Propanamide, N,N',N''-1,3,5-benzenetriyltris[2,2-dimethyl-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

70.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

25

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:

10 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

Worker:

 

Based on the available data, Propanamide, N, N', N''-1,3,5-benzenetriyltris[2,2-dimethyl-(9Cl)] does not need to be classified and labelled concerning human health hazards according to the Dangerous Substance Directive (67/548/EEC) and the Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008 (CLP).

 

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 NOAEL from an oral repeated dose study with rats conducted according to OECD TG 408 (BASF SE 2012) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal contact. The oral administration of the test substance via the diet over a period of 3 months revealed no signs of toxicity up to a concentration of 15000 ppm in male (961 mg/kg bw/d) and female Wistar rats (1104 mg/kg bw/d).

Thus, the NOAEL for general, systemic toxicity of the test substance was 1000 mg/kg bw/d for male and female rats equivalent to the highest dose tested.

As recommended by REACh TGD (R.8, 2010), dermal absorption is not assumed to be higher than oral absorption. Therefore, no additional default factor (factor 1) was introduced.

 

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

 

- Interspecies factor: 4

For allometric scaling a factor of 4 for differences in metabolic rate and toxicokinetics was used as recommended by Reach TGD.

 

- Remaining differences: 2.5

As recommended by Reach TGD an additional interspecies factor of 2.5 for remaining differences has been used.

 

- Intraspecies factor: 5

Based on REACh TGD, an intraspecies assessment factor of 5 (worker) was adopted here.

 

- Exposure duration: 2

An assessment factor of 2 was chosen for extrapolation of a subchronic study to chronic exposure, according to Reach TGD.

 

- Dose-response: 1 (default)

 

- Uncertainty factor: 1 (default)

 

Total AF = 2.5 x 4 x 5 x 2 = 100.

Based on this calculation the resulting DNEL is 10 mg/kg bw/d.

 

 

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

 

 

Inhalation long-term exposure –systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 408 (BASF SE 2012) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The oral administration of the test substance via the diet over a period of 3 months revealed no signs of toxicity up to a concentration of 15000 ppm in male (961 mg/kg bw/d) and female Wistar rats (1104 mg/kg bw/d).

Thus, the NOAEL for general, systemic toxicity of the test substance was 1000 mg/kg bw/d for male and female rats equivalent to the highest dose tested.

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 NOAEL was converted into the inhalative human NAEC 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 no additional assessment factor (factor 1) was used, since no considerable bioavailability of the substance by inhalation is expected based on the physical-chemical data and the complete lack of toxicity by the oral and dermal route.

The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 1763 mg/m³.

 

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

 

- Interspecies factor: 2.5

Besides the applied allometric scaling factors (see modification of point of departure) an additional interspecies factor of 2.5 for remaining differences has been used.

 

- Intraspecies factor: 5

Based on REACh TGD, an intraspecies assessment factor of 5 (worker) was adopted here.

 

- Exposure duration: 2

An assessment factor of 2 was chosen for extrapolation of a subchronic study to chronic exposure, according to Reach TGD.

 

- Dose-response: 1 (default)

 

- Uncertainty factor: 1 (default)

 

Total AF = 2.5 x 5 x 2 = 25

Based on this calculation the resulting DNEL is 70.5 mg/m³.

 

 

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

 

 

 

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

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

50

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:

5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

200

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:

5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

General population:

 

Based on the available data, Propanamide, N, N', N''-1,3,5-benzenetriyltris[2,2-dimethyl-(9Cl)] does not need to be classified and labelled concerning human health hazards according to the Dangerous Substance Directive (67/548/EEC) and the Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008 (CLP).

 

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 NOAEL from an oral repeated dose study with rats conducted according to OECD TG 408 (BASF SE 2012) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal contact. The oral administration of the test substance via the diet over a period of 3 months revealed no signs of toxicity up to a concentration of 15000 ppm in male (961 mg/kg bw/d) and female Wistar rats (1104 mg/kg bw/d).

Thus, the NOAEL for general, systemic toxicity of the test substance was 1000 mg/kg bw/d for male and female rats equivalent to the highest dose tested.

As recommended by REACh TGD (R.8, 2010), dermal absorption is not assumed to be higher than oral absorption. Therefore, no additional default factor (factor 1) was introduced.

 

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

 

- Interspecies factor: 4

For allometric scaling a factor of 4 for differences in metabolic rate and toxicokinetics was used as recommended by Reach TGD.

 

- Remaining differences: 2.5

As recommended by Reach TGD an additional interspecies factor of 2.5 for remaining differences has been used.

 

- Intraspecies factor: 10

Based on REACh TGD, an intraspecies assessment factor of 10 (general population) was adopted here.

 

- Exposure duration: 2

An assessment factor of 2 was chosen for extrapolation of a subchronic study to chronic exposure, according to Reach TGD.

 

- Dose-response: 1 (default)

 

- Uncertainty factor: 1 (default)

 

Total AF = 2.5 x 4 x 10 x 2 = 200.

Based on this calculation the resulting DNEL is 5 mg/kg bw/d.

 

 

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

 

 

 

Inhalation long-term exposure –systemic effects:

The NOAEL from an oral repeated dose study with rats conducted according to OECD TG 408 (BASF SE 2012) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The oral administration of the test substance via the diet over a period of 3 months revealed no signs of toxicity up to a concentration of 15000 ppm in male (961 mg/kg bw/d) and female Wistar rats (1104 mg/kg bw/d).

Thus, the NOAEL for general, systemic toxicity of the test substance was 1000 mg/kg bw/d for male and female rats equivalent to the highest dose tested.

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 NOAEL was converted into the inhalative human NAEC 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 no additional assessment factor (factor 1) was used, since no considerable bioavailability of the substance by inhalation was expected based on the physical-chemical data and the complete lack of toxicity by the oral and dermal route.

The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 870 mg/m³.

 

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

 

- Interspecies factor: 2.5

Besides the applied allometric scaling factors (see modification of point of departure) an additional interspecies factor of 2.5 for remaining differences has been used.

 

- Intraspecies factor: 10

Based on REACh TGD, an intraspecies assessment factor of 10 (general population) was adopted here.

 

- Exposure duration: 2

An assessment factor of 2 was chosen for extrapolation of a subchronic study to chronic exposure, according to Reach TGD.

 

- Dose-response: 1 (default)

 

- Uncertainty factor: 1 (default)

 

Total AF = 2.5 x 10 x 2 = 50

Based on this calculation the resulting DNEL is 17.4 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 no observed adverse effect level obtained in a diet study conducted with the substance in rats according to OECD TG 408 (BASF SE, 2012).

The oral administration of the test substance via the diet over a period of 3 months revealed no signs of toxicity up to a concentration of 15000 ppm in male (961 mg/kg bw/d) and female Wistar rats (1104 mg/kg bw/d).

Thus, the NOAEL for general, systemic toxicity of the test substance was 1000 mg/kg bw/d for male and female rats equivalent to the highest dose tested.

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

 

- Interspecies factor: 4

For allometric scaling a factor of 4 for differences in metabolic rate and toxicokinetics was used as recommended by Reach TGD.

 

- Remaining differences: 2.5

As recommended by Reach TGD an additional interspecies factor of 2.5 for remaining differences has been used.

 

- Intraspecies factor: 10

Based on REACh TGD, an intraspecies assessment factor of 10 (general population) was adopted here.

 

- Exposure duration: 2

An assessment factor of 2 was chosen for extrapolation of a subchronic study to chronic exposure, according to Reach TGD.

 

- Dose-response: 1 (default)

 

- Uncertainty factor: 1 (default)

 

Total AF = 2.5 x 4 x 10 x 2 = 200.

Based on this calculation the resulting DNEL is 5 mg/kg bw/d.

 

 

 

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

 

 

 

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