Triisooctylamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.987 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):

50

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

49.36 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL derived from an OECD 422 compliant oral repeated dose toxicity study of 10 mg/kg bw/d was applied as point of departure for derivation of long-term systemic inhalation DNEL. This NOAEL was corrected based on the following formula:

Corrected NOAEC (inhalation) for workers:

= 10 mg/kg bw/day x 2 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 49.36 mg/m3

As worst case, inhalative absorption is assumed to be two times less than oral absorption which allows for a modification of the starting point by at least 2.

For more details please refer to the discussion below.

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:

4

Justification:

The exposure duration of the OECD TG 422 study performed with the test item up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied

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 quality of the whole data base is considered to be sufficient and uncritical.
The OECD TG 422 toxicity study 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:

0.28 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):

200

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

56 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker. As worst case, dermal absorption is assumed to be four times less than oral absorption which allows for a modification of the starting point by at least 4.

Corrected NOAEL (dermal) for workers:

= 10 mg/kg bw/day x 1.4 x 4

= 56 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:

4

Justification:

The exposure duration of the OECD TG 422 study was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

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 quality of the whole data base is considered to be sufficient and uncritical.
The OECD TG 422 toxicity study 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:

no hazard identified

Additional information - workers

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 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 also 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 test item is available. Therefore, long-term inhalation DNEL was derived by route-to-route extrapolation from an oral repeated dose toxicity study:

Based on the conditions of an OECD TG 422 study with the test item, daily oral administration to Wistar rats revealed signs of toxicity in the high and mid dose i. e. 100 and 30 mg/kg bw/d. The NOAEL for systemic toxicity, was therefore considered to be 10 mg/kg bw/day. NOAEL for fertility and developmental toxicity was determined to be 100 and 30 mg/kg bw/d, respectively under the conditions of this study. The NOAEL of systemic toxicity is applied as Point of Departure for DNEL derivation since it is considered to reflect worst case assumption.

Step 1: PoD: NOAEL = 10 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume, human (sRVhuman) for 8 h per person (70 kg): 6.7 m3

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

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

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 2

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

Corrected NOAEC (inhalation) for workers:

= 10 mg/kg bw/day x 2 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 7/5

= 49.36 mg/m3

Due to a very low vapor pressure of 0,000927 Pa it is very unlikely that the substance is available as a vapor. Boiling point of the substance could not be determined due to technical reasons of limited stability. Therefore, regarding inhalation, exposure is not relevant since the substance is a non-volatile liquid. However, in the case of inhalation the substance is expected to not easily pass biological membranes of the respiratory tract based on the same indications as outlined above. As worst case, inhalative absorption is assumed to be two times less than oral absorption which allows for a modification of the starting point by at least 2.

Step 3: Overall AF= 50

Intraspecies AF (worker): 5

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

Interspecies AF, remaining differences: 2.5

The recommended AF for other interspecies differences is applied.

Allometric scaling AF: 1

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

Dose response relationship AF: 1

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

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

Whole database AF: 1

The OECD TG 422 toxicity study 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.

In conclusion, long term systemic inhalation DNEL, workers = 0.9872 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

There is no short-term or long-term toxicity study via inhalation route available for the test item. Due to its very low vapour pressure (< 1 Pa), high peak-inhalation exposure is not considered as relevant. The test item is unlikely to be available as a vapour to a large extent. Thus, the acute inhalation DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur. In addition, the test item is not classified as acutely toxic via inhalation or dermal route.

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

The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). Therefore, it is not considered to pose a hazard for local effects on the mucous membranes of respiratory tract when inhaled. Further, the test item is not expected to be available as a vapour due to its very low vapour pressure. Thus, the inhalation route is not considered relevant for humans

 

Dermal

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

No repeated dose dermal toxicity study with the test item is available. Therefore, long-term dermal DNEL was derived by route-to-route extrapolation. The NOAEL of 10 mg/kg bw/day derived from an OECD TG 422 study performed with the test item was used as the Point of Departure.

Step 1: PoD: NOAEL = 10 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.

Regarding dermal application, physico-chemical properties of the test item indicate that it probably does not becomes readily bioavailable. According to ECHA guidance on toxicokinetics, there are no exclusion criteria for skin permeability (ECHA, 2017). However, a molecular weight of > 500 Da and a log Pow of > 4 are given as indicators for low absorption (10% or less). Considering the calculated log Pow of 10, the latter criteria is fulfilled by the test item. The molecular weight of 353.67 g/mol, however, could still support dermal absorption. The same applies for water solubility which favors a low to moderate dermal absorption being between ca. 30 and 150 mg/L. Based on the findings of an acute dermal toxicity study no signs toxicity were observed when the limit dose of 2000 mg/kg bw was applied to rat skin. Even though local effects of skin irritation were observed (classified as skin irritant cat. 2), no signs of systemic toxicity were recorded as observed in the acute oral toxicity study at doses as low as 300 mg/kg. This supports the assumption that the substance becomes bioavailable to a less extent via the dermal route. However, the substance has been identified as skin sensitizer indicating that at least some dermal uptake takes place. This is probably accomplished by tissue damage due to irritating properties of the test item. As worst case, dermal absorption is assumed to be four times less than oral absorption which allows for a modification of the starting point by at least 4.

Corrected NOAEL (dermal) for workers:

= 10 mg/kg bw/day x 7/5 x 4

= 56 mg/kg bw/day

Step 3: Overall AF= 200

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

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

 

Interspecies AF, remaining differences: 2.5

The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (worker): 5

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

 

Dose-response relationship AF: 1

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

 

Exposureduration AF: 4
The exposure duration of the OECD TG 422 study was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

In conclusion, long term systemic dermal DNEL, workers = 0.28 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

An acute dermal toxicity study is available for the test item. Based on the results the test item is not classified for acute dermal toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, the acute systemic dermal DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur.

 

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

The test substance is classified for skin irritation and skin sensitization. Therefore, appropriate qualitative risk managements measures should be implemented to avoid exposure. Thus, a qualitative risk assessment is applied and the substance is assigned to the high hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

Hazard to the eye-local effects (worker)

The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP).

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:

0.173 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):

100

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

17.39 mg/m³

Explanation for the modification of the dose descriptor starting point:

Corrected NOAEC (inhalation) for general population:

= 10 mg/kg bw/day x 2 x 1/1.15 m3/kg bw/day

= 17.39 mg/m3

As worst case, inhalative absorption is assumed to be two times less than oral absorption which allows for a modification of the starting point by at least 2.

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:

4

Justification:

The exposure duration of the OECD TG 422 study was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

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

AF for the quality of the whole database:

1

Justification:

The OECD TG 422 toxicity study 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:

0.1 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):

400

Dose descriptor starting point:

NOAEL

Value:

10 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

40 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As worst case, dermal absorption is assumed to be four times less than oral absorption which allows for a modification of the starting point by at least 4.

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:

4

Justification:

The exposure duration of the OECD TG 422 study was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for the relatively heterogeneous group "general population" is applied

AF for the quality of the whole database:

1

Justification:

The OECD TG 422 toxicity study 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)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.025 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):

400

Dose descriptor starting point:

NOAEL

Value:

10 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:

4

Justification:

The exposure duration of the OECD TG 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

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

AF for the quality of the whole database:

1

Justification:

The OECD TG 422 toxicity study 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:

DNEL (Derived No Effect Level)

Value:

0.075 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):

0.33

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Inhalation

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

Using a conservative approach, a DNEL for general population (long-term inhalation exposure) is calculated. This long-term DNEL is considered to ensure also 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 test item is available. Therefore, long-term inhalation DNEL was derived by route-to-route extrapolation from an oral repeated dose toxicity study:

Based on an OECD TG 422 study with the test item, daily oral administration to Wistar rats revealed signs of toxicity in the high and mid dose tested i. e. 100 and 30 mg/kg bw/d, respectively. The NOAEL for systemic toxicity, was therefore considered to be 10 mg/kg bw/day. NOAEL for fertility and developmental toxicity was determined to be 100 and 30 mg/kg bw/d, respectively based on the conditions of this study. The NOAEL of systemic toxicity is used as Point of Departure for DNEL derivation since it can be considered reflecting a worst case assumption.

Step 1: PoD: NOAEL = 10 mg/kg bw/day

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): 2

Corrected NOAEC (inhalation) for general population:

= 10 mg/kg bw/day x 2 x 1/1.15 m3/kg bw/day

= 17.39 mg/m3

Due to a very low vapor pressure of 0,000927 Pa it is very unlikely that the substance is available as a vapor. Boiling point of the substance could not be determined due to technical reasons of limited stability. Therefore, regarding inhalation, exposure is not relevant since the substance is a non-volatile liquid. However, in the case of inhalation the substance is expected to not easily pass biological membranes of the respiratory tract based on the same indications as outlined above. As worst case, inhalative absorption is assumed to be two times less than oral absorption which allows for a modification of the starting point by at least 2.

Step 3: Overall AF= 100

Intraspecies AF (General population): 10
The default value for the relatively heterogeneous group "general population" is used

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

Allometric scaling AF: 1
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

Dose response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

Exposure duration AF: 4
The exposure duration of the OECD TG 422 study was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

Whole database AF: 1
The OECD TG 422 toxicity study 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:
The approach used for DNEL derivation is conservative. No further assessment factors are required.

In conclusion,long term systemic inhalation DNEL, general population = 0.173 mg/m3

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

There is no short-term or long-term toxicity study via inhalation route available for the test item. Due to its very low vapour pressure (< 1 Pa), high peak-inhalation exposure is not considered as relevant. The test item is unlikely to be available as a vapour to a large extent. Thus, the acute inhalation DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur. In addition, the test item is not classified as acutely toxic via inhalation or dermal route.

Long-term and short-term, local DNEL- exposure via inhalation (general population)

The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). Therefore, it is not considered to pose a hazard for local effects on the mucous membranes of respiratory tract when inhaled. Further, the test item is not expected to be available as a vapour due to its very low vapour pressure. Thus, the inhalation route is not considered relevant for humans.

 

Dermal

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

No repeated dose dermal toxicity study with the test item is available. Therefore, long-term dermal DNEL was derived by route-to-route extrapolation. The NOAEL of 10 mg/kg bw/day derived from an OECD TG 422 study performed with the test item was used as the Point of Departure.

Step 1: PoD: NOAEL= 10 mg/kg bw/day

Step 2: Modification into a correct starting point:

Regarding dermal application, physico-chemical properties of the test item indicate that it probably does not becomes readily bioavailable. According to ECHA guidance on toxicokinetics, there are no exclusion criteria for skin permeability (ECHA, 2017). However, a molecular weight of > 500 Da and a log Pow of > 4 are given as indicators for low absorption (10% or less). Considering the calculated log Pow of 10, the latter criteria is fulfilled by the test item. The molecular weight of 353.67 g/mol, however, could still support dermal absorption. The same applies for water solubility which favors a low to moderate dermal absorption being between ca. 30 and 150 mg/L. Based on the findings of an acute dermal toxicity study no signs toxicity were observed when the limit dose of 2000 mg/kg bw was applied to rat skin. Even though local effects of skin irritation were observed (classified as skin irritant cat. 2), no signs of systemic toxicity were recorded as observed in the acute oral toxicity study at doses as low as 300 mg/kg. This supports the assumption that the substance becomes bioavailable to a less extent via the dermal route. However, the substance has been identified as skin sensitizer indicating that at least some dermal uptake takes place. This is probably accomplished by tissue damage due to irritating properties of the test item. As worst case, dermal absorption is assumed to be four times less than oral absorption which allows for a modification of the starting point by at least 4.

Corrected NOAEL (dermal) for consumers:

NOAEL = 40 mg/kg bw/day

Step 3: Overall AF= 400

Interspecies AF, allometric scaling (rat to human): 4
The default allometric scaling factor for the differences between rats and humans is applied.

 

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (general population): 10
The default value for the relatively heterogeneous group "general population" is applied

 

Dose-response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

 

Exposure duration AF: 4
The exposure duration of the OECD TG 422 study was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

 

In conclusion, long term systemic dermal DNEL, general population = 0.1 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

An acute dermal toxicity study is available for the test item. Based on the results the test item is not classified for acute dermal toxicity according to Regulation (EC) No 1272/2008 (CLP). Thus, the acute systemic dermal DNEL was not derived. Further, long-term DNELs are considered sufficient to ensure that acute effects do not occur.

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

The test substance is classified for skin irritation and skin sensitization. Therefore, appropriate qualitative risk managements measures should be implemented to avoid exposure. Thus, a qualitative risk assessment is applied and the substance is assigned to the high hazard band in accordance with ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation (2016).

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

An oral repeated dose toxicity study with the test item is available. Here, daily oral administration of the test item to Wistar rats revealed signs of toxicity in the high and mid dose i. e. 100 and 30 mg/kg bw/d. The NOAEL for systemic toxicity was therefore considered to be 10 mg/kg bw/day. NOAEL for fertility and developmental toxicity was determined to be 100 and 30 mg/kg bw/d, respectively under the conditions of this study. The NOAEL of systemic toxicity is applied as Point of Departure for DNEL derivation since it is considered to reflect worst case assumption.

Step 1: PoD: NOAEL = 10 mg/kg bw/day

Step 2: Overall AF= 400

Interspecies AF, allometric scaling (rat to human): 4
The default allometric scaling factor for the differences between rats and humans is applied.

 

Interspecies AF, remaining differences: 2.5
The recommended AF for other interspecies differences is applied.

 

Intraspecies AF (general population): 10
The default value for the relatively heterogeneous group "general population" is used.

 

Dose-response relationship AF: 1
The dose response relationship is considered unremarkable, therefore no additional factor is used.

 

Exposure duration AF: 4
The exposure duration of the OECD TG 422 study performed with the test item was up to 63 days for females and 29 days for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the assessment factor of 4.

In conclusion, long term systemic oral DNEL, general population= 0.025 mg/kg bw/day

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

Due to the acute oral toxicity observed for the test item (LD50 >300 < 2000 mg/kg bw), the substance is considered to be classified for acute oral toxicity Cat.4 under Regulation (EC) No. 1272/2008 (CLP). ECHA Guidance states that “[..],the acute DNEL can by default be set as 1-5 times the long-term DNEL”. Therefore, the DNEL for acute systemic oral, general population was extrapolated according to the ECHA Guidance by applying the AF of 0.33.

 

DNEL, long-term systemic oral (0.025 mg/kg bw/day)/ AF (0.33)

 

DNEL, short-term systemic oral = 0.075 mg/kg bw/day

Hazard to the eye-local effects (general population)

The test item is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP).

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