Phenol, 2,4-dinitro-, sulfurized, leuco derivatives

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

176 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

Acute/short term exposure – systemic and local effects

Leuco Sulfur Black 1 did not induce any toxic effects in the acute oral and dermal and oral repeated dose toxicity study. It did not induce skin irritation in the acute dermal toxicity study in rats, induced only minimal signs of irritation to the rabbit eye shortly after instillation without any relevance for classification and was not sensitising in the LLNA.

As Leuco Sulfur Black 1 did not show acute systemic nor acute local toxicity, the derivation of acute DNELs for systemic and local effects is not required. This is in accordance with the ECHA guidance document on information requirements and chemical safety assessment, chapter R.8.

 

Long-term exposure – systemic effects

In a repeated dose toxicity study with reproduction/developmental toxicity screening according to OECD guideline 422 and GLP Leuco Sulfur Black 1 was administered by gavage to groups of 10 rats per sex and dose at 0, 100, 300 and 1000 mg/kg bw/d. Male rats were treated for 29 days, female rats for 14 days prior to pairing, though the pairing and gestation periods until the F1 generation had reached day 4 post partum.

The only effect seen was a dark discolouration of faeces in all high dose animals starting on day 3 of the study and lasting until termination. Discolouration of organs or urine or substance deposits in organs were not found. This is strongly indicates that systemic absorption did not occur.

Based on the results obtained in this study a NOAEL of 1000 mg/kg bw/d was derived.

 

Leuco Sulfur Black 1 is an UVCB substance with a mean molecular weight > 8000 Da. It is very poorly or even not soluble in common polar and non-polar solvents such as water (solubility of 62.4 mg/L), DMSO, methanol, DMF, THF, chloroform and not soluble in acids like sulfuric acid and trifluoroacetic acid. Due to these substance characteristics it is very unlikely that Leuco Sulfur Black 1 can cross any biological membrane.

 

In summary, no evidence of toxicity was seen in the OECD 422 guideline study. The outcome of the study and the substance characteristics show that an absorption of toxicologically significant amounts of Leuco Sulfur Black 1 subsequent to oral, dermal or inhalation exposure is negligible.

 

Nevertheless, a DNEL for the dermal and inhalation exposure route is derived assuming absorption of 5 % for all exposure routes.

 

Dermal exposure to Leuco Sulfur Black 1 and the formulated Sulfur dye preparation can occur at the workplace. Inhalation exposure to Leuco Sulfur Black 1 is not possible due to pasty consistence and can only occur when the substance is formulated in aqueous media.

 

The NOAEL of 1000 mg/kg bw/d from the OECD guideline 422 study in rats is used as starting points for the establishment of the DNELs.

The oral NOAEL reflects also the dermal NOAEL because no difference in absorption is expected between both routes.

For the derivation of the worker inhalation DNEL (assuming a daily exposure for 8 hours), the oral NOAEL is converted into a repeated inhalation NOAEC according to the following formula:

inhalation NOAEC =

oral NOAEL * 1/sRV(rat) * ABSoral-rat/ABSinh-human * sRV(human)/wRV(human)

 

with:

oral NOAEL = 1000 mg/kg bw/d

sRV(rat) = standard respiratory volume (rat) = 0.38 m³/kg (8 h)

ABSoral-rat/ABSinh-human = 1

sRV(human)/wRV(human) = 6.7 m³/10m³

 

Thus, the inhalation NOAEC is 1763 mg/m³ for the worker.

 

The following assessment factors are used for the derivation of the long-term systemic DNELs:

Interspecies (allometric scaling rat -> human (not to be applied for inhalation exposure): 4

(no additional factor for remaining differences is needed because of the substance characteristics (see above))

Intraspecies:                5 (worker)

Exposure duration:     2 (subacute to chronic)

(the factor of 2 instead of 6 is used as there was no effect seen in the OECD guideline 422 study justifying a higher factor)

Dose-response:          1

Quality of database:    1

 

The resulting overall assessment factors and DNELs are:

worker (dermal exposure)

overall assessment factor: 4 x 5 x 2 x 1 x 1 = 40

DNEL: 1000 mg/kg bw/d / 40 = 25 mg/kg bw/d

 

worker (inhalation exposure):

overall assessment factor: 5 x 2 x 1 x 1 = 10

DNEL: 1763 mg/kg bw/d / 10 = 176 mg/kg bw/d

 

Long-term exposure – local effects

Leuco Sulfur Black 1 does not induce any local toxic effects. Moreover, no evidence of toxicity was seen in any of the available tests. Thus, the derivation of a long-term DNEL for local effects is not required. This is in line with the ECHA guidance document on information requirements and chemical safety assessment, chapter R.8.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

43.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

Acute/short term exposure – systemic and local effects

Leuco Sulfur Black 1 did not induce any toxic effects in the acute oral and dermal and oral repeated dose toxicity study. It did not induce skin irritation in the acute dermal toxicity study in rats, induced only minimal signs of irritation to the rabbit eye shortly after instillation without any relevance for classification and was not sensitising in the LLNA.

As Leuco Sulfur Black 1 did not show acute systemic nor acute local toxicity, the derivation of acute DNELs for systemic and local effects is not required. This is in accordance with the ECHA guidance document on information requirements and chemical safety assessment, chapter R.8.

 

Long-term exposure – systemic effects

 

No evidence of toxicity was seen in the OECD 422 guideline study (NOAEL of 1000 mg/kg bw/d). The outcome of the study and the substance characteristics show that an absorption of toxicologically significant amounts of Leuco Sulfur Black 1 subsequent to oral, dermal or inhalation exposure is negligible. (See also discussion under DNEL derivation for the worker.)

 

Leucosulfur Black 1 is only used professionally and not included in articles intended to release the substance. Nevertheless, a DNEL for the oral, dermal and inhalation exposure route is derived assuming absorption of 5 % for all exposure routes.

The NOAEL of 1000 mg/kg bw/d from the OECD guideline 422 study in rats is used as starting points for the establishment of the DNELs.

The oral NOAEL reflects also the dermal NOAEL because no difference in absorption is expected between both routes.

 

For the derivation of the consumer inhalation DNEL (assuming a daily exposure for 24 hours), the oral NOAEL is converted into a repeated inhalation NOAEC according to the following formula:

inhalation NOAEC =

oral NOAEL * 1/sRV(rat) * ABSoral-rat/ABSinh-human

 

with:

oral NOAEL = 1000 mg/kg bw/d

sRV(rat) = standard respiratory volume (rat) = 1.15 m³/kg (24 h)

ABSoral-rat/ABSinh-human = 1

 

Thus, the inhalation NOAEC is 870 mg/m³ for the consumer.

 

The following assessment factors are used for the derivation of the long-term systemic DNELs:

Interspecies (allometric scaling rat -> human (not to be applied for inhalation exposure): 4

(no additional factor for remaining differences is needed because of the substance characteristics (see above))

Intraspecies:                10 (consumer)

Exposure duration:     2 (subacute to chronic)

(the factor of 2 instead of 6 is used as there was no effect seen in the OECD guideline 422 study justifying a higher factor)

Dose-response:          1

Quality of database:    1

 

The resulting overall assessment factors and DNELs are:

consumer (oral exposure)

overall assessment factor: 4 x 10 x 2 x 1 x 1 = 80

DNEL: 1000 mg/kg bw/d / 80 = 12.5 mg/kg bw/d

 

consumer (dermal exposure)

overall assessment factor: 4 x 10 x 2 x 1 x 1 = 80

DNEL: 1000 mg/kg bw/d / 80 = 12.5 mg/kg bw/d

 

consumer (inhalation exposure):

overall assessment factor: 10 x 2 x 1 x 1 = 20

DNEL: 870 mg/kg bw/d / 20 = 43.5 mg/m³

 

Long-term exposure – local effects

Leuco Sulfur Black 1 does not induce any local toxic effects. Moreover, no evidence of toxicity was seen in any of the available tests. Thus, the derivation of a long-term DNEL for local effects is not required. This is in line with the ECHA guidance document on information requirements and chemical safety assessment, chapter R.8.