Stoddard solvent

Endpoint summary

Description of key information

Oral repeated dose toxicity

Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 28 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined. There was no mortality during the experiment. Renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans. Female rats exhibited adaptive liver changes at the highest dosage. There were no pathological findings of the liver and was therefore not considered an adverse effect. The LOAEL for male rats was 0.14 ml/kg/day based on renal damage, which is not relevant to human health. The female NOAEL was 1.28 (1056 mg/kg) mL/kg.

Inhalation repeated dose toxicity

Sub-chronic exposure to male rats for of 13 weeks(6 h/day, 5 days/week) periods produced no significant finding.

The only significant finding was slight to moderate tubular regeneration in male rats which is consistent with alpha-2u-globulin induced nephropathy. 

The no-observed-adverse-effect concentration (NOAEC) was considered to be 1100 mg/m³.

Dermal repeated dose toxicity

The shaved intact skin (15 × 20 cm) of groups of 10 New Zealand White rabbits was exposed to doses of 200, 1000, and 2000 mg/kg of white spirit (Stoddard solvent). Exposure was carried out using occlusion bandage for a duration of 6 h and was given 3 times weekly for 4 weeks. At the highest dose level, there was a significant  reduction in weight gain in both sexes, whereas only the female body  weight gain was reduced at 1000 mg/kg. Changes in haematological parameters noted at 2000 mg/kg were judged not to be treatment-related. At 2000 mg/kg, female rabbits developed liver lesions characterized as white streaks or foci with granular surface

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Remarks:

Oral gavage application of different doses to rats 7 days/week, 28 days

Type of information:

other: published data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

Oral gavage application of different doses to rats 7 days/week, 28 days; Determination of Body weights, clinical pathology and organ weights

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%)

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Crj: CD (SD) rats
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 8 weeks
- Weight at study initiation (mean): males: 177-217 g; females: 134-149 g
- Housing: 5 per cage
- Diet ad libitum
- Water ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.3-25 (65-77 °F)
- Humidity (%): 35-60
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 28 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once per day,7 days/week, 28 days

Dose / conc.:

116 mg/kg bw/day (actual dose received)

Dose / conc.:

347 mg/kg bw/day (actual dose received)

Dose / conc.:

1 056 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Number of animals: 5 animals sex / dose group

Control animals:

yes

Details on study design:

- Post-exposure period: None; animals euthanized at end of 28-day treatment period

Positive control:

Sham-treated (corn oil) negative control.

Observations and examinations performed and frequency:

Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion.
After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all animals

HISTOPATHOLOGY: Yes, histopathological examination performed

Other examinations:

no data

Statistics:

According to Kaplan and Meier, method of Cox (1972) and Tarone's (1975) life table test

Clinical signs:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, non-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:

not examined

Urinalysis findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, non-treatment-related

Neuropathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

not examined

Details on results:

NOAEL = 1056 mg/kg
Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) (CAS # 64742-81-0) using male and female Crj: CD (SD) rats. Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 30 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined. There was no mortality during the experiment. Renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans. Female rats exhibited adaptive liver changes at the highest dosage and was not considered an adverse effect. The LOAEL for male rats was 0.14 ml/kg/day based on renal damage, which is not relevant to human health. The female NOAEL was 1.28 (1056 mg/kg) mL/kg.

Dose descriptor:

NOAEL

Effect level:

1 056 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

Remarks on result:

other: based on renal damage

Critical effects observed:

not specified

Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 28 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined. There was no mortality during the experiment. Renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans. Female rats exhibited adaptive liver changes at the highest dosage. There were no pathological findings of the liver and was therefore not considered an adverse effect. The LOAEL for male rats was 0.14 ml/kg/day based on renal damage, which is not relevant to human health. The female NOAEL was 1.28 (1056 mg/kg) mL/kg.

 

Conclusions:

The LOAEL for male rats was 0.14 ml/kg/day based on renal damage, which is not relevant to human health. The female NOAEL was 1.28 (1056 mg/kg) mL/kg.
Based on based on renal damage at 1056 mg/kg bw the NOAEL was considered to be 1056 mg/kg bw/day

Executive summary:

Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 28 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined. There was no mortality during the experiment. Renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans. Female rats exhibited adaptive liver changes at the highest dosage. There were no pathological findings of the liver and was therefore not considered an adverse effect. The LOAEL for male rats was 0.14 ml/kg/day based on renal damage, which is not relevant to human health. The female NOAEL was 1.28 (1056 mg/kg) mL/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 056 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 28 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined. There was no mortality during the experiment. Renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans. Female rats exhibited adaptive liver changes at the highest dosage. There were no pathological findings of the liver and was therefore not considered an adverse effect. The LOAEL for male rats was 0.14 ml/kg/day based on renal damage, which is not relevant to human health. The female NOAEL was 1.28 (1056 mg/kg) mL/kg.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 weeks

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Principles of method if other than guideline:

25 male Harlan-Wistar rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 480 mg/m3 (84 ppm), 1100 mg/m3 (190 ppm) and 1900 mg/m3 (330 ppm) (boiling range, 152-194°C; 47.7% aliphatics, 37.6% cyclic aliphatics, 14.7% aromatics) for a period of 13 weeks(6 h/day, 5 days/week).

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Stoddard solvent;boiling range, 152-194°C; 47.7% aliphatics, 37.6% cyclic aliphatics, 14.7% aromatics

Species:

rat

Strain:

Wistar

Details on species / strain selection:

25 male Harlan-Wistar rats

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Harlan-Wistar rats
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 8-9 weeks
- Weight at study initiation (mean): 211-213 g;
- Housing: 5 per cage
- Acclimation period: 26 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

no data

Details on inhalation exposure:

25 male Harlan-Wistar rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 480 mg/m3 (84 ppm), 1100 mg/m3 (190 ppm) and 1900 mg/m3 (330 ppm) (boiling range, 152-194°C; 47.7% aliphatics, 37.6% cyclic aliphatics, 14.7% aromatics) for a period of 13 weeks(6 h/day, 5 days/week).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Nominal concentrations were determined daily, and calculations of concentration in ppm were made by using weight loss data and assuming an average molecular weight of 142 g/mol for the Stoddard solvent. Analytical concentrations were determined by drawing samples from the chambers into a gas chromatograph equipped with a flame ionization detector.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 h/day, 5 days/week

Dose / conc.:

0 mg/m³ air

Dose / conc.:

480 mg/m³ air

Remarks:

84 ppm=480 mg/m3

Dose / conc.:

1 100 mg/m³ air

Remarks:

190 ppm=1100 mg/m3

Dose / conc.:

1 900 mg/m³ air

Remarks:

330 ppm=1900 mg/m3

No. of animals per sex per dose:

25 male Harlan-Wistar rats

Control animals:

yes

Details on study design:

25 male Harlan-Wistar rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 480 mg/m3 (84 ppm), 1100 mg/m3 (190 ppm) and 1900 mg/m3 (330 ppm) (boiling range, 152-194°C; 47.7% aliphatics, 37.6% cyclic aliphatics, 14.7% aromatics) for a period of 13 weeks(6 h/day, 5 days/week).

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, all animals
- Time schedule: twice daily

BODY WEIGHT: Yes, all animals
- Time schedule for examinations: weighed initially and 1 x week thereafter

CLINICAL PATHOLOGY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

no data

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Histopathological lesions of the kidneys and dilated tubules were found in 6 out of 9 and 3 out of 9 rats exposed to 1900 and 1100 mg/m3, respectively

Mortality:

no mortality observed

Description (incidence):

No treatment-related deaths were observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

Histopathological lesions of the kidneys and dilated tubules were found in 6 out of 9 and 3 out of 9 rats exposed to 1900 and 1100 mg/m3, respectively.
These lesions were also noted in rats killed after only 8 weeks of exposure.
Significant, although not dose-related, changes in haematological values were thought to be mainly a consequence of the deviant values found in the control group. No differences were found in weight gain.

Dose descriptor:

NOAEC

Effect level:

1 100 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

Remarks on result:

other:

Remarks:

Based on histopathological lesions of the kidneys and dilated tubules found in 3 out of 9 rats exposed to 1100 mg/m3,

Dose descriptor:

LOAEC

Effect level:

1 900 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

organ weights and organ / body weight ratios

Remarks on result:

other:

Remarks:

Based on histopathological lesions of the kidneys and dilated tubules found in 6 out of 9 rats exposed to 1900 mg/m3,

Critical effects observed:

not specified

Based on histopathological lesions of the kidneys and dilated tubules found in 3 out of 9 rats exposed to 1100 mg/m3,

The no-observed-adverse-effect concentration (NOAEC) was considered to be 1100 mg/m³.

Conclusions:

Sub-chronic exposure to male rats for of 13 weeks(6 h/day, 5 days/week) periods produced no significant finding.
The only significant finding was slight to moderate tubular regeneration in male rats which is consistent with alpha-2u-globulin induced nephropathy.
The no-observed-adverse-effect concentration (NOAEC) was considered to be 1100 mg/m³.

Executive summary:

Based on the results of this study, repeated inhalation exposure of male rats to Stoddard solvent at mean analytical concentrations of 1100 mg/m³ (190 ppm) and 1900 mg/m³ (330 ppm) was well-tolerated with no adverse effects .

The no-observed-adverse-effect concentration (NOAEC) was considered to be 1100 mg/m³.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 weeks

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Principles of method if other than guideline:

Groups of 18 males and 18 females were exposed to LAWS vapour (7500, 4000 and 2000 mg/m3) for 6 h, 5 days/week, for 13 weeks. Body weight, food and water consumption and clinical observations were recorded every week. At the end of the study, organ weight, blood chemistry and haematology parameters and complete histopathological evaluations were performed.

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

Stoddard solvent;Low Aromatic White Spirit (LAWS)

Species:

rat

Strain:

Wistar

Details on species / strain selection:

Groups of 18 males and 18 females Wistar rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Wistar rats
- Source: Rats: Charles River Breeding Laboratory, Wilmington, Massachusetts
- Age at study initiation: Approximately 10 weeks old
- Housing: gang-caged
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 25
- Humidity (%): 30 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

no data

Details on inhalation exposure:

Groups of 18 males and 18 females were exposed to LAWS vapour (7500, 4000 and 2000 mg/m3) for 6 h, 5 days/week, for 13 weeks. Body weight, food and water consumption and clinical observations were recorded every week. At the end of the study, organ weight, blood chemistry and haematology parameters and complete histopathological evaluations were performed.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Nominal concentrations were determined daily, and calculations of concentration in ppm were made by using weight loss data and assuming an average molecular weight of 142 g/mol for the Stoddard solvent. Analytical concentrations were determined by drawing samples from the chambers into a gas chromatograph equipped with a flame ionization detector.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 h, 5 days/week, for 13 weeks.

Dose / conc.:

2 000 mg/m³ air

Dose / conc.:

4 000 mg/m³ air

Dose / conc.:

7 500 mg/m³ air

No. of animals per sex per dose:

25 male Harlan-Wistar rats

Control animals:

yes

Details on study design:

Groups of 18 males and 18 females were exposed to LAWS vapour (7500, 4000 and 2000 mg/m3) for 6 h, 5 days/week, for 13 weeks. Body weight, food and water consumption and clinical observations were recorded every week. At the end of the study, organ weight, blood chemistry and haematology parameters and complete histopathological evaluations were performed.

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, all animals
- Time schedule: twice daily

BODY WEIGHT: Yes, all animals
- Time schedule for examinations: weighed initially and 1 x week thereafter

CLINICAL PATHOLOGY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

no data

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs and toxicity were observed except that the high-dose groups were slightly lethargic when examined 30 min after cessation of exposure.

Mortality:

no mortality observed

Description (incidence):

No treatment-related deaths were observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

One exposure to LAWS caused low-grade anaemia and mild degenerative changes in the kidneys of males at all exposure levels. In female rats there were dose-related increases in the liver weight of exposed animals. However, there were no histopathological lesions observed in the livers of treated animals. In the kidneys, hyaline droplets were found most frequently in the proximal tubular epithelium of the outer cortex.

Details on results:

No clinical signs and toxicity were observed except that the high-dose groups were slightly lethargic when examined 30 min after cessation of exposure.
One exposure to LAWS caused low-grade anaemia and mild degenerative changes in the kidneys of males at all exposure levels. In female rats there were dose-related increases in the liver weight of exposed animals. However, there were no histopathological lesions observed in the livers of treated animals. In the kidneys, hyaline droplets were found most frequently in the proximal tubular epithelium of the outer cortex.

Dose descriptor:

NOAEC

Effect level:

4 000 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

Remarks on result:

other:

Remarks:

Based on No clinical signs and toxicity

Dose descriptor:

LOAEC

Effect level:

7 500 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

organ weights and organ / body weight ratios

Remarks on result:

other:

Remarks:

Based on slightly lethargic when examined 30 min after cessation of exposure.

Critical effects observed:

not specified

Based on No clinical signs and toxicity to rats exposed to 4000 mg/m3,

The no-observed-adverse-effect concentration (NOAEC) was considered to be 4000 mg/m³.

Conclusions:

Sub-chronic exposure to male rats for of 13 weeks(6 h/day, 5 days/week) periods produced no significant finding.
Based on the results of this study, repeated inhalation exposure of male rats to Stoddard solvent at mean analytical concentrations of 4000 mg/m³ was well-tolerated with no adverse effects .
The no-observed-adverse-effect concentration (NOAEC) was considered to be 4000 mg/m³.

Executive summary:

Sub-chronic exposure to male rats for of 13 weeks(6 h/day, 5 days/week) periods produced no significant finding. Based on the results of this study, repeated inhalation exposure of male rats to Stoddard solvent at mean analytical concentrations of 4000 mg/m³ was well-tolerated with no adverse effects .

The no-observed-adverse-effect concentration (NOAEC) was considered to be 4000 mg/m³.

Reference 3

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

6 months

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Principles of method if other than guideline:

Groups of 30 young (3 months old) and groups of 14 old (15 months old) male rats were exposed to vapour concentrations of 0, 2290 and 4580 mg/m3 (0, 400 and 800 ppm) of white spirit (boiling range, 148-200°C; 20 v/v% aromatics).
After exposure for 6 months (6 h/day, 5 days/week) and a follow-up period without exposure of 4 months, the animals were killed.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Stoddard solvent;boiling range, 148-200°C; 20 v/v% aromatics).

Species:

rat

Strain:

Wistar

Details on species / strain selection:

Groups of 30 young (3 months old) and groups of 14 old (15 months old) male rats

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain:Wistar rats
- Groups of 30 young (3 months old) and groups of 14 old (15 months old) male rats

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

no data

Details on inhalation exposure:

Groups of 30 young (3 months old) and groups of 14 old (15 months old) male rats were exposed to vapour concentrations of 0, 2290 and 4580 mg/m3 (0, 400 and 800 ppm) of white spirit (boiling range, 148-200°C; 20 v/v% aromatics).
After exposure for 6 months (6 h/day, 5 days/week) and a follow-up period without exposure of 4 months, the animals were killed.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Nominal concentrations were determined daily, and calculations of concentration in ppm were made by using weight loss data and assuming an average molecular weight of 142 g/mol for the Stoddard solvent. Analytical concentrations were determined by drawing samples from the chambers into a gas chromatograph equipped with a flame ionization detector.

Duration of treatment / exposure:

6 months

Frequency of treatment:

6 h/day, 5 days/week

Dose / conc.:

0 mg/m³ air

Dose / conc.:

2 290 mg/m³ air

Remarks:

400 ppm=2290 mg/m3

Dose / conc.:

4 580 mg/m³ air

Remarks:

800 ppm=4580mg/m3

No. of animals per sex per dose:

groups of 30 young (3 months old) and groups of 14 old (15 months old) male rats

Control animals:

yes

Details on study design:

Groups of 30 young (3 months old) and groups of 14 old (15 months old) male rats were exposed to vapour concentrations of 0, 2290 and 4580 mg/m3 (0, 400 and 800 ppm) of white spirit (boiling range, 148-200°C; 20 v/v% aromatics).
After exposure for 6 months (6 h/day, 5 days/week) and a follow-up period without exposure of 4 months, the animals were killed.

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, all animals
- Time schedule: twice daily

BODY WEIGHT: Yes, all animals
- Time schedule for examinations: weighed initially and 1 x week thereafter

CLINICAL PATHOLOGY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

no data

Clinical signs:

effects observed, treatment-related

Mortality:

no mortality observed

Description (incidence):

No treatment-related deaths were observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

The animals showed signs of discomfort during exposure, especially during the initial exposure period. Mucosal irritation, bloody discharge from the nose and lacrimation were present. Narcotic effects were gradually reduced. Although the body weights of the high-dose group were reduced, this difference disappeared during the follow-up period.
At both exposure levels the rats had a significantly higher water consumption than controls (only the group of young rats were monitored). Clinical chemical parameters of the urine were unaffected, but significant increases were found for plasma urea and creatinine levels at both exposure levels. Serum alanine aminotransferase activity was significantly reduced. No macroscopic or histopathological changes were found at sacrifice, and no differences in the kidney tubules were noted between exposed and unexposed rats.

Dose descriptor:

NOAEC

Effect level:

2 290 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

water consumption and compound intake

Dose descriptor:

LOAEC

Effect level:

4 580 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

organ weights and organ / body weight ratios

water consumption and compound intake

Critical effects observed:

not specified

The no-observed-adverse-effect concentration (NOAEC) was considered to be 2290 mg/m³.

Conclusions:

Chronic exposure to male rats for of 6 months (6 h/day, 5 days/week) periods produced no significant finding.
The animals showed signs of discomfort during exposure, especially during the initial exposure period. Mucosal irritation, bloody discharge from the nose and lacrimation were present. Narcotic effects were gradually reduced. Although the body weights of the high-dose group were reduced, this difference disappeared during the follow-up period.
At both exposure levels the rats had a significantly higher water consumption than controls (only the group of young rats were monitored). Clinical chemical parameters of the urine were unaffected, but significant increases were found for plasma urea and creatinine levels at both exposure levels. Serum alanine aminotransferase activity was significantly reduced. No macroscopic or histopathological changes were found at sacrifice, and no differences in the kidney tubules were noted between exposed and unexposed rats.
The no-observed-adverse-effect concentration (NOAEC) was considered to be 2290 mg/m³.

Executive summary:

Chronic exposure to male rats for of 6 months (6 h/day, 5 days/week) periods produced no significant finding. The animals showed signs of discomfort during exposure, especially during the initial exposure period. Mucosal irritation, bloody discharge from the nose and lacrimation were present. Narcotic effects were gradually reduced. Although the body weights of the high-dose group were reduced, this difference disappeared during the follow-up period. At both exposure levels the rats had a significantly higher water consumption than controls (only the group of young rats were monitored). Clinical chemical parameters of the urine were unaffected, but significant increases were found for plasma urea and creatinine levels at both exposure levels. Serum alanine aminotransferase activity was significantly reduced. No macroscopic or histopathological changes were found at sacrifice, and no differences in the kidney tubules were noted between exposed and unexposed rats. The no-observed-adverse-effect concentration (NOAEC) was considered to be 2290 mg/m³.

Reference 4

Endpoint:

repeated dose toxicity: inhalation, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 weeks

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Principles of method if other than guideline:

35 male Harlan-Wistar rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 49 mg/m3 (7.8 ppm), 100 mg/m3 (16 ppm) and 230 mg/m3 (37 ppm))
140° flash aliphatic solvent (C5-12 mixed aliphatic with 3% C7-12 aromatics) for a period of 14 weeks (6 hours a day, 5 days per week).

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Stoddard solvent;140° flash aliphatic solvent (C5-12 mixed aliphatic with 3% C7-12 aromatics)

Species:

rat

Strain:

Wistar

Details on species / strain selection:

35 male Harlan-Wistar rats

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Harlan-Wistar rats
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 8-9 weeks
- Weight at study initiation (mean): 211-213 g;
- Housing: 5 per cage
- Acclimation period: 26 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

no data

Details on inhalation exposure:

35 male Harlan-Wistar rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 49 mg/m3 (7.8 ppm), 100 mg/m3 (16 ppm) and 230 mg/m3 (37 ppm))
140° flash aliphatic solvent (C5-12 mixed aliphatic with 3% C7-12 aromatics) for a period of 14 weeks (6 hours a day, 5 days per week).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Nominal concentrations were determined daily, and calculations of concentration in ppm were made by using weight loss data and assuming an average molecular weight of 142 g/mol for the Stoddard solvent. Analytical concentrations were determined by drawing samples from the chambers into a gas chromatograph equipped with a flame ionization detector.

Duration of treatment / exposure:

14 weeks

Frequency of treatment:

6 hours a day, 5 days

Dose / conc.:

0 mg/m³ air

Dose / conc.:

49 mg/m³ air

Remarks:

7.8 ppm=49 mg/m3

Dose / conc.:

100 mg/m³ air

Remarks:

16 ppm=100 mg/m3

Dose / conc.:

230 mg/m³ air

Remarks:

37 ppm=230 mg/m3

No. of animals per sex per dose:

35 male Harlan-Wistar rats

Control animals:

yes

Details on study design:

35 male Harlan-Wistar rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 49 mg/m3 (7.8 ppm), 100 mg/m3 (16 ppm) and 230 mg/m3 (37 ppm))
140° flash aliphatic solvent (C5-12 mixed aliphatic with 3% C7-12 aromatics) for a period of 14 weeks (6 hours a day, 5 days per week).

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, all animals
- Time schedule: twice daily

BODY WEIGHT: Yes, all animals
- Time schedule for examinations: weighed initially and 1 x week thereafter

CLINICAL PATHOLOGY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

no data

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

The only significant finding was slight to moderate tubular regeneration in male rats which is consistent with alpha-2u-globulin induced nephropathy.

Mortality:

no mortality observed

Description (incidence):

No treatment-related deaths were observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

Histopathological lesions of the kidneys and dilated tubules were found in 6 out of 9 and 3 out of 9 rats exposed to 1900 and 1100 mg/m3, respectively.
These lesions were also noted in rats killed after only 8 weeks of exposure.
Significant, although not dose-related, changes in haematological values were thought to be mainly a consequence of the deviant values found in the control group. No differences were found in weight gain.

Dose descriptor:

NOAEC

Effect level:

230 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

Critical effects observed:

not specified

The no-observed-adverse-effect concentration (NOAEC) was considered to be 230 mg/m³.

Conclusions:

Sub-chronic exposure to male rats for of 14 weeks(6 hours a day, 5 days per week ) periods produced no significant finding.
No treatment-related deaths were observed. The only significant finding was slight to moderate tubular regeneration in male rats which is consistent with alpha-2u-globulin induced nephropathy. The NOAEC in this study was 230 mg/m3 or 37 ppm.

Executive summary:

Sub-chronic exposure to male rats for of 14 weeks(6 hours a day, 5 days per week ) periods produced no significant finding. No treatment-related deaths were observed. The only significant finding was slight to moderate tubular regeneration in male rats which is consistent with alpha-2u-globulin induced nephropathy. The NOAEC in this study was 230 mg/m3 or 37 ppm.

Reference 5

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

12 weeks

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Principles of method if other than guideline:

25 male Sprague-Dawley rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 571.4 mg/m3 (100 ppm), and 1714.3mg/m3 (300 ppm) C8-C13 Mixed paraffin and aromatics (8052-41-3) for a period of 12 weeks(6 h/day, 5 days/week).

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

C8-C13 Mixed paraffin and aromatics (8052-41-3)

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

25 male Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Sprague-Dawley
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 6 weeks
- Weight at study initiation (mean): 126 to 191g;
- Housing: 5 per cage
- Acclimation period: 26 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

no data

Details on inhalation exposure:

25 male Sprague-Dawley rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 571.4 mg/m3 (100 ppm), and 1714.3 mg/m3 (300 ppm) C8-C13 Mixed paraffin and aromatics (8052-41-3) for a period of 12 weeks(6 h/day, 5 days/week).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Nominal concentrations were determined daily, and calculations of concentration in ppm were made by using weight loss data and assuming an average molecular weight of 142 g/mol for the Stoddard solvent. Analytical concentrations were determined by drawing samples from the chambers into a gas chromatograph equipped with a flame ionization detector.

Duration of treatment / exposure:

12 weeks

Frequency of treatment:

6 h/day, 5 days/week

Dose / conc.:

0 mg/m³ air

Dose / conc.:

571.4 mg/m³ air

Remarks:

100 ppm=571.4 mg/m3

Dose / conc.:

1 714.3 mg/m³ air

Remarks:

300 ppm=1714.3 mg/m3

No. of animals per sex per dose:

25 male Harlan-Wistar rats

Control animals:

yes

Details on study design:

25 male Sprague-Dawley rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 571.4 mg/m3 (100 ppm), and 1714.3mg/m3 (300 ppm) C8-C13 Mixed paraffin and aromatics (8052-41-3) for a period of 12 weeks(6 h/day, 5 days/week).

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, all animals
- Time schedule: twice daily

BODY WEIGHT: Yes, all animals
- Time schedule for examinations: weighed initially and 1 x week thereafter

CLINICAL PATHOLOGY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

no data

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

The only adverse effects observed in this study were significant elevations in absolute and relative kidney weights in male rats. These observed effects were consistent with alpha-2u-globulin induced nephropathy in male rats.

Mortality:

no mortality observed

Description (incidence):

No treatment-related deaths were observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

The only adverse effects observed in this study were significant elevations in absolute and relative kidney weights in male rats. These observed effects were consistent with alpha-2u-globulin induced nephropathy in male rats.
The NOAEC for this study was 1714.3mg/m3 or 300 ppm

Dose descriptor:

NOAEC

Effect level:

1 714.3 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

Remarks on result:

other:

Remarks:

The only adverse effects observed in this study were significant elevations in absolute and relative kidney weights in male rats.

Critical effects observed:

not specified

The only adverse effects observed in this study were significant elevations in absolute and relative kidney weights in male rats. These observed effects were consistent with alpha-2u-globulin induced nephropathy in male rats.

The NOAEC for this study was 1714.3mg/m3 or 300 ppm

Conclusions:

The only adverse effects observed in this study were significant elevations in absolute and relative kidney weights in male rats. These observed effects were consistent with alpha-2u-globulin induced nephropathy in male rats.
The NOAEC for this study was 1714.3mg/m3 or 300 ppm

Executive summary:

The only adverse effects observed in this study were significant elevations in absolute and relative kidney weights in male rats. These observed effects were consistent with alpha-2u-globulin induced nephropathy in male rats.

The NOAEC for this study was 1714.3mg/m3 or 300 ppm

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 100 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Sub-chronic exposure to male rats for of 13 weeks(6 h/day, 5 days/week) periods produced no significant finding.
The only significant finding was slight to moderate tubular regeneration in male rats which is consistent with alpha-2u-globulin induced nephropathy.
The no-observed-adverse-effect concentration (NOAEC) was considered to be 1100 mg/m³.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 weeks

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Principles of method if other than guideline:

25 male Harlan-Wistar rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 480 mg/m3 (84 ppm), 1100 mg/m3 (190 ppm) and 1900 mg/m3 (330 ppm) (boiling range, 152-194°C; 47.7% aliphatics, 37.6% cyclic aliphatics, 14.7% aromatics) for a period of 13 weeks(6 h/day, 5 days/week).

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Stoddard solvent;boiling range, 152-194°C; 47.7% aliphatics, 37.6% cyclic aliphatics, 14.7% aromatics

Species:

rat

Strain:

Wistar

Details on species / strain selection:

25 male Harlan-Wistar rats

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Harlan-Wistar rats
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 8-9 weeks
- Weight at study initiation (mean): 211-213 g;
- Housing: 5 per cage
- Acclimation period: 26 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

no data

Details on inhalation exposure:

25 male Harlan-Wistar rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 480 mg/m3 (84 ppm), 1100 mg/m3 (190 ppm) and 1900 mg/m3 (330 ppm) (boiling range, 152-194°C; 47.7% aliphatics, 37.6% cyclic aliphatics, 14.7% aromatics) for a period of 13 weeks(6 h/day, 5 days/week).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Nominal concentrations were determined daily, and calculations of concentration in ppm were made by using weight loss data and assuming an average molecular weight of 142 g/mol for the Stoddard solvent. Analytical concentrations were determined by drawing samples from the chambers into a gas chromatograph equipped with a flame ionization detector.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 h/day, 5 days/week

Dose / conc.:

0 mg/m³ air

Dose / conc.:

480 mg/m³ air

Remarks:

84 ppm=480 mg/m3

Dose / conc.:

1 100 mg/m³ air

Remarks:

190 ppm=1100 mg/m3

Dose / conc.:

1 900 mg/m³ air

Remarks:

330 ppm=1900 mg/m3

No. of animals per sex per dose:

25 male Harlan-Wistar rats

Control animals:

yes

Details on study design:

25 male Harlan-Wistar rats to white spirit (Stoddard solvent) vapour at levels of 0 mg/m3, 480 mg/m3 (84 ppm), 1100 mg/m3 (190 ppm) and 1900 mg/m3 (330 ppm) (boiling range, 152-194°C; 47.7% aliphatics, 37.6% cyclic aliphatics, 14.7% aromatics) for a period of 13 weeks(6 h/day, 5 days/week).

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, all animals
- Time schedule: twice daily

BODY WEIGHT: Yes, all animals
- Time schedule for examinations: weighed initially and 1 x week thereafter

CLINICAL PATHOLOGY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

no data

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Histopathological lesions of the kidneys and dilated tubules were found in 6 out of 9 and 3 out of 9 rats exposed to 1900 and 1100 mg/m3, respectively

Mortality:

no mortality observed

Description (incidence):

No treatment-related deaths were observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No differences were found in weight gain.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Details on results:

Histopathological lesions of the kidneys and dilated tubules were found in 6 out of 9 and 3 out of 9 rats exposed to 1900 and 1100 mg/m3, respectively.
These lesions were also noted in rats killed after only 8 weeks of exposure.
Significant, although not dose-related, changes in haematological values were thought to be mainly a consequence of the deviant values found in the control group. No differences were found in weight gain.

Dose descriptor:

NOAEC

Effect level:

1 100 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

Remarks on result:

other:

Remarks:

Based on histopathological lesions of the kidneys and dilated tubules found in 3 out of 9 rats exposed to 1100 mg/m3,

Dose descriptor:

LOAEC

Effect level:

1 900 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

organ weights and organ / body weight ratios

Remarks on result:

other:

Remarks:

Based on histopathological lesions of the kidneys and dilated tubules found in 6 out of 9 rats exposed to 1900 mg/m3,

Critical effects observed:

not specified

Based on histopathological lesions of the kidneys and dilated tubules found in 3 out of 9 rats exposed to 1100 mg/m3,

The no-observed-adverse-effect concentration (NOAEC) was considered to be 1100 mg/m³.

Conclusions:

Sub-chronic exposure to male rats for of 13 weeks(6 h/day, 5 days/week) periods produced no significant finding.
The only significant finding was slight to moderate tubular regeneration in male rats which is consistent with alpha-2u-globulin induced nephropathy.
The no-observed-adverse-effect concentration (NOAEC) was considered to be 1100 mg/m³.

Executive summary:

Based on the results of this study, repeated inhalation exposure of male rats to Stoddard solvent at mean analytical concentrations of 1100 mg/m³ (190 ppm) and 1900 mg/m³ (330 ppm) was well-tolerated with no adverse effects .

The no-observed-adverse-effect concentration (NOAEC) was considered to be 1100 mg/m³.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 100 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Sub-chronic exposure to male rats for of 13 weeks(6 h/day, 5 days/week) periods produced no significant finding.
The only significant finding was slight to moderate tubular regeneration in male rats which is consistent with alpha-2u-globulin induced nephropathy.
The no-observed-adverse-effect concentration (NOAEC) was considered to be 1100 mg/m³.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

28 days

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 10 of each gender per test group and control group

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

Stoddard Solvent CAS# 8052-41-3) was evaluated for toxicity in New Zealand White (NZW) rabbits when administered to the skin 3 times per week over the course of 4 weeks. Stoddard Solvent was applied to the clipped, intact skin of groups of male and female rabbits (5/sex/group) at dose levels of 0, 200, 1000, or 2000 mg/kg. Immediately following application, the sites were covered with surgical gauze, wrapped with polyethylene material and taped for 6 hours. At the end of 6 hours, the occlusive wrapping was removed and any excess material gently wiped off. One female from the high dose group (group 4) was sacrificed in a moribund condition on Day 14, after showing decreased feed intake on Days 12 through 14 and marked weight loss on Day 14. Microscopic examination revealed mucoid enteritis as a probable cause of morbidity and was considered incidental to treatment. Weight gains of males from groups 2 and 3 (200 and 1000 mg/kg) were comparable to those of control males.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks.

Frequency of treatment:

Once per day, 3 times per week (12 total applications)

Dose / conc.:

200 mg/kg bw/day

Dose / conc.:

1 000 mg/kg bw/day

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose:

groups of male and female rabbits (5/sex/group)

Control animals:

yes, concurrent no treatment

Details on study design:

The shaved intact skin (15 × 20 cm) of groups of 10 New Zealand White rabbits was exposed to doses of 200, 1000, and 2000 mg/kg of white spirit (Stoddard solvent).
Exposure was carried out usining occlusion bandage for a duration of 6 h and was given 3 times weekly for 4 weeks.

Observations and examinations performed and frequency:

The animals were observed for signs of overt toxicity, dermal irritation, effects on body weight and consumption, haematology and serum chemistry parameters.

Sacrifice and pathology:

Complete necropsies were performed on all animals.

Other examinations:

Selected organs were weighed and a microscopic examination was conducted on selected tissues from all animals at the scheduled necropsy.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 2000 mg/kg, female rabbits developed liver lesions characterized as white streaks or foci with granular surface

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Dermal irritation was scored as being severe in group 4 males and females and group 3 males and moderate in group 3 females and group 2 animals (males and females).

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At the highest dose level, there was a significant reduction in weight gain in both sexes, whereas only the female body weight gain was reduced at 1000 mg/kg.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Mean food consumption (evaluated as g/animal/day) was slightly but consistently decreased in the high dose group (males) during the first two thirds of the study period, and this was attributed to the test article.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Description (incidence and severity):

No information provided

Ophthalmological findings:

not specified

Description (incidence and severity):

No test related ophthalmic lesions were present at the week 12 opthalmologic examinations.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Changes in haematological parameters noted at 2000 mg/kg were judged not to be treatment- related.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In the serum chemistry parameters albumin means were decreased and globulin means were increased (resulting in decreased A/G ratios). Again this was attributed to the acute dermal inflammation that was observed.

Urinalysis findings:

not specified

Description (incidence and severity):

No information provided

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Group 4 females (2000 mg/kg) showed a negative weight gain and significantly lower terminal body weights relative to controls.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significant changes reported (except for the dermal application sites for all the dose groups)

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No significant changes reported (except for the dermal application sites for all the dose groups)

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

other: on the basis of a l reduced absolute mean liver weight and increased relative mean kidney weight (left kidney).

Critical effects observed:

not specified

Microscopic examination revealed mucoid enteritis as a probable cause of morbidity and was considered incidental to treatment. Weight gains of males from groups 2 and 3 (200 and 1000 mg/kg) were comparable to those of control males.

Males from group 4 (2000 mg/kg) showed significantly lower weight gains and, subsequently, significantly lower body weights than controls at terminal sacrifice. Females from group 2 had body weight gains comparable to controls, while group 3 females had significantly lower weight gains and terminal body weights than control females.

Group 4 females (2000 mg/kg) showed a negative weight gain and significantly lower terminal body weights relative to controls.

Dermal irritation was scored as being severe in group 4 males and females and group 3 males and moderate in group 3 females and group 2 animals (males and females).

 

 Group 4 (2000 mg/kg) males had significantly reduced absolute mean liver weight and increased relative mean kidney weight (left kidney). Females from groups 4 and 3 showed a significant increase in relative cerebrum weight over controls.

 

The majority of lesions noted upon gross examination at necropsy were seen in the skin and were associated with dermal irritation. Females in the high dose group were seen to have white streaks or foci on the livers of 2 animals, while a third exhibited a granular surface on the liver. Other gross lesions observed in treated animals were few, uniformly small, and occurred with the same frequency as in controls. Microscopic examination of treated animals revealed lesions in the skin at the application site including thickening and down-growth of the epidermis, hyperkeratosis, and dermal fibrosis. The incidence and severity of the observed lesions were significantly greater in high dose animals compared to controls and animals in the lower dose groups. There were a small number of lesions noted from other tissues (heart, trachea, pancreas, testes, and spleen) but these were considered unrelated to treatment.

Conclusions:

The NOAEL for this study was determined to be 2000 mg/kg.

Executive summary:

The shaved intact skin (15 × 20 cm) of groups of 10 New Zealand White rabbits was exposed to doses of 200, 1000, and 2000 mg/kg of white spirit (Stoddard solvent). Exposure was carried out using occlusion bandage for a duration of 6 h and was given 3 times weekly for 4 weeks. At the highest dose level, there was a significant  reduction in weight gain in both sexes, whereas only the female body  weight gain was reduced at 1000 mg/kg. Changes in haematological parameters noted at 2000 mg/kg were judged not to be treatment-related. At 2000 mg/kg, female rabbits developed liver lesions characterized as white streaks or foci with granular surface

.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Study duration:

subchronic

Species:

rabbit

Quality of whole database:

The shaved intact skin (15 × 20 cm) of groups of 10 New Zealand White rabbits was exposed to doses of 200, 1000, and 2000 mg/kg of white spirit (Stoddard solvent). Exposure was carried out using occlusion bandage for a duration of 6 h and was given 3 times weekly for 4 weeks. At the highest dose level, there was a significant reduction in weight gain in both sexes, whereas only the female body weight gain was reduced at 1000 mg/kg. Changes in haematological parameters noted at 2000 mg/kg were judged not to be treatment-related. At 2000 mg/kg, female rabbits developed liver lesions characterized as white streaks or foci with granular surface

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

28 days

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 10 of each gender per test group and control group

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

Stoddard Solvent CAS# 8052-41-3) was evaluated for toxicity in New Zealand White (NZW) rabbits when administered to the skin 3 times per week over the course of 4 weeks. Stoddard Solvent was applied to the clipped, intact skin of groups of male and female rabbits (5/sex/group) at dose levels of 0, 200, 1000, or 2000 mg/kg. Immediately following application, the sites were covered with surgical gauze, wrapped with polyethylene material and taped for 6 hours. At the end of 6 hours, the occlusive wrapping was removed and any excess material gently wiped off. One female from the high dose group (group 4) was sacrificed in a moribund condition on Day 14, after showing decreased feed intake on Days 12 through 14 and marked weight loss on Day 14. Microscopic examination revealed mucoid enteritis as a probable cause of morbidity and was considered incidental to treatment. Weight gains of males from groups 2 and 3 (200 and 1000 mg/kg) were comparable to those of control males.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks.

Frequency of treatment:

Once per day, 3 times per week (12 total applications)

Dose / conc.:

200 mg/kg bw/day

Dose / conc.:

1 000 mg/kg bw/day

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose:

groups of male and female rabbits (5/sex/group)

Control animals:

yes, concurrent no treatment

Details on study design:

The shaved intact skin (15 × 20 cm) of groups of 10 New Zealand White rabbits was exposed to doses of 200, 1000, and 2000 mg/kg of white spirit (Stoddard solvent).
Exposure was carried out usining occlusion bandage for a duration of 6 h and was given 3 times weekly for 4 weeks.

Observations and examinations performed and frequency:

The animals were observed for signs of overt toxicity, dermal irritation, effects on body weight and consumption, haematology and serum chemistry parameters.

Sacrifice and pathology:

Complete necropsies were performed on all animals.

Other examinations:

Selected organs were weighed and a microscopic examination was conducted on selected tissues from all animals at the scheduled necropsy.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 2000 mg/kg, female rabbits developed liver lesions characterized as white streaks or foci with granular surface

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Dermal irritation was scored as being severe in group 4 males and females and group 3 males and moderate in group 3 females and group 2 animals (males and females).

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At the highest dose level, there was a significant reduction in weight gain in both sexes, whereas only the female body weight gain was reduced at 1000 mg/kg.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Mean food consumption (evaluated as g/animal/day) was slightly but consistently decreased in the high dose group (males) during the first two thirds of the study period, and this was attributed to the test article.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Description (incidence and severity):

No information provided

Ophthalmological findings:

not specified

Description (incidence and severity):

No test related ophthalmic lesions were present at the week 12 opthalmologic examinations.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Changes in haematological parameters noted at 2000 mg/kg were judged not to be treatment- related.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In the serum chemistry parameters albumin means were decreased and globulin means were increased (resulting in decreased A/G ratios). Again this was attributed to the acute dermal inflammation that was observed.

Urinalysis findings:

not specified

Description (incidence and severity):

No information provided

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Group 4 females (2000 mg/kg) showed a negative weight gain and significantly lower terminal body weights relative to controls.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significant changes reported (except for the dermal application sites for all the dose groups)

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No significant changes reported (except for the dermal application sites for all the dose groups)

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

other: on the basis of a l reduced absolute mean liver weight and increased relative mean kidney weight (left kidney).

Critical effects observed:

not specified

Microscopic examination revealed mucoid enteritis as a probable cause of morbidity and was considered incidental to treatment. Weight gains of males from groups 2 and 3 (200 and 1000 mg/kg) were comparable to those of control males.

Males from group 4 (2000 mg/kg) showed significantly lower weight gains and, subsequently, significantly lower body weights than controls at terminal sacrifice. Females from group 2 had body weight gains comparable to controls, while group 3 females had significantly lower weight gains and terminal body weights than control females.

Group 4 females (2000 mg/kg) showed a negative weight gain and significantly lower terminal body weights relative to controls.

Dermal irritation was scored as being severe in group 4 males and females and group 3 males and moderate in group 3 females and group 2 animals (males and females).

 

 Group 4 (2000 mg/kg) males had significantly reduced absolute mean liver weight and increased relative mean kidney weight (left kidney). Females from groups 4 and 3 showed a significant increase in relative cerebrum weight over controls.

 

The majority of lesions noted upon gross examination at necropsy were seen in the skin and were associated with dermal irritation. Females in the high dose group were seen to have white streaks or foci on the livers of 2 animals, while a third exhibited a granular surface on the liver. Other gross lesions observed in treated animals were few, uniformly small, and occurred with the same frequency as in controls. Microscopic examination of treated animals revealed lesions in the skin at the application site including thickening and down-growth of the epidermis, hyperkeratosis, and dermal fibrosis. The incidence and severity of the observed lesions were significantly greater in high dose animals compared to controls and animals in the lower dose groups. There were a small number of lesions noted from other tissues (heart, trachea, pancreas, testes, and spleen) but these were considered unrelated to treatment.

Conclusions:

The NOAEL for this study was determined to be 2000 mg/kg.

Executive summary:

The shaved intact skin (15 × 20 cm) of groups of 10 New Zealand White rabbits was exposed to doses of 200, 1000, and 2000 mg/kg of white spirit (Stoddard solvent). Exposure was carried out using occlusion bandage for a duration of 6 h and was given 3 times weekly for 4 weeks. At the highest dose level, there was a significant  reduction in weight gain in both sexes, whereas only the female body  weight gain was reduced at 1000 mg/kg. Changes in haematological parameters noted at 2000 mg/kg were judged not to be treatment-related. At 2000 mg/kg, female rabbits developed liver lesions characterized as white streaks or foci with granular surface

.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

37.8 mg/cm²

Study duration:

subchronic

Species:

rabbit

Quality of whole database:

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

The dose descriptor for dermal irritation/corrosion come from dermal subchronic study
In these studies, the dose is reported in the unit mg/kg of body weight/day.
This needs to be modified to enable comparison with the human exposure, generally expressed in mg/cm2/day.
We have taken that:
• the average weight of rabbits is 2400g (2100 -2550g),
• the dose is applied over an area which is approximately 10% of the total body surface, and
• the total body surface of rabbits is on the average 1270 cm2

The generic modification from the dose in mg/kg bw to NOAECmodified(in mg/cm2/day) will be
NOAEC in mg/cm2 =((average animal weight in kg) x (dose in mg/kg bw)) / Treated surface in cm2)
NOAEC in mg/cm2 = (2.4 x 2000)/127 =37.80 mg/cm2
-The dose was 2000 mg/kg bw in the subchronic study
- average animal weight in kg was 2.4 kg
- Treated surface in cm2 was 1270 cm2
NOAEC in mg/cm2 = (2.4 x 2000)/127 =37.80 mg/cm2

Additional information

Justification for selection of repeated dose toxicity dermal - local effects endpoint: 

 

The dose descriptor for dermal irritation/corrosion come from dermal subchronic study

In these studies, the dose is reported in the unit mg/kg of body weight/day.

This needs to be modified to enable comparison with the human exposure, generally expressed in mg/cm2/day.

We have taken that:

• the average weight of rabbits is 2400g (2100 -2550g),

• the dose is applied over an area which is approximately 10% of the total body surface, and

• the total body surface of rabbits is on the average 1270 cm2 

           

The generic modification from the dose in mg/kg bw to NOAECmodified(in mg/cm2/day) will be  

NOAEC in mg/cm2 =((average animal weight in kg) x (dose in mg/kg bw)) / Treated surface in cm2)  

NOAEC in mg/cm2 =     (2.4 x 2000)/127 =37.80 mg/cm2  

-The dose was 2000 mg/kg bw in the subchronic study

- average animal weight in kg was 2.4 kg

 - Treated surface in cm2 was 1270 cm2

 NOAEC in mg/cm2 =      (2.4 x 2000)/127 =37.80 mg/cm2

Justification for classification or non-classification

Based on the hazard assessment of Stoddard solventin section 2.1 and 2.2. in IUCLID 6., available data for the substance and following the “Guidance on Information Requirement and Chemical Safety Assessment R.8. Characterisation of dose [concentration]- response for human health”, according to the EU’s list of dangerous substances (OJEC No L200/130.7.99) and according to the criteria described in Directive 67/548 and in the CLP Regulation:

 

Directive 67/548

Repeated dose toxicity R33 Danger of cumulative effects. T; R48/23 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation. T; R48/23/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin. T; R48/23/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. T; R48/23/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. T; R48/24 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin. T; R48/24/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed. T; R48/25 Toxic; Toxic: danger of serious damage to health by prolonged exposure if swallowed. Xn; R48/20 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation. Xn; R48/20/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin. Xn; R48/20/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed. Xn; R48/20/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed. Xn; R48/21 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin. Xn; R48/21/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed. Xn; R48/22 Harmful; Harmful: danger of serious damage to health by prolonged exposure if swallowed

CLP

Repeated dose toxicity STOT Rep. Exp. 1 STOT Rep. Exp. 2 H372: Causes damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>. H373: May cause damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.

 

It is concluded that the substance Stoddard solvent does not meet the criteria to be classified for human health hazards for Repeated dose toxicity