Benzenamine, N,N-dimethyl-, oxidized, molybdatetungstatephosphates

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1 234 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study is available. Therefore, the DNEL is derived on basis of an OECD TG 422 toxicity study with oral test material administration performed in the rat. This oral NOEL of 1000 mg/kg bw/day for rats was converted to the corresponding air concentration using a standard breathing volume for the rat of 0.38 m³ /kg (for 8 hours exposure of workers). In the absence of substance-specific data on absorption via the different exposure routes, the worst case assumption of a 2 -fold higher absorption via inhaltory exposure compared to oral exposure was made. The resulting air concentration was additionally corrected for the difference between basal caloric demand and caloric demand under light activity. This correction factor derives from the inhalative volumes in 8 hours under the respective conditions (6.7 m³ for base level, 10 m³ for light activity). Furthermore, the dose descriptor starting point was corrected for differences in experimental exposure conditions (7d/w) versus worker exposure conditions (5d/w).

See "Additional Information" for more details.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default assessment factor for subacute to chronic duration extrapolation is used.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The study according to OECD TG 422 was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

4.7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction for experimental versus worker exposure condition: Frequency of exposure in study: 7 days/week; frequency of worker exposure: 5 days/week.

See "Additional Information" for more details.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default assessment factor for subacute to chronic duration extrapolation is used.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The study according to OECD TG 422 was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the registered substance is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Inhalation

Long term, systemic DNEL – exposure via inhalation (workers)

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is calculated. This worker long-term DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

No repeated dose inhalation toxicity study with the registered substance is available. Therefore, it is necessary to obtain a long-term DNEL by route-to-route extrapolation:

An OECD TG 422 study with the registered substance is available. Here, daily oral administration of the test item to Wistar rats did not elicit any signs of systemic, reproductive or developmental toxicity up to the limit dose. The NOEL for systemic toxicity, developmental toxicity and fertility was established at ≥ 1000 mg/kg bw/day. This NOEL is used as Point of Departure (PoD) for DNEL derivation.

Step 1: PoD: NOEL = 1000 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw

Standard respiratory volume, human (sRVhuman): 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50 %/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOEC (inhalation) for workers:

= 1000 mg/kg bw/day x 0.5 x 1/0.38 m³/kg bw/day x (6.7 m³/10 m³) x (7/5)

= 1234 mg/m³

Step 3: Overall AF= 75

Intraspecies AF (workers): 5

Interspecies AF, remaining differences: 2.5

Interspecies, allometric scaling: 1 (Covered by route to route extrapolation)

Dose response relationship AF: 1

Exposure duration AF: 6

Whole database AF: 1

In conclusion, long term systemic inhalation DNEL, workers = 16.5 mg/m³

Acute, systemic DNEL- exposure via inhalation (workers)

In two acute aerosol inhalation studies in rats with analogue substances no hazard was identified. As the registered substance is not classified for acute inhalation toxicity no DNEL was derived.

Long term & acute, local DNEL- exposure via inhalation (workers)

A DNEL long term & acute - local effects is not established because no local irritation or sensitisation of the respiratory system is expected based on the results of two acute aerosol inhalation studies with analogue substances.

Dermal

Long term, systemic DNEL- exposure via dermal route (workers)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it is necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOEL of ≥ 1000 mg/kg bw/day derived from an OECD TG 422 study performed with the registered substance was used as the PoD.

Step 1: PoD: NOEL = 1000 mg/kg bw/day

Step 2: Modification into a correct starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOEL (dermal) for workers:

= 1000 mg/kg bw/day x (7/5)

= 1400 mg/kg bw/day

Step 3: Overall AF= 300

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF: 6

Whole database AF: 1

In conclusion, long term systemic dermal DNEL, workers = 4.7 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

A DNEL for acute systemic-dermal exposure was not derived since the substance is not classified for acute dermal toxicity based on the results of an acute dermal toxicity study in rats with an analogue substance.

Long term & acute, local DNEL- dermal exposure (workers)

The substance is a skin sensitiser according to Regulation EC No 1272/2008 (CLP), and allocated to the high hazard band for qualitative risk assessment.

Hazard to the eye-local effects (workers)

The registered substance is classified with Eye Dam. 1, H318 according to Regulation (EC) No 1272/2008 (CLP), and allocated to the medium hazard band for qualitative risk assessment.

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.9 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

434.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study is available. The DNEL is derived on basis of an OECD TG 422 study with oral administration of the test material. This oral NOAEL for rats was converted to the corresponding air concentration using a standard breathing volume for the rat of 1.15 m³/kg for 24 hours exposure, and assuming a two-times higher absorption via inhalation than oral absorption (see "Additional Information").

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default assessment factor for subacute to chronic duration extrapolation is used.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The study according OECD TG 422 was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

1.7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default assessment factor for subacute to chronic duration extrapolation is used.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 422 toxicity study performed with the test item was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

1.7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

The default assessment factor for subacute to chronic duration extrapolation is used.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The study according OECD TG 422 was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

 

Inhalation

Long term, systemic DNEL – exposure by inhalation (general population)

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it is necessary to obtain a long-term DNEL by route-to-route extrapolation:

An OECD TG 422 study with the registered substance is available. Here, daily oral administration of the test item to Wistar rats did not elicit any signs of systemic, reproductive or developmental toxicity up to the limit dose. The NOEL for systemic toxicity, developmental toxicity and fertility was established at ≥1000 mg/kg bw/day. This NOEL is used as PoD for DNEL derivation.

 

Step 1: PoD: NOEL = 1000 mg/kg bw/day

Correction for difference between human and experimental exposure conditions: 7 d rat, 24 h / 7 d, 24 h general population

Step 2: Modification of PoD:

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50 %/100 % (default)

Corrected NOEC (inhalation) for general population:

= 1000 mg/kg bw/day x 0.5 x 1/1.15 m³/kg bw/day

= 434.8 mg/m³

Step 3: Overall AF = 150

Intraspecies AF (General population): 10

Interspecies AF, remaining differences: 2.5

Interspecies, allometric scaling: 1

Dose response relationship AF: 1

Exposure duration AF: 6

Whole database AF: 1

 

In conclusion, long term systemic inhalation DNEL, general population = 2.9 mg/m³

 

Acute, systemic DNEL- exposure via inhalation (general population)

In two acute aerosol inhalation studies in rats with analogue substances no hazard was identified. As the registered substance is not classified for acute inhalation toxicity no DNEL was derived.

 

Long term & acute, local DNEL- exposure via inhalation (general population)

A DNEL long term & acute - local effects is not established because no local irritation or sensitisation of the respiratory system is expected based on the results of two acute aerosol inhalation studies with analogue substances.

 

Dermal

Long term, systemic DNEL- exposure via dermal route (general population)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it is necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOEL of 1000 mg/kg bw/day derived from an OECD TG 422 study performed with the registered substance was used as the PoD.

Step 1: PoD: NOEL= 1000 mg/kg bw/day

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS dermal-human): 100 %/ 100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d rat, 24 h/7 d, 24h general population

Step 2: Overall AF= 600

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 6

Whole database AF: 1

 

In conclusion, long term systemic dermal DNEL, general population = 1.7 mg/kg bw/day.

 

Acute, systemic DNEL- dermal exposure (general population)

A DNEL for acute systemic-dermal exposure was not derived since the substance is not classified for acute dermal toxicity based on the results of an acute dermal toxicity study in rats with an analogue substance.

 

Long term & acute, local DNEL- dermal exposure (general population)

The registered substance is a skin sensitiser according to Regulation EC No 1272/2008 (CLP). As the substance is only used in very low concentrations (max. 0.1% w/w) for shading applications in paper and board, no hazard of colored paper and board regarding local effects after dermal exposureis to be expected.

 

Oral

Long term, systemic DNEL- exposure by oral route (general population)

A study according OECD TG 422 with the target substance is available. Here, daily oral administration of the test item to Wistar rats did not elicit any signs of systemic, reproductive or developmental toxicity up to the highest dose tested. The NOEL for systemic toxicity, developmental toxicity and fertility was considered to be ≥1000 mg/kg bw/day. This NOEL is used as PoD for DNEL derivation.

Step 1: PoD: NOEL = 1000 mg/kg bw/day

No modifications were done as same exposure route is considered.

Step 2: Overall AF= 600

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 6

Whole database AF: 1

 

In conclusion, long term systemic oral DNEL, general population = 1.7 mg/kg bw/day

 

Acute, systemic DNEL- exposure by oral route (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified". The registered substance has very low acute oral toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

 

Hazard to the eye-local effects (general population)

The registered substance is classified with Eye Dam. 1, H318 according to Regulation (EC) No 1272/2008 (CLP). As the substance is only used in very low concentrations (max. 0.1% w/w) for shading applications in paper and board, no hazard of coloured paper and board for the eyes has to be expected.

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterization of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterization, Version 3.0, May 2016