Carbon black

Endpoint summary

Description of key information

A relevant systemic exposure after oral, dermal or respiratory administration is not expected (see section on toxicokinetics for details). Because a lack systemic availability is expected for the non-nanoforms of carbon black, since carbon black, irrespective of form display a similar surface chemistry; the functional groups on surface of their particles are essentially the same but may differ in concentration, differences in toxicological outcome is not expected. Both bulk and untreated nanoforms are insoluble in water, and biological fluids. As a consequence, toxicity if any, will be driven by the physical presence of the particles in the lung. Consequentially, they share a common mode of action that involves ROS generation and inflammation in lung. It is therefore justified to read-across the data for the bulk form from the untreated carbon black nanoforms to assess the repeated dose toxicity of the bulk forms. Data generated for the untreated forms are used to predict the properties of the bulk forms (see discussion for the untreated nanoform of carbon black).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Endpoint-specific read-across justification" attached under section 13.2

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: neoplastic

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

water consumption and compound intake

Key result

Critical effects observed:

no

Conclusions:

There were no adverse effects found in a modern 90 day GLP and guideline study after repeated oral administration by gavage. The study authors concluded that the repeated daily oral administration to rats of carbon black for 13 weeks at 100, 300 or 1000 mg/kg/day was well tolerated, with some nonadverse findings related to the staining properties of carbon black. Accordingly, under the conditions of this study, the No Observed Adverse Effect Level (NOAEL) was 1000 mg/kg/day.

Executive summary:

The results of a 90 -day GLP and guideline study in rats are summarised by the EU Scientific Committee on Consumer Products (2015) as follows: "Following daily administration of carbon black, there were no deaths, no adverse clinical signs, no ocular findings or changes in body weight gain and food intake when compared to controls. Dark coloured faeces were observed in animals given carbon black at all dose levels. This finding is related to the coloured nature of the test item and hence considered to be non-adverse. There were no relevant changes in laboratory parameters. Some haematology and blood clinical chemistry parameters showed minimal changes when compared to controls. However, as they remained minor and showed no dose-relationship, these changes were considered to be unrelated to the administration of carbon black. There were no changes attributed to carbon black in any of the urinary parameters evaluated. Dosing with carbon black did not produce any changes in organ weights. The only finding at necropsy consisted of black gastro-intestinal tract contents in all animals given carbon black, without any associated gross or microscopic changes in the gastro-intestinal mucosa apart from black discolouration. These findings were also considered to be related to the coloured nature of the test item and hence non adverse. There were no other histopathological findings attributed to carbon black."

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

given in respective reports

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Endpoint-specific read-across justification" attached under section 13.2

Reason / purpose for cross-reference:

read-across source

Remarks:

Human data

Qualifier:

no guideline required

Principles of method if other than guideline:

The studies were designed and performed in accordance with standard epidemiological methods taking into criteria the Bradford Hill's criteria for causation

GLP compliance:

no

Species:

other: human

Route of administration:

inhalation: dust

Key result

Dose descriptor:

NOAEC

Remarks on result:

not determinable

Remarks:

Human study

Key result

Critical effects observed:

no

System:

other: lungs

Executive summary:

The critical human health effect is upon the airways. Large multi-centre studies in Europe by Gardiner et al. (1993, 2001) and in the USA by Harber et al. (2003) demonstrate that long-term heavy occupational carbon black exposure is associated with reductions in the forced expiratory volume in 1 second (FEV1). These data indicate that there would be minimal, non-adverse effects on lung function parameters after 40 years of exposure to 1.0 mg/m3 (inhalable fraction, 8-hr TWA). A working lifetime of 40 years to inhalable carbon black at 1 mg/m3 (8-hour TWA) would lead to a mean decrease in FEV1 of 49 mL based on the European study. The comparable study in US carbon black-production workers resulted in a decrease in FEV1 of 28 mL for this exposure and duration scenario. These may be compared to the average age-related FEV1 loss in adult males of about 1,200 ml over this same 40-year period. These studies also demonstrated that carbon black exposure is NOT associated with significant consistent reductions in the forced vital capacity.

Longitudinal follow-up from 1987-1995 of the multi-plant European cohort (van Tongeren et al. 2002) and long-term follow-up of persons with minor radiographic abnormalities over 25 years in one US plant (Harber et al., 2003) do not show progression to advanced pneumoconiosis. The paucity of high profusion radiographic findings, the absence of progression to extensive radiographic abnormality, and the absence of restrictive physiologic abnormalities show that carbon black does not lead to a fibrotic pneumoconiosis.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

not reported

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Endpoint-specific read-across justification" attached under section 13.2

Reason / purpose for cross-reference:

read-across source

Qualifier:

no guideline followed

Species:

rat

Strain:

Fischer 344

Sex:

male

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

air

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 hours/day; 5 days/week

Key result

Dose descriptor:

NOAEC

Effect level:

1.1 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

other: pulmonary inflammation

Key result

Dose descriptor:

LOAEC

Effect level:

7.1 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

other: pulmonary inflammatory response; impairment of lung dust clearance mechanisms; increased lung weight

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

7.1 mg/m³ air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Executive summary:

Rats were exposed for 6 hr/day, 5 days/week for up to 13 weeks to 1.1, 7.1, and 52.8 mg/m3 carbon black and the effects on the lung were characterized after 6.5 and 13 weeks of exposure and 3 and 8 months of recovery. Endpoints characterized after carbon black exposure included mutation in the hprt gene of alveolar epithelial cells, changes in bronchoalveolar lavage fluid markers of lung injury and inflammation, expression of mRNA for the chemokines, MIP-2 and MCP-1, and lung histopathology. Lung burdens of carbon black were also determined. After 13 weeks of exposure to 1.1, 7.1, and 52.8 mg/m3 carbon black, lung burdens were 354, 1826, and 7861 micrograms carbon black, respectively. The lung clearance of carbon black appeared impaired after exposure to 7.1 and 52.8 mg/m3 carbon black, with the effects being more pronounced at the higher exposure level. Subchronic inhalation of 1.1 mg/m3 carbon black did not elicit any detectable adverse lung effects.

Reference 3

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Endpoint-specific read-across justification" attached under section 13.2

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Fischer 344

Sex:

female

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Duration of treatment / exposure:

6 hours/day, 5 days/week for 13 weeks

Frequency of treatment:

daily on 5 days/week

Positive control:

no

Key result

Dose descriptor:

NOAEC

Effect level:

1 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects found (high surface carbon black)

Key result

Dose descriptor:

NOAEC

Effect level:

50 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects found (low surface carbon black)

Key result

Critical effects observed:

no

Conclusions:

In rats, exposure for 13 weeks (6 hours/day, 5 days/week), to 1 mg/m3 high-surface carbon black or 50 mg/m3 low-surface carbon black induced only minimal nasal epithelial lesions that resolved by 13 weeks post-exposure (NOAEC).

Executive summary:

The nasal histopathology in groups of animals sacrificed 1 day, 13 weeks or 11 months after 13 week of exposure to high- or low-surface carbon black was studied (0, 1, 7, 50 mg/m3 high surface carbon black, HSCB; 50 mg/m3 low-surface carbon black (LSCB). Nasal inflammatory and epithelial lesions were found at one day after the last day of exposure in the rats with mid- or high-dose HSCB exposures, including some nasal epithelial lesions that remained present at 11 months following high-dose HSCB exposure, while LSCB elicited only minimal epithelial or inflammatory lesions that had all resolved by 13 weeks after exposure. After low-dose HSCB exposure, the only detectable exposure-related microscopic change in the nasal airways was a minimal mucous cell metaplasia (MCM) with an increase in intraepithelialy stored mucosubstances. The minimal and mild MCM induced by the low- and mid-dose HSCB exposures resolved by 13 weeks, but was still microscopically and morphometrically detectable in some intranasal regions 11 months after the end of the high-dose exposure to HSCB. Since airway mucus is known to be an effective antioxidant (Crosset al., 1984), MCM is likely one of the airway’s adaptive responses. 

Reference 4

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

not reported

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Endpoint-specific read-across justification" attached under section 13.2

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Clinical signs:

effects observed, treatment-related

Key result

Dose descriptor:

NOEC

Remarks:

(rat, mouse)

Effect level:

1 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: pulmonary inflammation

Dose descriptor:

LOEC

Remarks:

(rat, mouse)

Effect level:

7 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: histopathology; lung inflammation; prolonged carbon black retention in lungs

Key result

Dose descriptor:

NOEC

Remarks:

(hamster)

Effect level:

7 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: pulmonary inflammation

Dose descriptor:

LOAEC

Remarks:

(hamster)

Effect level:

50 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: histopathology; prolonged carbon black retention in lung; lung inflammation

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

7 mg/m³ air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

The results show that hamsters have the most efficient clearance mechanisms and least severe responses of the threee species tested. The results from rats also showe that particle surfae area is an important determinant of target tissue dose and, therefore, effects. From these results, a subchronic NOAEL of 1 mg/m3 respirable HSCb (Printex 90) can be assigned to female rats, mice, and hamsters.

Executive summary:

Particle retention kinetics, inflammation, and histopathology were examined in female rats, mice, and hamsters exposed for 13 weeks to high surface area Cb (HSCb) at doses chosen to span a no observable adverse effects level (NOAEL) to particle overload (0, 1, 7, 50 mg/m3, nominal concentrations). Rats were also exposed to low surface area Cb (50 mg/m3, nominal; LSCb). Retention and effects measurements were performed immediately after exposure and 3 and 11 months post-exposure; retention was also evaluated after 5 weeks of exposure. Significant decreases in body weight during exposure occurred only in hamsters exposed to high-dose HSCb. Lung weights were increased in high-dose Cb-exposed animals, but this persisted only in rats and mice up to the end of the study period. Equivalent or similar mass burdens were achieved in rats exposed to high-dose HSCb and LSCb, whereas surface area burdens were equivalent for mid-dose HSCb and LSCb. Prolonged retention was found in rats exposed to mid- and high-dose HSCb and to LSCb, but LSCb was cleared faster than HSCb. Retention was also prolonged in mice exposed to mid- and high-dose HSCb, and in hamsters exposed to high-dose HSCb. Lung inflammation and histopathology were more severe and prolonged in rats than in mice and hamsters, and both were similar in rats exposed to mid-dose HSCb and LSCb. The results show that hamsters have the most efficient clearance mechanisms and least severe responses of the three species. The results from rats also show that particle surface area is an important determinant of target tissue dose and, therefore, effects. From these results, a subchronic NOAEL of 1 mg/m3 respirable HSCb (Printex 90) can be assigned to female rats, mice, and hamsters.

Reference 5

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

given in respective reports

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Endpoint-specific read-across justification" attached under section 13.2

Reason / purpose for cross-reference:

read-across source

Remarks:

Human data

Qualifier:

no guideline required

Principles of method if other than guideline:

The studies were designed and performed in accordance with standard epidemiological methods taking into criteria the Bradford Hill's criteria for causation

GLP compliance:

no

Species:

other: human

Route of administration:

inhalation: dust

Key result

Dose descriptor:

NOAEC

Remarks on result:

not determinable

Remarks:

Human study

Key result

Critical effects observed:

no

System:

other: lungs

Executive summary:

The critical human health effect is upon the airways. Large multi-centre studies in Europe by Gardiner et al. (1993, 2001) and in the USA by Harber et al. (2003) demonstrate that long-term heavy occupational carbon black exposure is associated with reductions in the forced expiratory volume in 1 second (FEV1). These data indicate that there would be minimal, non-adverse effects on lung function parameters after 40 years of exposure to 1.0 mg/m3 (inhalable fraction, 8-hr TWA). A working lifetime of 40 years to inhalable carbon black at 1 mg/m3 (8-hour TWA) would lead to a mean decrease in FEV1 of 49 mL based on the European study. The comparable study in US carbon black-production workers resulted in a decrease in FEV1 of 28 mL for this exposure and duration scenario. These may be compared to the average age-related FEV1 loss in adult males of about 1,200 ml over this same 40-year period. These studies also demonstrated that carbon black exposure is NOT associated with significant consistent reductions in the forced vital capacity.

Longitudinal follow-up from 1987-1995 of the multi-plant European cohort (van Tongeren et al. 2002) and long-term follow-up of persons with minor radiographic abnormalities over 25 years in one US plant (Harber et al., 2003) do not show progression to advanced pneumoconiosis. The paucity of high profusion radiographic findings, the absence of progression to extensive radiographic abnormality, and the absence of restrictive physiologic abnormalities show that carbon black does not lead to a fibrotic pneumoconiosis.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

not reported

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Endpoint-specific read-across justification" attached under section 13.2

Reason / purpose for cross-reference:

read-across source

Qualifier:

no guideline followed

Species:

rat

Strain:

Fischer 344

Sex:

male

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

air

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 hours/day; 5 days/week

Key result

Dose descriptor:

NOAEC

Effect level:

1.1 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

other: pulmonary inflammation

Key result

Dose descriptor:

LOAEC

Effect level:

7.1 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

other: pulmonary inflammatory response; impairment of lung dust clearance mechanisms; increased lung weight

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

7.1 mg/m³ air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Executive summary:

Rats were exposed for 6 hr/day, 5 days/week for up to 13 weeks to 1.1, 7.1, and 52.8 mg/m3 carbon black and the effects on the lung were characterized after 6.5 and 13 weeks of exposure and 3 and 8 months of recovery. Endpoints characterized after carbon black exposure included mutation in the hprt gene of alveolar epithelial cells, changes in bronchoalveolar lavage fluid markers of lung injury and inflammation, expression of mRNA for the chemokines, MIP-2 and MCP-1, and lung histopathology. Lung burdens of carbon black were also determined. After 13 weeks of exposure to 1.1, 7.1, and 52.8 mg/m3 carbon black, lung burdens were 354, 1826, and 7861 micrograms carbon black, respectively. The lung clearance of carbon black appeared impaired after exposure to 7.1 and 52.8 mg/m3 carbon black, with the effects being more pronounced at the higher exposure level. Subchronic inhalation of 1.1 mg/m3 carbon black did not elicit any detectable adverse lung effects.

Reference 3

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Endpoint-specific read-across justification" attached under section 13.2

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Fischer 344

Sex:

female

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Duration of treatment / exposure:

6 hours/day, 5 days/week for 13 weeks

Frequency of treatment:

daily on 5 days/week

Positive control:

no

Key result

Dose descriptor:

NOAEC

Effect level:

1 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects found (high surface carbon black)

Key result

Dose descriptor:

NOAEC

Effect level:

50 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects found (low surface carbon black)

Key result

Critical effects observed:

no

Conclusions:

In rats, exposure for 13 weeks (6 hours/day, 5 days/week), to 1 mg/m3 high-surface carbon black or 50 mg/m3 low-surface carbon black induced only minimal nasal epithelial lesions that resolved by 13 weeks post-exposure (NOAEC).

Executive summary:

The nasal histopathology in groups of animals sacrificed 1 day, 13 weeks or 11 months after 13 week of exposure to high- or low-surface carbon black was studied (0, 1, 7, 50 mg/m3 high surface carbon black, HSCB; 50 mg/m3 low-surface carbon black (LSCB). Nasal inflammatory and epithelial lesions were found at one day after the last day of exposure in the rats with mid- or high-dose HSCB exposures, including some nasal epithelial lesions that remained present at 11 months following high-dose HSCB exposure, while LSCB elicited only minimal epithelial or inflammatory lesions that had all resolved by 13 weeks after exposure. After low-dose HSCB exposure, the only detectable exposure-related microscopic change in the nasal airways was a minimal mucous cell metaplasia (MCM) with an increase in intraepithelialy stored mucosubstances. The minimal and mild MCM induced by the low- and mid-dose HSCB exposures resolved by 13 weeks, but was still microscopically and morphometrically detectable in some intranasal regions 11 months after the end of the high-dose exposure to HSCB. Since airway mucus is known to be an effective antioxidant (Crosset al., 1984), MCM is likely one of the airway’s adaptive responses. 

Reference 4

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

not reported

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Endpoint-specific read-across justification" attached under section 13.2

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Clinical signs:

effects observed, treatment-related

Key result

Dose descriptor:

NOEC

Remarks:

(rat, mouse)

Effect level:

1 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: pulmonary inflammation

Dose descriptor:

LOEC

Remarks:

(rat, mouse)

Effect level:

7 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: histopathology; lung inflammation; prolonged carbon black retention in lungs

Key result

Dose descriptor:

NOEC

Remarks:

(hamster)

Effect level:

7 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: pulmonary inflammation

Dose descriptor:

LOAEC

Remarks:

(hamster)

Effect level:

50 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

other: histopathology; prolonged carbon black retention in lung; lung inflammation

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

7 mg/m³ air

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

The results show that hamsters have the most efficient clearance mechanisms and least severe responses of the threee species tested. The results from rats also showe that particle surfae area is an important determinant of target tissue dose and, therefore, effects. From these results, a subchronic NOAEL of 1 mg/m3 respirable HSCb (Printex 90) can be assigned to female rats, mice, and hamsters.

Executive summary:

Particle retention kinetics, inflammation, and histopathology were examined in female rats, mice, and hamsters exposed for 13 weeks to high surface area Cb (HSCb) at doses chosen to span a no observable adverse effects level (NOAEL) to particle overload (0, 1, 7, 50 mg/m3, nominal concentrations). Rats were also exposed to low surface area Cb (50 mg/m3, nominal; LSCb). Retention and effects measurements were performed immediately after exposure and 3 and 11 months post-exposure; retention was also evaluated after 5 weeks of exposure. Significant decreases in body weight during exposure occurred only in hamsters exposed to high-dose HSCb. Lung weights were increased in high-dose Cb-exposed animals, but this persisted only in rats and mice up to the end of the study period. Equivalent or similar mass burdens were achieved in rats exposed to high-dose HSCb and LSCb, whereas surface area burdens were equivalent for mid-dose HSCb and LSCb. Prolonged retention was found in rats exposed to mid- and high-dose HSCb and to LSCb, but LSCb was cleared faster than HSCb. Retention was also prolonged in mice exposed to mid- and high-dose HSCb, and in hamsters exposed to high-dose HSCb. Lung inflammation and histopathology were more severe and prolonged in rats than in mice and hamsters, and both were similar in rats exposed to mid-dose HSCb and LSCb. The results show that hamsters have the most efficient clearance mechanisms and least severe responses of the three species. The results from rats also show that particle surface area is an important determinant of target tissue dose and, therefore, effects. From these results, a subchronic NOAEL of 1 mg/m3 respirable HSCb (Printex 90) can be assigned to female rats, mice, and hamsters.

Reference 5

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

1 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

1

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

start of study: 1949

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Carbon blacks were suspended in mineral oil, cottonseed oil, cooking oil or water with 1% carboxymethyl cellulose. The backs of the test animals were painted with a brush three times per week with 20% emulsions of the designated carbon blacks, benzene extracts thereof or extracted carbon black for 12-18 months. Additional groups were treated with known carcinogens (methylcholanthrene, 3,4-benzpyrene). The negative controls were treated with the corresponding vehicle.

GLP compliance:

no

Limit test:

no

Species:

mouse

Strain:

other: CFW white and C3H brown

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not reported
- Age at study initiation: 6-10 weeks
- Weight at study initiation: not reported
- Fasting period before study: not reported
- Housing: the mice were kept in Monel pans - 10 to each pan in air-conditioned quarters
- Diet (e.g. ad libitum): Purina Dog Chow ad lib.
- Water (e.g. ad libitum): ad lib.
- Acclimation period: not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25.5
- Humidity (%): 55
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported


IN-LIFE DATES: From: 1949 To: not reported

Type of coverage:

open

Vehicle:

other: 1% aqueous carboxymethyl cellulose, cottonseed oil, cooking oil or mineral oil

Details on exposure:

TEST SITE
- Area of exposure: up to the middle of the unshaven back from the base of the tail to the neck
- % coverage: not reported
- Type of wrap if used: none used
- Time intervals for shavings or clipplings: unshaven


REMOVAL OF TEST SUBSTANCE
- Washing (if done): not reported
- Time after start of exposure: not reported


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): the weight of the material applied to 10 mice was determined, and this value was divided by the number of mice painted. Fairly consistent results for each application were obtained (no quantities reported)
- Concentration (if solution): 20% mixtures/emulsions
- Constant volume or concentration used: yes
- For solids, paste formed: not reported


VEHICLE
- Justification for use and choice of vehicle (if other than water): not reported
- Amount(s) applied (volume or weight with unit): not reported
- Concentration (if solution): 20%
- Lot/batch no. (if required): not reported
- Purity: not reported


USE OF RESTRAINERS FOR PREVENTING INGESTION: not reported

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No details reported

Duration of treatment / exposure:

12-18 months

Frequency of treatment:

3 times/week

Dose / conc.:

20 other: %

Remarks:

carbon black suspensions in cottonseed oil, mineral oil, cooking oil or in 1% aqueous carboxymethylcellulose

No. of animals per sex per dose:

10-40 mice / group (sex not always specified)

Control animals:

yes, concurrent no treatment

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: not reported
- Rationale for animal assignment (if not random): not reported
- Rationale for selecting satellite groups: no satellite groups used
- Section schedule rationale (if not random): animals found to show abnormal signs were isolated and killed at such time as was deemed desirable, and a complete gross and microscopic pathological examination was made of all organs and tisues. Mice found dead on routine checking were studied in the same manner

Positive control:

Groups painted with known carcinogens (methylcholanthrene, 3,4-benzpyrene (in 1% benzene solutions, water or oil suspension)

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice each day

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION: No data

BODY WEIGHT: No data

FOOD CONSUMPTION: No data

FOOD EFFICIENCY: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (all organs and tissues). Animals found to show abnormal signs were isolated and killed at such time as was deemed desirable, and a complete gross and microscopic pathological examination was made of all organs and tisues. Mice found dead on routine checking were studied in the same manner
HISTOPATHOLOGY: Yes (all organs and tissues). Animals found to show abnormal signs were isolated and killed at such time as was deemed desirable, and a complete gross and microscopic pathological examination was made of all organs and tisues. Mice found dead on routine checking were studied in the same manner

Other examinations:

Not reported

Statistics:

Not reported

Clinical signs:

effects observed, treatment-related

Dermal irritation:

not specified

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
59 of 170 animals painted with whole carbon black were found dead during the course of the study (no details provided).
56 of 140 animals painted with extracted carbon black were found dead during the course of the study (no details provided).

ORGAN WEIGHTS
not reported

GROSS PATHOLOGY
Mice painted with medium processing channel black: 1 mesenteric tumour was found in a group of 20 female mice painted with carbon black in cooking oil; 1 mesenteric tumour was found in another group of 40 mice painted with carbon black in mineral oil.
No changes from the normal were found in the groups treated with extracted carbon black.

HISTOPATHOLOGY: NON-NEOPLASTIC
not reported

HISTOPATHOLOGY: NEOPLASTIC
The painting of whole carbon black of the fast extrusion furnace and medium thermal types produced no changes from the normal in C3H mice. There occurred, however, observable tumours (adenoma and lymphosarcoma) in a few mice painted with the medium processing channel black. These did not occur at the site of painting but primarily in the gastrointestinal tract. These tumours were: 1 diffuse lymphosarcoma and 1 lymphoblastic proliferation in spleen and lymph nodes of a CFW mouse in a group of 20 mice painted with the carbon black in cooking oil for 12 months; 1 lymphosarcoma of colon in a CFW mouse of a group of 20 painted with carbon black in cooking oil for 17 months; 1 squamous cell adenoma of stomach in a group of 40 C3H mice painted with the CMC-suspension for 18 months, 1 squamouscell adenoma of stomach in a group of 20 C3H mice painted with the CMC-suspension for 12 months (in this group benzene was applied as a local irritant before painting); and 1 lymposarcoma of the spleen in a CFW mouse of a group of 40, painted with carbon black in mineral oil for 13 months.
The painting of the extracted carbon black of the fast extrusion furnace type led to no changes from the normal in 128 mice; 2 CFW mice treated with the extracted carbon black in mineral oil for 12 months, had lymphosarcoma (lymph nodes and spleen).
The whole benzene extracts (in a water suspension or 1% benzene solution) were found to be carcinogenic except for the extract of the channel furnace type of carbon. Painting of the known "free" carcinogens methylcholanthrene and 3,4-benzpyrene produced skin cancer in a high percentage of the animals. When these carcinogens are adsorbed on carbon black, the incidence of skin cancer resulting from the skin application of the absorbed carcinogen was reduced or abolished.

HISTORICAL CONTROL DATA (if applicable): there were 13 mice in the control group of 943 mice which developed spontaneous malignant neoplasms (6 malignant skin neoplasms, 1 malignant spleen neoplasm, 6 malignant liver neoplasms)

Key result

Dose descriptor:

NOEL

Effect level:

20 other: %

Sex:

male/female

Basis for effect level:

other: gross pathology; histopathology;

Key result

Critical effects observed:

no

None

Conclusions:

Carbon blacks, as is, produced no significant changes from the normal following skin contact. Carbon blacks have adsorbed components which, when free, and applied to the skin of mice, produce skin cancer. The adsorbed components, however, are ineffective as a carcinogen. Carbon blacks can adsorb effectively known carcinogens such as methylcholanthrene and 3,4-benzpyrene and by such adsorption do eliminate or reduce the carcinogenicity of these substances.

Executive summary:

In this study with limited documentation, no changes in organs or tissues of C3H mice were found after treating them three times per week with various types of carbon blacks (20% carbon black suspensions in cottonseed oil, mineral oil or in 1% aqueous carboxymethylcellulose, painted onto the animals’ backs) for 12 -18 months.

Reference 2

Endpoint:

chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

study start: 1949

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Animals were painted with a 20 percent suspension of a channel black in cooking oil or water (1% carboxy methylcellulose suspension) three times a week for 8 - 30 months. A single monkey was painted with benzene extracted furnace black in 1% aqueous carboxymethyl cellulose. 2 monkeys were treated with channel black, 4 rabbits were treated with channel black, 1 monkey was treated with benzene extracted furnace black

GLP compliance:

no

Limit test:

no

Species:

other: rabbit, monkey

Strain:

other: Rhesus monkeys; rabbit strain not reported ("white rabbits")

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not reported
- Age at study initiation: not reported
- Weight at study initiation: Rhesus monkeys weighed 5 to 7 lb.; weight of rabbits not reported
- Fasting period before study: not reported
- Housing: not reported
- Diet (e.g. ad libitum): not reported
- Water (e.g. ad libitum): not reported
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported

IN-LIFE DATES: From: 1949 To: not reported

Type of coverage:

open

Vehicle:

other: in water (1% carboxy methylcellulose suspension), cooking oil, cotton seed oil or mineral oil

Details on exposure:

TEST SITE
- Area of exposure: rabbits were painted on the shaven abdominal surface; monkeys were painted in four areas - both arm pits and both groins.
- % coverage: not reported
- Type of wrap if used: not wrapped
- Time intervals for shavings or clipplings: not reported

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not reported
- Time after start of exposure: not reported

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): amounts of test materials determined by weighing
- Concentration (if solution): 20%
- Constant volume or concentration used: not reported
- For solids, paste formed: not reported

VEHICLE
- Justification for use and choice of vehicle (if other than water): not reported
- Amount(s) applied (volume or weight with unit): not reported
- Concentration (if solution): 20% test material, 80% vehicle
- Purity: not reported

USE OF RESTRAINERS FOR PREVENTING INGESTION: not reported

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not reported

Duration of treatment / exposure:

8-30 months

Frequency of treatment:

three times a week

Dose / conc.:

20 other: %

Remarks:

20% suspension in cooking oil or 1% aqueous carboxymethyl cellulose

No. of animals per sex per dose:

2 monkeys treated with channel black, 4 rabbits treated with channel black, 1 monkey treated with extracted furnace black

Control animals:

no

Details on study design:

- Dose selection rationale: not reported
- Rationale for animal assignment (if not random): not reported
- Rationale for selecting satellite groups: no satellite group
- Section schedule rationale (if not random): not reported

Positive control:

2 rabbits painted with methylcholanthrene: no pathological findings

Observations and examinations performed and frequency:

Not reported

Sacrifice and pathology:

Not reported

Other examinations:

Not reported

Statistics:

Not reported

Clinical signs:

not specified

Dermal irritation:

not specified

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

GROSS PATHOLOGY
No changes from normal in the rabbits or monkeys painted with whole carbon black. The monkey painted with extracted furnace carbon black was set aside 3 1/2 months after painting (for 26 1/2 months) was stopped; then killed; one tumour on sternum.

HISTOPATHOLOGY: NEOPLASTIC
No changes from normal in the rabbits or monkeys painted with whole carbon black. The monkey painted with extracted furnace carbon black was found to have a small-cell sarcoma of the chest wall.

HISTORICAL CONTROL DATA
not reported

Dose descriptor:

NOEL

Effect level:

> 20 other: % in vehicle

Sex:

not specified

Basis for effect level:

other: gross pathology; histopathology;

Critical effects observed:

not specified

None

Conclusions:

No changes from the normal observed in animals treated with whole channel carbon black.

Executive summary:

4 rabbits and 2 monkeys were painted with a 20 percent suspension of a channel black in cooking oil or water (1% carboxy methylcellulose suspension), three times a week for 8 - 30 months. A single monkey was painted with benzene extracted furnace black in 1% aqueous carboxymethyl cellulose. No changes from the normal were found in the animals treated with whole channel black. The monkey painted with benzene extracted furnace black had a sarcoma of the chest. This may be due to residual benzene solution used as extraction medium.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

see sets of nanoforms for details

Additional information

see set_not treated

Justification for classification or non-classification

Based on available toxicological data and chemico-physical properties (insolubility, low absorption potential), systemic organ toxicity is not expected after repeated dermal or oral exposure. Several repeated dose inhalation toxicity studies (90-day studies) conducted in rats indicate a No Observed Adverse Effect Concentration (NOAEC) of 1.0 mg/m3 (respirable). Target organ effects at higher doses are lung inflammation, hyperplasia, and fibrosis (Carter et al., 2006; Elder et al., 2005; Driscoll et al., 1996). As stated in ECETOC (2013) “the rat represents a particularly sensitive model concerning the development of pulmonary non-neoplastic lesions (inflammation and fibro-proliferation) and, moreover, a unique model with regard to lung neoplastic responses under conditions of lung overload.” Results of epidemiological studies of carbon black production workers suggest that cumulative exposure to carbon black may result in small, non-clinical decrements in lung function. A U.S. respiratory morbidity study suggested a 27 mL decline in FEV1 from a 1 mg/m3 8-hour TWA daily (inhalable fraction) exposure over a 40-year period (Harber et al., 2003). A European investigation suggested that exposure to 1 mg/m3 (inhalable fraction) of carbon black over a 40-year working lifetime would result in a 48 mL decline in FEV1 (Gardiner et al., 2001). However, the estimates from both studies were only of borderline statistical significance. Further, normal age-related decline among healthy male non-smokers is approximately 30 mL/year, resulting in an approximately 1200 mL decline over a 40-year working lifetime (Burrows et al., 1986; Sherrill et al., 1992). In the U.S. study, 9% of workers in highest non-smoker exposure group (in contrast to 5% of the unexposed group) reported symptoms consistent with chronic bronchitis. In the European study, methodological limitations in the administration of the questionnaire limit the conclusions that can be drawn about reported symptoms. A longitudinal study based on the cohort of the European study, however, indicated a link between carbon black and small opacities on chest films, with negligible effects on lung function. Moreover, a review of chest film abnormalities performed by Meyer et al (1997) among unexposed workers indicated that a high percentage of workers unexposed to dust, particularly in workers over age 40 and among cigarette smokers, already had similar opacities. The paucity of high profusion radiographic findings, the absence of progression to extensive radiographic abnormality and the absence of restrictive physiologic abnormalities show that carbon black does not lead to a fibrotic pneumoconiosis.

Applying the guidelines of self-classification under CLP, carbon black is therefore not classifiable under STOT-RE for effects on the lung. Classification is not warranted on the basis of the unique response of rats resulting from the “lung overload” following exposure to poorly soluble particles such as carbon black. The pattern of pulmonary effects in the rat, such as inflammation and fibrotic responses, are not observed in other rodent species, non-human primates, or humans under similar exposure conditions. Lung overload does not appear to be relevant for human health. Overall, the epidemiological evidence from well-conducted investigations has shown no causal link between carbon black exposure and the risk of non-malignant and malignant respiratory diseases in humans.