[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxoallyl]oxy]ethyl][3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxoallyl]oxy]propyl]dimethylammonium chloride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29 mg/m³

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance and ECETOC Technical Report No. 110

Overall assessment factor (AF):

18

Modified dose descriptor starting point:

NOAEC

Value:

529 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no experimental data available on repeated exposure by the inhalatory route.

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 value for extrapolation from subacute to chronic exposure is used.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.

AF for other interspecies differences:

1

Justification:

Interspecies differences are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics (ECETOC). Therefore, no additional factor is used.

AF for intraspecies differences:

3

Justification:

The study used as point of departure for DNEL derivation indicates the kidney and the liver as slightly affected target organs at the limit dose level of 1000 mg/kg bw/day. For the observed minimal effects a low intraspecies variability for humans has to be expected.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

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:

20.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance and ECETOC Technical Report No. 110

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

NOAEL

Value:

1 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by the dermal route.

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 value for extrapolation from subacute to chronic exposure is used in order to cover the min. exposure duration for male animals.

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:

1

Justification:

Interspecies differences are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics (ECETOC). Therefore, no additional factor is used.

AF for intraspecies differences:

3

Justification:

The study used as point of departure for DNEL derivation indicates the kidney and the liver as slightly affected target organs at the limit dose level of 1000 mg/kg bw/day. For the observed minimal effects a low intraspecies variability for humans has to be expected. Therefore, an assessment factor of 3 is proposed to be sufficient to ensure the safety of human workers.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Long-term exposure - systemic effects

Inhalation exposure

In the absence of an inhalation toxicity study with repeated exposure, the worker-DNEL long-term for inhalation route - systemic was derived from the NOAEL obtained in the key subacute oral repeated dose study in Wistar rats. A corrected inhalatory NOAEC (NOAECcorr) was calculated using a default respiratory volume for the rat and a correction for the difference between human respiratory rats under standard conditions and under conditions of light activity (under the assumption of no difference in absorption between rat and human, and between routes). Using this NOAECcorr and considering the appropriate modification and assessment factors, the worker-DNEL (long-term for inhalation route-systemic) was calculated to be 29 mg/m³.

 

Calculation of the NOAECcorr

- Standard dose descriptor (NOAEL): 300 mg/kg bw/d

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

- Oral absorption of the rat/inhalation absorption of humans (ABSoral-rat)/ABSinhal-human): 1/1

- Standard respiratory volume of humans (sRV_human) for 8 hours: 6.7 m³

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

Corrected inhalatory NOAEC for workers:

= NOAEL * (1/sRV_rat) * (ABSoral-rat/ABSinhal-human) *(sRV_human/wRV)

= 300 mg/kg bw/d * (1/0.38 m³/kg bw/d)* (1/1) * (6.7m³/10 m³)

= 529 mg/m³

Dermal exposure

In the absence of a repeated dose toxicity study with dermal test substance application, the worker-DNEL long-term for dermal route - systemic was derived from the NOAEL obtained in the key subacute oral repeated dose study in Wistar rats. A corrected dermal NOAEL (NOAELcorr) was calculated under the assumption of a 5-times lower dermal absorption compared to oral absorption. Using this NOAELcorr and considering the appropriate modification and assessment factors, the worker-DNEL (long-term for dermal route-systemic) was calculated to be 20.8 mg/kg bw/d.

Calculation of the NOAELcorr

- Standard dose descriptor (NOAEL): 300 mg/kg bw/d

- Oral absorption of the rat/dermal absorption of humans (ABSoral-rat)/ABSdermal-human): 5/1

Corrected dermal NOAEL for workers:

= NOAEL * (ABSoral-rat/ABSdermal-human)

= 300 mg/kg bw/d * (5/1)

= 1500 mg/kg bw/d

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, ECHA-2012 -G-19 -EN.

ECETOC (2010). Guidance on assessment factors to derive a DNEL. ECETOC TR No. 110.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance and ECETOC Technical Report No. 110

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Value:

261 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no experimental data available on repeated exposure by the inhalatory route.

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 value for extrapolation from subacute to chronic exposure is used.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.

AF for other interspecies differences:

1

Justification:

Interspecies differences are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics (ECETOC). Therefore, no additional factor is used.

AF for intraspecies differences:

5

Justification:

The study used as point of departure for DNEL derivation indicates the kidney and the liver as slightly affected target organs at the limit dose level of 1000 mg/kg bw/day. For the observed minimal effects a low intraspecies variability for humans has to be expected.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

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:

12.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance and ECETOC Technical Report No. 110

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

1 500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by the dermal route

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 value for extrapolation from subacute to chronic exposure is used in order to cover the min. exposure duration for male animals.

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:

1

Justification:

Interspecies differences are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics (ECETOC). Therefore, no additional factor is used.

AF for intraspecies differences:

5

Justification:

The study used as point of departure for DNEL derivation indicates the kidney and the liver as slightly affected target organs at the limit dose level of 1000 mg/kg bw/day. For the observed minimal effects a low intraspecies variability for humans has to be expected.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

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:

2.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance and ECETOC Technical Report No. 110

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

300 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 value for extrapolation from subacute to chronic exposure is used in order to cover the min. exposure duration for male animals.

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:

1

Justification:

Interspecies differences are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics (ECETOC). Therefore, no additional factor is used.

AF for intraspecies differences:

5

Justification:

The study used as point of departure for DNEL derivation indicates the kidney and the liver as slightly affected target organs at the limit dose level of 1000 mg/kg bw/day. For the observed minimal effects a low intraspecies variability for humans has to be expected.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

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

Long-term exposure - systemic effects

Inhalation exposure

In the absence of an inhalation toxicity study with repeated exposure, the general population-DNEL long-term for inhalation route - systemic was derived from the NOAEL obtained in the key subacute oral repeated dose study in Wistar rats. A corrected inhalatory NOAEC (NOAECcorr) was calculated using a default respiratory volume for the rat (under the assumption of no difference in absorption between rat and human, and between routes). Using this NOAECcorr and considering the appropriate modification and assessment factors, the general population-DNEL (ong-term for inhalation route-systemic was calculated to be 8.7 mg/m³.

 

Calculation of the NOAECcorr

- Standard dose descriptor (NOAEL): 300 mg/kg bw

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

- Oral absorption of the rat/inhalation absorption of humans (ABSoral-rat)/ABSinhal-human): 1/1

Corrected inhalatory NOAEC for general population:

= NOAEL * (1/sRV_rat) * (ABSoral-rat/ABSinhal-human)

= 300 mg/kg bw/d * (1/1.15 m³/kg bw/d)* (1/1)

= 261 mg/m³

Dermal exposure

In the absence of a repeated dose toxicity study with dermal test substance application, the general population-DNEL long-term for dermal route - systemic was derived from the NOAEL obtained in the key subacute oral repeated dose study in Wistar rats. A corrected dermal NOAEL (NOAELcorr) was calculated under the assumption of a 5-times lower dermal absorption compared to oral absorption. Using this NOAELcorr and considering the appropriate modification and assessment factors, the general population-DNEL (long-term for dermal route-systemic) was calculated to be 12.5 mg/kg bw/d.

Calculation of the NOAELcorr

- Standard dose descriptor (NOAEL): 300 mg/kg bw/d

- Oral absorption of the rat/dermal absorption of humans (ABSoral-rat)/ABSdermal-human): 5/1

Corrected dermal NOAEL for the general population:

= NOAEL * (ABSoral-rat/ABSdermal-human)

= 300 mg/kg bw/d * (5/1)

= 1500 mg/kg bw/d

Oral exposure

The general population DNEL long-term for oral route - systemic was derived from the NOAEL of 300 mg/kg bw/day obtained in the key oral repeated dose toxicity study in rats. No modification of the dose descriptor is necessary. Using this NOAEL and considering the appropriate assessment factors, the general population-DNEL (long-term for oral route-systemic) was calculated to be 2.5 mg/kg bw/d.

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, ECHA-2012 -G-19 -EN.

ECETOC (2010). Guidance on assessment factors to derive a DNEL. ECETOC TR No. 110.