long-term systemic hazards of these streams after inhalation.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
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, notable limitations in design, but contributing to weight of evidence.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
- only 5/sex/group examined for chronic toxicity at 1 year
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: Fischer-344 rats [CDF(F-344)/CrIBr]
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA., USA
- Age at study initiation: approx. 6-7 weeks
- Housing: group housed, sexes separately, 10/cage in stainless steel suspended cages
- Diet: standard laboratory diet (Wayne Lab-Blox F6, Allied Mills Inc., Chicago, IL., USA) ad libitum (except during exposure)
- Water: ad libitum
- Acclimation period: quarantined for at least 10 days

ENVIRONMENTAL CONDITIONS: No details reported

IN-LIFE DATES: Not reported
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: rectangular stainless steel and glass chambers (nominal volume 8.0 m3)
- Source and rate of air: absolute and charcoal filtered air separate from the room air supply
- Temperature, humidity, pressure in air chamber: temperature 22°C / relative humidity 50%. The inhalation chambers containing toluene were maintained at slight sub-atmospheric pressure (0.1 in - 0.5 in H2O). Control chambers were under slight positive pressure (0.1 in - 0.5 in H20).
- Air flow rate: approx. 2000 L/min
- Generation: toluene vapour was generated by bubbling clean dry air (dew point -40°C) through liquid toluene. The rate of vapour generation was regulated by controlling airflow into the generator flask.

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
- Samples taken from breathing zone: not reported
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The time weighted average concentration of toluene for each exposure group was 0.0, 30.1, 99.7, 299.0 ppm for target concentrations of 0, 30, 100 and 300 ppm, respectively.
Duration of treatment / exposure:
6 h/day
Frequency of treatment:
5 days/week, up to 24 months (interim kills at 6, 12 and 18 months)
Remarks:
Doses / Concentrations:
0, 30, 100, 300 ppm
Basis:
other: target concentration
Remarks:
Doses / Concentrations:
0, 30.1, 99.7, 299.0 ppm
Basis:
other: time weighted average concentration
Remarks:
Doses / Concentrations:
0, 113, 377 or 1131 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
120
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes (for dead and moribund animals)
- Time schedule: once/day non-exposure days, twice/day exposure days

DETAILED CLINICAL OBSERVATIONS: Yes (including palpation and measurement of tissue masses)
- Time schedule: every 2 weeks

BODY WEIGHT: Yes
- Time schedule for examinations: beginning of the study (week 0), weekly for the first 6 months, every other week from 6 to 24 months and immediately prior to sacrifice

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to sacrifice
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6, 12, 18 and 24 months (prior to termination)
- Anaesthetic used for blood collection: no data
- Animals fasted: yes
- How many animals: selected (no further detail reported)
- Parameters examined: haemoglobin concentrations, haematocrits, total erythrocyte counts and total and differential leukocyte count. Mean corpuscular volumes, mean corpuscular haemoglobins, and mean corpuscular haemoglobin concentrations were calculated.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6, 12, 18 and 24 (months prior to termination)
- Animals fasted: yes
- How many animals: selected (no further detail reported)
- Parameters examined: blood urea nitrogen (BUN), serum glutamic pyruvic transaminase (SGPT) activity, and serum alkaline phosphatase (SAP) activity

URINALYSIS: Yes
- Time schedule for collection of urine: 16 hour period prior to blood collection (at 6, 12, 18 and 24 months)
- Metabolism cages used for collection of urine: yes
- Animals fasted: yes
- Parameters examined: appearance, specific gravity, protein, pH, ketones, glucose and microscopic particles
Sacrifice and pathology:
SACRIFICE AND GROSS PATHOLOGY: Animals killed at each interval, and all survivors at 24 months, were exsanguinated following carbon dioxide anaesthesia. Each was examined grossly and the brain, heart, kidneys, liver, lungs and gonads weighed.

HISTOPATHOLOGY: The following tissues were examined histopathologically: brain, spinal cord, peripheral nerve, pituitary, parathyroid, salivary gland, heart, lungs, spleen, liver, pancreas, oesophagus, adrenals, lymph nodes, kidneys, bladder, prostate, ovaries, uterus, fallopian tubes, stomach, small intestine, large intestine, skeletal muscle, thymus, skin, mammary gland, bone marrow, adipose tissue, aorta, ear canal, nasal turbinate, trachea, tibial and plantar nerves, lumbar, sacral and dorsal ganglia, proximal and distal hind limb, eyes and testes.
Statistics:
Analysis of variance (Kruskal-Wallis test for ratios): absolute body weight, total body weight change (surviving animals), organ weights, organ weight/body weight and organ weight/brain weight ratios. Other techniques for multiple comparisons: Tukey's for equal-sized groups, Scheffe's for groups of unequal sizes. Tests for homogeneity of variance, transformed (natural logarithm) as needed, and analysis of variance were used for haematology data.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
There were 140 unscheduled deaths (14.6% of 960 animals) over the 2-year course of the study. The distribution of spontaneous deaths among the treatment groups was not significantly different from controls.

There were no differences between control and toluene exposed groups with regard to clinical observations, blood chemistry analyses, urinalysis, ophthalmology, gross or histopathological findings.

The males in the toluene treatment groups were significantly heavier than the control males throughout the study although there was no clear cut dose response relationship. A similar finding was noted for the females but the effect disappeared during the final weeks of the study. Neither observation was considered to be adverse.

Female rats exposed to 100 and 300 ppm of toluene for 24 months had slightly, but significantly, reduced haematocrits and for the 300 ppm group only the mean corpuscular haemoglobin concentration was slightly, but significantly, increased. Other haematology parameters were not significantly different from controls.
Key result
Dose descriptor:
NOAEC
Remarks:
chronic toxicity
Effect level:
300 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: no toxicologically significant effects at highest dose tested (300 ppm)
Key result
Dose descriptor:
NOAEC
Effect level:
1 131 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: no toxicologically significant effects at highest dose tested (1131 mg/m3)
Critical effects observed:
not specified

All statistically significant differences from control were considered to be of no toxicological significance.

Conclusions:
Toluene does not cause adverse effects in the rat following inhalation exposure to 300 ppm for up to 24 months. The NOAEC for chronic systemic or local toxicity in this study was 300 ppm (1131 mg/m3).
Executive summary:

Chronic toxicity of inhaled toluene was assessed in Fischer-344 rats exposed to 0, 30, 100 or 300 ppm 6 h/day, 5 days/week for 6, 12 or 18 months. There were no toxicologically significant effects on bodyweight, clinical signs, ophthalmoscopy, haematology, blood and urine clinical chemistry, organ weights or gross and microscopic pathology. The NOAEC for chronic systemic and local toxicity from this study was 300 ppm (1131 mg/m3) for an exposure duration of 18 months.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
1 131 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
Adequate information is available on the marker substance toluene to characterise the long-term local hazards of these streams after inhalation.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP compliant, near guideline study, available as unpublished report, minor restrictions in design and/or reporting but otherwise adequate for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
dosing 3 times per week
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Dutchland Inc., Denver, Pennsylvania, USA
- Age at study initiation: Young adult
- Weight at study initiation: mean weights per group 2.6-3.6 kg (males), 2.4-3.4 kg (females)
- Housing: Individually in stainless steel cages with grid bottoms
- Diet: Purina Laboratory Rabbit Chow #5321 ad libitum
- Water: ad libitum
- Acclimation period: 20-24 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22±3°C
- Humidity: 63-83%:
- Air changes: 10-15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 23 July 1984 To: 24 August 1984
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: trunk (approximately 15 cm x 20 cm)
- % coverage: approximately 10% of total body surface
- Type of wrap if used: surgical gauze pad, wrapped with a sheet of polythene and secured with hypoallergenic tape.
- Time intervals for shavings or clippings: approximately 24 hours prior to each application

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with a clean dry absorbent gauze pad (not washed).
- Time after start of exposure: 6 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Based on the weekly bodyweight of each animal and the specific gravity (0.7480 g/mL) of API 83-06.

USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
three times per week (total of 12 applications)
Remarks:
Doses / Concentrations:
0, 200, 1000, 2000 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Doses determined in a pilot 5 day dermal study in which moderate dermal irritation was the only treatment-related finding. No justification is provided for the frequency of dosing in the main study.
Observations and examinations performed and frequency:
MORTALITY AND CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily.

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: twice daily (Draize scoring system used).

BODY WEIGHT: Yes.
- Time schedule for examinations: At start, weekly thereafter and at termination.

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all
- Parameters examined: erythrocyte count, total leukocyte count, differential leukocyte count, haemoglobin, haematocrit

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all
- Parameters examined: glucose, blood urea nitrogen, alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, total protein

URINALYSIS: No (urine collected from all control and high dose animals prior to initiation of dosing and at termination. Frozen and stored for possible future evaluation).

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: heart, liver, spleen, kidneys, adrenals, thyroids (with parathyroids), pituitary, testes, ovaries, brain
HISTOPATHOLOGY: Yes. The following tissues from all control and high dose animals were examined: heart, lungs, bronchi, trachea, thyroids, parathyroids, cervical lymph nodes, salivary gland, tongue, oesophagus, stomach, duodenum, jejunum, ileum, sacculus rotundus, colon, thymus, spleen, liver, pancreas, kidneys, adrenals, vagina, seminal vesicles, testes/ovaries, epididymes, prostate, uterus, mesenteric lymph nodes, urinary bladder, mammary gland, brain (cerebellum, cerebrum, pons), pituitary, spinal cord (2 sections), skeletal muscle, sciatic nerve, skin (treated and untreated), bone, bone marrow (smear), eyes, gross lesions
Statistics:
2-tailed Student's t-test at the 5% probability level.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: No mortalities and no clinical signs of systemic toxicity.

DERMAL IRRITATION: Erythema and oedema, cracked, flaky and/or leathery skin at or around application site in all rabbits. 2000 and 1000 mg/kg - severe irritant, 200 mg/kg moderate irritant (males), slight/moderate irritant (females). Erythema (scores of 1-4 in males; 1-3 in females) were seen in all animals from about day 5 and persisted until the end of the study. Oedema was also seen in males.

BODY WEIGHT AND WEIGHT GAIN: Slight statistically significant reduction in overall bodyweight gain for males at 2000 mg/kg/day. Statistically significantly lower bodyweights for females at 1000 mg/kg/day (days 8 and 29) and at 2000 mg/kg/day (days 8, 15 and 29) and statistically significantly reduced overall bodyweight gain at 2000 mg/kg/day. However, since weight loss/gain of 0.1 or 0.2 kg is frequently observed in rabbits of this strain, no definite conclusions can be drawn from this data.

HAEMATOLOGY: No treatment-related effects.

CLINICAL CHEMISTRY: No treatment-related effects.

ORGAN WEIGHTS: No treatment-related effects.

GROSS PATHOLOGY: Effects confined to treated skin and consisted of reddened, dry, flaky, cracked, leathery and/or thickened skin

HISTOPATHOLOGY: In the high dose group: moderate to moderately severe proliferative and moderate to severe inflammatory changes of the treated skin. Concurrent with these changes there was increased granulopoiesis of the bone marrow, which may be related to the stress or other factors associated with the severe skin irritation. Low and intermediate dose groups were not examined histopathologically.

Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
2 000 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: no treatment-related effects at highest dose tested (2000 mg/kg/day)
Dose descriptor:
LOAEL
Remarks:
dermal irritation
Effect level:
200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: slight to moderate irritation at lowest dose tested
Critical effects observed:
not specified
Conclusions:
Following repeated 6-hour dermal applications of Heavy catalytic reformed naphtha (API 83-06) to the rabbit skin over a period of 28 days (3 times/week, total of 12 applications), the NOAEL was 2000 mg/kg/day for males and females. Signs of severe skin irritation were seen.
Executive summary:

Repeated dose (6-hour dermal applications) toxicity of heavy catalytic reformed naphtha (API 83-06) was investigated in groups of 5 male and 5 female rabbits. The neat test substance was applied to skin over a period of 28 days (3 times/week, total of 12 applications) at doses of 0, 200, 1000 or 2000 mg/kg/day. Animals were observed daily for clinical signs of toxicity and skin irritation, bodyweight was measured at intervals and at the end of the study blood samples were analysed for changes in haematology and clinical chemistry, a selection of organs were weighed and a full range of tissues examined histopathologically.

The NOAEL for heavy catalytic reformed naphtha (API 83-06) (CAS 64741-68-0) for systemic toxicity was 2000 mg/kg/day. A NOAEL was not established for local irritant effects - 200 mg/kg was a LOAEL based on slight to moderate irritation based on Draize scores.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Adequate information is available for a representative stream to characterise the long-term systemic hazards of these streams after skin contact.

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP compliant, near guideline study, available as unpublished report, minor restrictions in design and/or reporting but otherwise adequate for assessment
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
dosing 3 times per week
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Dutchland Inc., Denver, Pennsylvania, USA
- Age at study initiation: Young adult
- Weight at study initiation: mean weights per group 2.6-3.6 kg (males), 2.4-3.4 kg (females)
- Housing: Individually in stainless steel cages with grid bottoms
- Diet: Purina Laboratory Rabbit Chow #5321 ad libitum
- Water: ad libitum
- Acclimation period: 20-24 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22±3°C
- Humidity: 63-83%:
- Air changes: 10-15 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 23 July 1984 To: 24 August 1984
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: trunk (approximately 15 cm x 20 cm)
- % coverage: approximately 10% of total body surface
- Type of wrap if used: surgical gauze pad, wrapped with a sheet of polythene and secured with hypoallergenic tape.
- Time intervals for shavings or clippings: approximately 24 hours prior to each application

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with a clean dry absorbent gauze pad (not washed).
- Time after start of exposure: 6 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Based on the weekly bodyweight of each animal and the specific gravity (0.7480 g/mL) of API 83-06.

USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
three times per week (total of 12 applications)
Remarks:
Doses / Concentrations:
0, 200, 1000, 2000 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Doses determined in a pilot 5 day dermal study in which moderate dermal irritation was the only treatment-related finding. No justification is provided for the frequency of dosing in the main study.
Observations and examinations performed and frequency:
MORTALITY AND CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily.

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: twice daily (Draize scoring system used).

BODY WEIGHT: Yes.
- Time schedule for examinations: At start, weekly thereafter and at termination.

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all
- Parameters examined: erythrocyte count, total leukocyte count, differential leukocyte count, haemoglobin, haematocrit

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all
- Parameters examined: glucose, blood urea nitrogen, alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, total protein

URINALYSIS: No (urine collected from all control and high dose animals prior to initiation of dosing and at termination. Frozen and stored for possible future evaluation).

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: heart, liver, spleen, kidneys, adrenals, thyroids (with parathyroids), pituitary, testes, ovaries, brain
HISTOPATHOLOGY: Yes. The following tissues from all control and high dose animals were examined: heart, lungs, bronchi, trachea, thyroids, parathyroids, cervical lymph nodes, salivary gland, tongue, oesophagus, stomach, duodenum, jejunum, ileum, sacculus rotundus, colon, thymus, spleen, liver, pancreas, kidneys, adrenals, vagina, seminal vesicles, testes/ovaries, epididymes, prostate, uterus, mesenteric lymph nodes, urinary bladder, mammary gland, brain (cerebellum, cerebrum, pons), pituitary, spinal cord (2 sections), skeletal muscle, sciatic nerve, skin (treated and untreated), bone, bone marrow (smear), eyes, gross lesions
Statistics:
2-tailed Student's t-test at the 5% probability level.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: No mortalities and no clinical signs of systemic toxicity.

DERMAL IRRITATION: Erythema and oedema, cracked, flaky and/or leathery skin at or around application site in all rabbits. 2000 and 1000 mg/kg - severe irritant, 200 mg/kg moderate irritant (males), slight/moderate irritant (females). Erythema (scores of 1-4 in males; 1-3 in females) were seen in all animals from about day 5 and persisted until the end of the study. Oedema was also seen in males.

BODY WEIGHT AND WEIGHT GAIN: Slight statistically significant reduction in overall bodyweight gain for males at 2000 mg/kg/day. Statistically significantly lower bodyweights for females at 1000 mg/kg/day (days 8 and 29) and at 2000 mg/kg/day (days 8, 15 and 29) and statistically significantly reduced overall bodyweight gain at 2000 mg/kg/day. However, since weight loss/gain of 0.1 or 0.2 kg is frequently observed in rabbits of this strain, no definite conclusions can be drawn from this data.

HAEMATOLOGY: No treatment-related effects.

CLINICAL CHEMISTRY: No treatment-related effects.

ORGAN WEIGHTS: No treatment-related effects.

GROSS PATHOLOGY: Effects confined to treated skin and consisted of reddened, dry, flaky, cracked, leathery and/or thickened skin

HISTOPATHOLOGY: In the high dose group: moderate to moderately severe proliferative and moderate to severe inflammatory changes of the treated skin. Concurrent with these changes there was increased granulopoiesis of the bone marrow, which may be related to the stress or other factors associated with the severe skin irritation. Low and intermediate dose groups were not examined histopathologically.

Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
2 000 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: no treatment-related effects at highest dose tested (2000 mg/kg/day)
Dose descriptor:
LOAEL
Remarks:
dermal irritation
Effect level:
200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: slight to moderate irritation at lowest dose tested
Critical effects observed:
not specified
Conclusions:
Following repeated 6-hour dermal applications of Heavy catalytic reformed naphtha (API 83-06) to the rabbit skin over a period of 28 days (3 times/week, total of 12 applications), the NOAEL was 2000 mg/kg/day for males and females. Signs of severe skin irritation were seen.
Executive summary:

Repeated dose (6-hour dermal applications) toxicity of heavy catalytic reformed naphtha (API 83-06) was investigated in groups of 5 male and 5 female rabbits. The neat test substance was applied to skin over a period of 28 days (3 times/week, total of 12 applications) at doses of 0, 200, 1000 or 2000 mg/kg/day. Animals were observed daily for clinical signs of toxicity and skin irritation, bodyweight was measured at intervals and at the end of the study blood samples were analysed for changes in haematology and clinical chemistry, a selection of organs were weighed and a full range of tissues examined histopathologically.

The NOAEL for heavy catalytic reformed naphtha (API 83-06) (CAS 64741-68-0) for systemic toxicity was 2000 mg/kg/day. A NOAEL was not established for local irritant effects - 200 mg/kg was a LOAEL based on slight to moderate irritation based on Draize scores.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
200 mg/cm²
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Adequate information is available for a representative stream to characterise the long-term local hazards of these streams after skin contact.

Additional information

Non human data

Repeat dose studies have been conducted for representative low benzene naphtha streams via the dermal and inhalation routes of exposure and indicate no significant target organ toxicity. It is noted that kidney effects in male rats in these studies are consistent with a well studied phenomenon known as light hydrocarbon nephropathy (Alden, 1986)." This phenomenon has been extensively evaluated and is a male rat-specific phenomenon and has no relevance for human risk assessment.”

Dermal

Stream CAS 64741-68-0 was evaluated in a 28-Day dermal toxicity study in the rabbit conducted according to OECD Guideline 410 in groups of 5 male and 5 female rabbits. The neat test substance was applied to skin over a period of 28 days (3 times/week, total of 12 applications) at doses of 0, 200, 1000 or 2000 mg/kg/day. Animals were observed daily for clinical signs of toxicity and skin irritation, bodyweight was measured at intervals and at the end of the study blood samples were analysed for changes in haematology and clinical chemistry, a selection of organs were weighed and a full range of tissues examined histopathologically. The NOAEL CAS 64741-68-0 for systemic toxicity was 2000 mg/kg/day. A NOAEL was not established for local irritant effects - 200 mg/kg was a LOAEL reflecting slight to moderate irritation based on Draize scores.

Inhalation

The general systemic toxicity of Pyrolysis C5 (CAS 68476 -55 -1) to rats by inhalation administration was assessed. Groups of twelve male and twelve female rats were exposed for 6 h/day, 7 days/week for a period of 4 weeks to vapour at concentrations of 0, 98, 302 or 1012 ppm. Assessments of clinical condition, detailed functional observational battery, motor activity, bodyweight, food consumption, haematology, blood chemistry, organ weight and macroscopic and microscopic pathology investigations were undertaken.No general systemic effects were observed during the routine clinical examination or in the functional observational battery. Histopathological changes were seen in the liver (minimal centrilobular hepatocyte hypertrophy) at 1012 ppm in both sexes. In male rats only higher kidney weights and renal cortical tubules with hyaline droplets were apparent in all treatment groups.

Toluene (Classification: EU - Harmful Xn, R48/20; GHS/CLP - STOT-RE Category 2, H373): Toluene exposure can produce central nervous system pathology in animals after high oral doses. Repeated inhalation exposure can produce ototoxicity in the rat and high concentrations are associated with local toxicity (nasal erosion). In humans neuropsychological effects and disturbances of auditory function and colour vision have been reported, particularly when exposures are not well controlled and/or associated with noisy environments. The NOAEC for subchronic oral toxicity in rats is 625 mg/kg/day based on neuropathology (Huff, 1990). The NOAEC for inhalation toxicity in the rat is 300 ppm (1131 mg/m3) based on effects on body weight, mortality and adverse local effects (nasal erosion) (Gibson and Hardisty, 1983). The NOAEC for neuropsychological effects, auditory dysfunction and disturbances of colour vision in humans is 26 ppm (98 mg/m3) (Seeber et al, 2004; Schaper et al, 2003, 2004).

References

Alden CL (1986) A Review of Unique Male Rat Hydrocarbon Nephropathy. Toxicologic Pathology14 (1).

Schaper M, Demes P, Kiesswetter E, Zupanic M and Seeber A (2004). Colour vision and occupational toluene exposure: results of repeated examinations. Toxicology Letters 151, 193-202.

Schaper M, Demes P, Zupanic M, Blaszkewicz M and Seeber A (2003). Occupational toluene exposure and auditory function: results from a follow-up study. Ann. Occup. Hyg., Vol 47, No 6, pp493-502.

Seeber A, Schaper M, Zupanic M, Blaskewicz M, Demes P, Kiesswetter E and van Thriel C (2004). Toluene exposure below 50 ppm and cognitive function: a follow-up study with four repeated measurements in rotogravure printing plants. Int Arch Occup Environ Health, 77, 1-9.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No repeat dose oral toxicity data are available for members of this category, however rats receiving high treatments of the key marker substance toluene for 13 wk showed signs of neuropathological changes with a NOAEL of 625 mg/kg bw/d.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Information available for the key component toluene indicates a potential auditory impairment and effects on the nervous system. The NOAEC for systemic inhalation toxicity in the rat is 300 ppm (1131 mg/m3) based on effects on body weight and mortality.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Information available for the key component toluene indicates a NOAEC for local inhalation toxicity in the rat of 300 ppm (1131 mg/m3) based on adverse local effects (nasal erosion).

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Information available for a representative stream indicate a systemic NOAEL of 2000 mg/kg/day, the highest dose tested.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Information available for a representative stream indicate a local LOAEL of 200 mg/kg, reflecting slight to moderate skin irritation.

Repeated dose toxicity: via oral route - systemic effects (target organ) neurologic: central nervous system

Repeated dose toxicity: inhalation - systemic effects (target organ) other: all gross lesions and masses

Justification for classification or non-classification

There are sufficient data available to conclude that streams within this category which contain less than 10% toluene do not require a label for this endpoint.

After repeated dose exposure, toluene causes a number of adverse effects including impairment of auditory function and morphological evidence of cell loss in the rat cochlea, neuron loss in the central nervous system of animals and in humans neuropsychological effects, auditory dysfunction and effects on colour vision have been reported. Consequently low benzene naphtha streams containing ≥ 10% toluene should be classified Cat 2, H373 according to CLP.