Stoddard solvent

Neurotoxicity

Description of key information

It is concluded that the substance Stoddard solvent meet the criteria to be classified for human health hazards for Aspiration Hazard

Asp. Tox. 1

H304: May be fatal if swallowed and enters airways.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

neurotoxicity: acute inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

It is conducted both acute and subchronic studies with white spirit vapors containing 20 volume % aromatics. Male Wistar rats were exposed to 0, 100, 200, 400, or 800 ppm white spirit vapors for 8 hrs/day for 3 consecutive days with behavioral tests conducted immediately after exposures
Before the exposure the rats were trained to react to a light stimulus on either of two panels and to depress a lever at the illuminated site to get access to water. Immediately after the first day of exposure the latency time from stimulus to reaction was significantly increased in an exposure-related manner.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Stoddard solvent, (boiling range, 158-193°C; 44% aliphatics, 36% cyclic aliphatics, 18% aromatics)

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

inhalation: vapour

Vehicle:

air

Details on exposure:

Male Wistar rats (8 per group) exposed to white spirit vapour levels of 0, 600, 1200, 2400 and 4800 mg/m3 (0, 100,200, 400 and 800 ppm) (boiling range, 158-193°C; 44% aliphatics, 36% cyclic aliphatics, 18% aromatics) 8 h/day for three consecutive days. Before the exposure the rats were trained to react to a light stimulus on either of two panels and to depress a lever at the illuminated site to get access to water. Immediately after the first day of exposure the latency time from stimulus to reaction was significantly increased in an exposure-related manner.

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:

3 consecutive days

Frequency of treatment:

8 hrs/day

Dose / conc.:

0 mg/m³ air

Dose / conc.:

600 mg/m³ air

Remarks:

600 mg/m3= 100 ppm

Dose / conc.:

1 200 mg/m³ air

Remarks:

1200 mg/m3= 200 ppm

Dose / conc.:

2 400 mg/m³ air

Remarks:

1200 mg/m3= 400 ppm

Dose / conc.:

4 800 mg/m³ air

Remarks:

4800 mg/m3= 800 ppm

No. of animals per sex per dose:

8 per group

Control animals:

yes

Clinical signs:

effects 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

Clinical biochemistry findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Neuropathological findings:

effects observed, treatment-related

Details on results:

Neurobehavioural effects were evaluated in rats.
In male rats exposed to white spirit type 1 (0, 600, 2400 or 4800 mg/m³ (approximately 0, 100, 400 and 800 ppm, respectively), 8 hours/day for three consecutive days), the spontaneous motor activity was decreased at the highest exposure level and the psychomotor speed was affected exposuredependently at the two highest levels.
Overall, the NOAEC was 600 mg/m3 (approximately 100 ppm).

Dose descriptor:

NOAEC

Effect level:

600 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

behaviour (functional findings)

neuropathology

Remarks on result:

other: the spontaneous motor activity was decreased at the highest exposure level and the psychomotor speed was affected exposuredependently at the two highest levels.

Critical effects observed:

not specified

Conclusions:

Neurobehavioural effects were evaluated in rats.
In male rats exposed to white spirit type 1 (0, 600, 2400 or 4800 mg/m³ (approximately 0, 100, 400 and 800 ppm, respectively), 8 hours/day for three consecutive days), the spontaneous motor activity was decreased at the highest exposure level and the psychomotor speed was affected exposuredependently at the two highest levels. This study confirmed that acute white spirit exposure at 200 to 800 ppm could produce transient behavioral effects. Overall, the NOAEC was 600 mg/m3 (approximately 100 ppm).

Executive summary:

 Minor behavioural changes were found in male Wistar rats  (8 per group) exposed to white spirit vapour levels of 0, 600 1200, 2400 and 4800 mg/m3 (0,100, 200, 400 and 800 ppm) (boiling range, 158-193°C;   44% aliphatics, 36% cyclic aliphatics, 18% aromatics) 8 h/day for   three consecutive days. Before the exposure the rats were trained to   react to a light stimulus on either of two panels and to depress a   lever at the illuminated site to get access to water. Immediatelyafter the first day of exposure the latency time from stimulus to   reaction was significantly increased in an exposure-related manner.

Reference 2

Endpoint:

neurotoxicity: sub-chronic inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26 weeks

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

In a subchronic study, male Wistar rats were exposed to 0, 200, 400, or 800 ppm white spirit vapors for 8 hrs/day, 5 days/week for 26 weeks with behavioral tests generally conducted weekly at least 10 hours after the last daily exposure.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Stoddard solvent, (boiling range, 158-193°C; 44% aliphatics, 36% cyclic aliphatics, 18% aromatics)

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

inhalation: vapour

Vehicle:

air

Details on exposure:

In a subchronic study, male Wistar rats were exposed to 0, 200, 400, or 800 ppm white spirit vapors for 8 hrs/day, 5 days/week for 26 weeks with behavioral tests generally conducted weekly at least 10 hours after the last daily exposure.

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:

26 weeks

Frequency of treatment:

8 hrs/day, 5 days/week

Dose / conc.:

0 mg/m³ air

Dose / conc.:

1 200 mg/m³ air

Remarks:

1200 mg/m3= 200 ppm

Dose / conc.:

2 400 mg/m³ air

Remarks:

1200 mg/m3= 400 ppm

Dose / conc.:

4 800 mg/m³ air

Remarks:

4800 mg/m3= 800 ppm

No. of animals per sex per dose:

8 per group

Control animals:

yes

Clinical signs:

effects 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

Clinical biochemistry findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Neuropathological findings:

effects observed, treatment-related

Details on results:

No differences in performance were seen compared to controls during the 26 weeks of exposure. In week 17, however, the test was done immediately after the end of the daily exposure and the exposed groups now had a poorer performance (increased response time) indicating that an acute effect was still demonstrable. Behavioural tests designed to measure changes in activity, coordination, grip strength and discrimination performance did not reveal significant differences compared to control rats. Measurements of tail nerve conduction velocity showed significant lower conduction velocities in rats exposed to 4800 mg/m3.

Dose descriptor:

NOAEC

Effect level:

4 800 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

behaviour (functional findings)

Remarks on result:

other: Psychomotor slowing was observed, but there was no carry over of effect into the post-exposureperiod.

Critical effects observed:

not specified

Conclusions:

No persistent changes in neurobehavioral functioning were observed.
In addition, no exposure-related changes in brain, spinal cord, or sciatic nerve were seen in light microscopy studies.
Behavioural tests designed to measure changes in activity, coordination, grip strength and discrimination performance did not reveal significant differences compared to control rats. Measurements of tail nerve conduction velocity showed significant lower conduction velocities in rats exposed to 4800 mg/m3.

Executive summary:

No persistent changes in neurobehavioral functioning were observed.

 In a study lasting 26 weeks,   the tests were performed at least 10 h after the daily exposure had  ceased. No differences in performance were seen compared to controls   during the 26 weeks of exposure. In week 17, however, the test was   done immediately after the end of the daily exposure and the exposed  groups now had a poorer performance (increased response time)  indicating that an acute effect was still demonstrable. Behavioural   tests designed to measure changes in activity, coordination, grip   strength and discrimination performance did not reveal significant   differences compared to control rats. Measurements of tail nerve   conduction velocity showed significant lower conduction velocities in  rats exposed to 4800 mg/m3.

Reference 3

Endpoint:

neurotoxicity: sub-chronic inhalation

Type of information:

experimental study

Adequacy of study:

key study

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:

no guideline followed

Principles of method if other than guideline:

In a subchronic study, rats were exposed to white spirits (0, 400, or 800 ppm) for 6 hrs/day, 5 days/week for 6 months. After an exposure-free period of two months, neurobehavioral, pathological, and neurochemical examinations were performed.

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Stoddard solvent, (boiling range, 148-200°C; 80% aliphatic and cycloaliphatic hydrocarbons, 20% aromatics)

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

inhalation: vapour

Vehicle:

air

Details on exposure:

Groups of male Wistar rats were exposed to 0, 2290 and 4580 mg/m3 (0, 400 and 800 ppm) of white spirit (boiling range, 148-200°C; 80% aliphatic and cycloaliphatic hydrocarbons, 20% aromatics) 6 h/day, 5 days/week, for 6 months. Neurobehavioural tests were performed after an exposure- free period of 2 months.

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:

2290 mg/m3= 400 ppm

Dose / conc.:

4 580 mg/m³ air

Remarks:

4580 mg/m3= 800 ppm

No. of animals per sex per dose:

36 rats in each group) of young rats (aged 3 months at the start of exposure) and with groups (14 rats in each group) of old rats (15 months old at the start of exposure)

Control animals:

yes

Clinical signs:

effects 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

Clinical biochemistry findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Neuropathological findings:

effects observed, treatment-related

Details on results:

There was no neurobehavioral white spirit-induced neurotoxicity. As expected, age-related differences in motor activity were detected, however, no dose-related macroscopic or histopathological changes were found. The concentration of neurotransmitters noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) in various brain regions and in whole brain was changed in the 400 and 800 ppm groups.
The authors conclude that this study revealed different irreversible changes within the CNS. However, the significance of changes in neurotransmitter levels is difficult to evaluate. In the absence of any pathological or functional changes, it is difficult to determine if this is toxicological, phenomenological, compensatory, or merely a random variation

Dose descriptor:

NOAEC

Effect level:

4 580 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

behaviour (functional findings)

Remarks on result:

other: different irreversible changes within the CNS.

Critical effects observed:

not specified

Conclusions:

There was no neurobehavioral white spirit-induced neurotoxicity. As expected, age-related differences in motor activity were detected, however, no dose-related macroscopic or histopathological changes were found. The concentration of neurotransmitters noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) in various brain regions and in whole brain was changed in the 400 and 800 ppm groups.
The authors conclude that this study revealed different irreversible changes within the CNS. However, the significance of changes in neurotransmitter levels is difficult to evaluate. In the absence of any pathological or functional changes, it is difficult to determine if this is toxicological, phenomenological, compensatory, or merely a random variation

Executive summary:

There was no neurobehavioral white spirit-induced neurotoxicity. As expected, age-related differences in motor activity were detected, however, no dose-related macroscopic or histopathological changes were found. The concentration of neurotransmitters noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) in various brain regions and in whole brain was changed in the 400 and 800 ppm groups.

The authors conclude that this study revealed different irreversible changes within the CNS. However, the significance of changes in neurotransmitter levels is difficult to evaluate. In the absence of any pathological or functional changes, it is difficult to determine if this is toxicological, phenomenological, compensatory, or merely a random variation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

600 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

Neurobehavioural effects were evaluated in rats.
In male rats exposed to white spirit type 1 (0, 600, 2400 or 4800 mg/m³ (approximately 0, 100, 400 and 800 ppm, respectively), 8 hours/day for three consecutive days), the spontaneous motor activity was decreased at the highest exposure level and the psychomotor speed was affected exposuredependently at the two highest levels. This study confirmed that acute white spirit exposure at 200 to 800 ppm could produce transient behavioral effects. Overall, the NOAEC was 600 mg/m3 (approximately 100 ppm).

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The results of available animal studies on mineral spirits containing up to 22 volume % aromatics demonstrate that the acute CNS effects produced by concentrations as high as 800 ppm are completely reversible. The potential for persistent effects is less clear. Several studies have reported changes in behavior, neurochemistry, and sensory evoked potentials that the authors have interpreted as evidence of long-lasting, perhaps irreversible changes. However, these findings have generally been subtle and not obviously associated with functional deficits or behavioral changes. Therefore, it is not clear whether these finding are a reflection of a true neurotoxic effect or simply a measured change from baseline values without toxicological significance. There is no consistent evidence that chronic low-level solvent exposure in animal models produces irreversible CNS effects.  

Justification for classification or non-classification

It is concluded that the substance Stoddard solvent meet the criteria to be classified for human health hazards forAspiration Hazard

Asp. Tox. 1

H304: May be fatal if swallowed and enters airways.