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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.23 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
LOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.13 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Worker:

 

The primary routes of anticipated industrial exposure to the substance are via inhalation and skin contact. In industrial settings, ingestion is not an anticipated route of exposure, but has to be considered for the general population (see below).

 

 

Dermal long-term exposure – systemic effects:

The LOAEL from an oral repeated dose study with rats conducted according to OECD TG 408 (BASF SE 2014) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal contact. No NOAEL could be derived in this study, since clinical-pathological and histopathological findings were observed in all treatment groups. Predominantly dose-related histiocytic/mixed cell infiltrates were observed in multiple organs (ovaries, intestines and their draining lymph nodes) which led to secondary multiple local inflammatory reactions. Thus, the LOAEL for general, systemic toxicity of the test substance was 20 mg/kg bw/d for male and female rats based on clinical-pathological and histopathological findings.

For DNEL derivation the LOAEL of 20 mg/kg bw/d was considered the most appropriate point of departure covering systemic effects.

For highly lipophilic substances (log P greater than 6) that come into contact with the skin, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Dermal uptake for such substances is expected to be low (ECHA GD 7c, 2008). Thus, for differences between oral and dermal absorption an additional assessment factor of 0.5 was used. The resulting corrected starting point for dermal DNEL derivation for workers is equal to 40 mg/kg bw/d.

 

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

 

- Interspecies factor: 4

Default assessment factor according to Reach TGD

 

- Intraspecies factor: 5

Default assessment factor according to Reach TGD

- Remaining differences: 2.5

Default assessment factor according to Reach TGD

 

- Exposure duration: 2

Extrapolation from subchronic to chronic exposure, according to Reach TGD and ECETOC specifications.

 

- Dose-response: 3

Since a LOAEL was chosen as starting point for DNEL derivation, an additional assessment factor of 3 for dose-response relationship had to be considered according to Reach TGD and ECETOC specifications.

 

- Uncertainty factor: 1 (default)

 

Total AF = 4 x 5 x 2.5 x 2 x 3 = 300

Based on this calculation the resulting DNEL is 0.13 mg/kg bw/d.

 

 

This value is considered protective for systemic effects by the dermal route.

 

 

Inhalation long-term exposure –systemic effects:

The LOAEL from an oral repeated dose study with rats conducted according to OECD TG 408 (BASF SE 2014) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. No NOAEL could be derived in this study, since clinical-pathological and histopathological findings were observed in all treatment groups. Predominantly dose-related histiocytic/mixed cell infiltrates were observed in multiple organs (ovaries, intestines and their draining lymph nodes) which led to secondary multiple local inflammatory reactions. Thus, the LOAEL for general, systemic toxicity of the test substance was 20 mg/kg bw/d for male and female rats based on clinical-pathological and histopathological findings.

For DNEL derivation the LOAEL of 20 mg/kg bw/d was considered the most appropriate point of departure covering systemic effects.

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 58 f.:

The oral rat LOAEL was converted into the inhalative human LAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). For differences between oral absorption in rats and inhalative absorption in humans an additional assessment factor of 2 was used. The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 17.6 mg/m³.

 

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

 

- Interspecies factor: 1

Besides the applied allometric scaling factors (see modification of point of departure) no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account.

 

- Intraspecies factor: 5

Default assessment factor according to Reach TGD

- Remaining differences: 2.5

Default assessment factor according to Reach TGD

 

- Exposure duration: 2

Extrapolation from subchronic to chronic exposure, according to Reach TGD and ECETOC specifications.

 

- Dose-response: 3

Since a LOAEL was chosen as starting point for DNEL derivation, an additional assessment factor of 3 for dose-response relationship had to be considered according to Reach TGD and ECETOC specifications.

 

- Uncertainty factor: 1 (default)

 

Total AF = 5 x 2,5 x 2 x 3 = 75

Based on this calculation the resulting DNEL is 0.23 mg/m³.

 

 

This value is considered protective for systemic effects by the inhalation route.

 

 

 

·        ECHA (2010). REACh Guidance document R.8

·        ECHA (2008). GD 7c. Endpoint specific Guidance.

·        ECETOC (2003).Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

·        ECETOC (2010). Guidance on Assessment Factors to Derive DNELs. Technical Report No. 110,, October 2010.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.06 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Modified dose descriptor starting point:
LOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.03 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General population:

 

For the general population, all three possible routes of exposure (oral, dermal, inhalation) have to be taken into account.

 

Dermal long-term exposure – systemic effects:

The LOAEL from an oral repeated dose study with rats conducted according to OECD TG 408 (BASF SE 2014) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal contact. No NOAEL could be derived in this study, since clinical-pathological and histopathological findings were observed in all treatment groups. Predominantly dose-related histiocytic/mixed cell infiltrates were observed in multiple organs (ovaries, intestines and their draining lymph nodes) which led to secondary multiple local inflammatory reactions. Thus, the LOAEL for general, systemic toxicity of the test substance was 20 mg/kg bw/d for male and female rats based on clinical-pathological and histopathological findings.

For DNEL derivation the LOAEL of 20 mg/kg bw/d was considered the most appropriate point of departure covering systemic effects.

For highly lipophilic substances (log P greater than 6) that come into contact with the skin, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Dermal uptake for such substances is expected to be low (ECHA GD 7c, 2008). Thus, for differences between oral and dermal absorption an additional assessment factor of 0.5 was used. The resulting corrected starting point for dermal DNEL derivation for workers is equal to 40 mg/kg bw/d.

 

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

 

- Interspecies factor: 4

Default assessment factor according to Reach TGD

 

- Intraspecies factor: 10

Default assessment factoraccording to Reach TGD

- Remaining differences factor: 2.5

Default assessment factor according to Reach TGD

 

- Exposure duration: 2

Extrapolation from subchronic to chronic exposure, according to Reach TGD and ECETOC specifications.

 

- Dose-response: 3

Since a LOAEL was chosen as starting point for DNEL derivation, an additional assessment factor of 3 for dose-response relationship had to be considered according to Reach TGD and ECETOC specifications.

 

- Uncertainty factor: 1 (default)

 

Total AF = 4 x 10 x 2.5 x 2 x 3 = 600

Based on this calculation the resulting DNEL is 0.07 mg/kg bw/d.

 

 

This value is considered protective for systemic effects by the dermal route.

 

 

Inhalation long-term exposure –systemic effects:

The LOAEL from an oral repeated dose study with rats conducted according to OECD TG 408 (BASF SE 2014) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. No NOAEL could be derived in this study, since clinical-pathological and histopathological findings were observed in all treatment groups. Predominantly dose-related histiocytic/mixed cell infiltrates were observed in multiple organs (ovaries, intestines and their draining lymph nodes) which led to secondary multiple local inflammatory reactions. Thus, the LOAEL for general, systemic toxicity of the test substance was 20 mg/kg bw/d for male and female rats based on clinical-pathological and histopathological findings at 20 mg/kg bw/d.

For DNEL derivation the LOAEL of 20 mg/kg bw/d was considered the most appropriate point of departure covering systemic effects.

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 58 f.:

The oral rat LOAEL was converted into the inhalative human LAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). For differences between oral absorption in rats and inhalative absorption in humans an additional assessment factor of 2 was used. The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 8.7 mg/m³.

 

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

 

- Interspecies factor: 1

Besides the applied allometric scaling factors (see modification of point of departure) no additional interspecies factor has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account.

 

- Intraspecies factor: 10

Default assessment factor according to Reach TGD

- Remaining differences factor: 2.5

Default assessment factoraccording to Reach TGD

 

- Exposure duration: 2

Extrapolation from subchronic to chronic exposure, according to Reach TGD and ECETOC specifications.

 

- Dose-response: 3

Since a LOAEL was chosen as starting point for DNEL derivation, an additional assessment factor of 3 for dose-response relationship had to be considered according to Reach TGD and ECETOC specifications.

 

- Uncertainty factor: 1 (default)

 

Total AF = 10 x 2.5 x 2 x 3 = 150

Based on this calculation the resulting DNEL is 0.06 mg/m³.

 

 

This value is considered protective for systemic effects by the inhalation route.

 

 

Oral long-term exposure – local and systemic effects:

In addition, the DNEL for oral long-term exposure was derived from the lowest observed adverse effect level obtained in a diet study conducted with the substance in rats according to OECD TG 408 (BASF SE, 2014).

No NOAEL could be derived in this study, since clinical-pathological and histopathological findings were observed in all treatment groups. Predominantly dose-related histiocytic/mixed cell infiltrates were observed in multiple organs (ovaries, intestines and their draining lymph nodes) which led to secondary multiple local inflammatory reactions. Thus, the LOAEL for general, systemic toxicity of the test substance was 20 mg/kg bw/d for male and female rats based on clinical-pathological and histopathological findings at 20 mg/kg bw/d.

For DNEL derivation the LOAEL of 20 mg/kg bw/d was considered the most appropriate point of departure covering systemic effects.

Subsequently, the following assessment factors (AF) were taken into account for the final DNEL calculation for the oral route:

 

- Interspecies factor: 4

Default assessment factor according to Reach TGD

 

- Intraspecies factor: 10

Default assessment factor according to Reach TGD

- Remaining differences: 2.5

Default assessment factor according to Reach TGD

- Exposure duration: 2

Extrapolation from subchronic to chronic exposure, according to Reach TGD and ECETOC specifications.

 

- Dose-response: 3

Since a LOAEL was chosen as starting point for DNEL derivation, an additional assessment factor of 3 for dose-response relationship had to be considered according to Reach TGD and ECETOC specifications.

 

- Uncertainty factor: 1 (default)

 

Total AF = 4 x 10 x 2.5 x 2 x 3 = 600

Based on this calculation the resulting DNEL is 0.03 mg/kg bw/d.

 

 

This value is considered protective for systemic effects by the oral route.

 

 

 

·        ECHA (2010). REACh Guidance document R.8

·        ECHA (2008). GD 7c. Endpoint specific Guidance.

·        ECETOC (2003).Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

·        ECETOC (2010). Guidance on Assessment Factors to Derive DNELs. Technical Report No. 110,, October 2010.