Tris(2-ethylhexyl)-4,4',4''-(1,3,5-triazine-2,4,6-triyltriimino)tribenzoate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

35.3 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):

25

Modified dose descriptor starting point:

NOAEC

Value:

882 mg/m³

Explanation for the modification of the dose descriptor starting point:

In the absence of absorption data, it is assumed that the modalities of absorption between animals and human are the same. Further, in absence of data, according to the R8 ECHA guidance, a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation was applied, i.e. a 1: 2 relationship has been applied to convert the oral NOAEL into the corrected NOAEC. Moreover, the oral dose has been corrected by the standard respiration volume in rats for a period of 8 hours (standard working shift), and then it has been also corrected for the differences of the sRV of rats (at rest) and workers (at light activity). Corrected inhalation NOAEC = 1000 mg/kg bw/day/2 x (1 / sRVrat) x (ABSoral rat / ABSinhalation rat) x (ABSinhalation rat / ABSinhalation human) x (sRVhuman / wRVhuman) = 1000/2 mg/kg bw/day x (1 / 0.38 m3/kg bw/day) x (1 / 1) x (6.7 m3 (8 hours) / 10 m3 (8 hours)) = 882 mg/m3. In practical, to correct the interspecies difference between rat and human and applying the route-to-route extrapolation the no observed effect level has to be corrected from 1000 mg/m3 to 882 mg/m3.

AF for differences in duration of exposure:

2

Justification:

from subchronic to chronic

AF for interspecies differences (allometric scaling):

2.5

Justification:

remaining interspecies differences

AF for intraspecies differences:

5

Justification:

intraspecies differences: worker

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:

100 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):

100

Modified dose descriptor starting point:

NOAEL

Value:

10 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin penetration are available for the test article. However, since the test article has a molecular weight of > 500 and the estimated log POW is not within -1 to 4, a skin penetration of 10% can be assumed and an assessment factor of 0.1 is applied

AF for differences in duration of exposure:

2

Justification:

from subacute to chronic

AF for interspecies differences (allometric scaling):

2.5

Justification:

remaining interspecies differences

AF for other interspecies differences:

4

Justification:

from rat to human

AF for intraspecies differences:

5

Justification:

intraspecies differences: worker

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

Identification of relevant dose descriptor

For the derivation of the DNELs, the 90 days feeding study in rats was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 1000 ppm test substance in food (highest dose,subchronic 90-day oral toxicity (gavage) study in the rat according to OECD 408) measured for the substance itself. This study was considered the most relevant for the hazard assessment.

Systemic, short-term, dermal and inhalative

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs for short-term exposures were calculated.

 

Local, long-term and short-term, dermal& inhalative

Based on the available key toxicological information, the test item is not subject to classification for skin and eye irritation and skin sensitization (according to 67/548/EEC and EC/1272/2008). Accordingly, no DNELs for local effects following acute/short-term or long-term exposure are derived. This is in line with the ECHA guidance document (Chapter R.8).

 

Systemic, long-term, inhalative

Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) is converted into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, November 2012.

In the absence of absorption data, it is assumed that the modalities of absorption between animals and human are the same. Further, in absence of data, according to the R8 ECHA guidance,a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation was applied, i.e.a 1: 2 relationship has been applied to convert the oral NOAEL into the corrected NOAEC. 

Moreover, the oral dose has been corrected by the standard respiration volume in rats for a period of 8 hours (standard working shift), and then it has been also corrected for the differences of the sRV of rats (at rest) and workers (at light activity). Corrected inhalation NOAEC = 1000 mg/kg bw/day/2 x (1 / sRVrat) x (ABSoral rat / ABSinhalation rat) x (ABSinhalation rat / ABSinhalation human) x (sRVhuman / wRVhuman) = 1000/2 mg/kg bw/day x (1 / 0.38 m3/kg bw/day) x (1 / 1) x (6.7 m3 (8 hours) / 10 m3 (8 hours)) = 882 mg/m³

In practical, to correct the interspecies difference between rat and human and applying the route-to.-route extrapolation the no observed effect level has to be corrected from 1000 mg/m³to 882 mg/m³.

Thus, the corrected startingpoint for workers was 882 mg/m³ for inhalation.

Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation:

1) Exposure duration (from subchronic to chronic) = (2)

2) Remaining interspecies differences – allometric scaling (2.5);

3) Intraspecies differences: worker (5);

Then, this results in anoverall assessment factor of 25

The DNEL for long-term inhalative exposure, systemic effects is therefore 35,3mg/m³.

 

 

Systemic, long-term, dermal:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin penetration are available for the test article. However, since the test article has a molecular weight of > 500 and the estimated log P_OW is not within -1 to 4, a skin penetration of 10% can be assumed and an assessment factor of 0.1 is applied (ECHA GD chapter R7c).

Thus, the corrected starting point for workers was 10000 mg/kg for dermal route.

Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation:

1) Exposure duration (from subacute to chronic) = (2)

2) Interspecies differences (from rat to human) (4)

3) remaining interspecies differences – allometric scaling (2.5);

4) intraspecies differences: worker (5);

 

Then, this results in anoverall assessment factor of 100

The resulting DNEL for long-term dermal systemic effects is 100 mg/kg for workers.

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:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

435 mg/m³

Explanation for the modification of the dose descriptor starting point:

Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) is converted into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, November 2012. In the absence of absorption data, it is assumed that the modalities of absorption between animals and human are the same. Further, in absence of data, according to the R8 ECHA guidance, a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation was applied, i.e. a 1: 2 relationship has been applied to convert the oral NOAEL into the NOAEC. To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows: Corrected starting point for the inhalative route for general population: NOAEL/2 * (1/1.15 m³/kg bw/day) Where: 1.15 m³/kg bw/day: default respiratory volume for the rat corresponding to the daily duration of human exposure.

AF for differences in duration of exposure:

2

Justification:

from subchronic to chronic

AF for interspecies differences (allometric scaling):

2.5

Justification:

remaining interspecies differences

AF for intraspecies differences:

10

Justification:

intraspecies differences: general population

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:

50 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

Modified dose descriptor starting point:

NOAEL

Value:

10 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin penetration is available for the test article. However, since the test article has a molecular weight of > 500 and the log POW is not within -1 to 4, a skin penetration of 10% can be assumed and an assessment factor of 0,1 is applied (ECHA GD chapter R7c). Thus, the corrected starting point for the general population was 10000 mg/kg/d for dermal route.

AF for differences in duration of exposure:

2

Justification:

from subchronic to chronic

AF for interspecies differences (allometric scaling):

2.5

Justification:

remaining interspecies differences

AF for other interspecies differences:

4

Justification:

from rat to human

AF for intraspecies differences:

10

Justification:

intraspecies differences: general population

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:

5 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

AF for differences in duration of exposure:

2

Justification:

from subchronic to chronic

AF for interspecies differences (allometric scaling):

2.5

Justification:

remaining interspecies differences

AF for other interspecies differences:

4

Justification:

from rat to human)

AF for intraspecies differences:

10

Justification:

intraspecies differences: general population

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

Identification of relevant dose descriptor

The dose descriptor chosen is the same as for workers (see above). The NOAEL of 1000 mg/kg observed in thesubchronic 90-day oral toxicity (gavage) study in ratswas used as starting point to derive the DNELs.

 

Systemic, short-term, dermal and inhalative

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs for short-term exposures were calculated.

 

Local, long-term and short-term, dermal& inhalative

Based on the available key toxicological information, the test item is not subject to classification for skin and eye irritation and skin sensitization (according to 67/548/EEC and EC/1272/2008). Accordingly, no DNELs for local effects following acute/short-term or long-term exposure are derived. This is in line with the ECHA guidance document (Chapter R.8).

 

Systemic, long-term, inhalative

Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) is converted into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, November 2012.

In the absence of absorption data, it is assumed that the modalities of absorption between animals and human are the same.Further, in absence of data, according to the R8 ECHA guidance,a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation was applied, i.e.a 1: 2 relationship has been applied to convert the oral NOAEL into the NOAEC. 

To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route forgeneral population:

NOAEL/2 * (1/1.15 m³/kg bw/day)

Where: 1.15 m³/kg bw/day: default respiratory volume for the rat corresponding to the daily duration of human exposure.

Thus, the corrected starting point for the general population, inhalative route, is435mg/m3

Subsequently other assessment factors are listed, which have to be taken into account for the final

1) Exposure duration (from subchronic to chronic) = (2)

2) remaining interspecies differences – allometric scaling (2.5);

3) intraspecies differences: general population (10);

 

Then, this results in an overall assessment factor of 50

The DNEL for long-term inhalative exposure, systemic effects is therefore considered to be 8,7mg/m³.

 

Systemic, long-term, dermal:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin penetration is available for the test article. However, since the test article has a molecular weight of > 500 and the log POW is not within -1 to 4, a skin penetration of 10% can be assumed and an assessment factor of 0,1 is applied (ECHA GD chapter R7c).

Thus, the corrected starting point for the general population was 10000 mg/kg/d for dermal route.

Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation:

1) Exposure duration (from subchronic to chronic) = (2)

2) Intraspecies differences (from rat to human) (4)

2) remaining interspecies differences – allometric scaling (2.5);

3) intraspecies differences: general population (10);

 

 Then, this results in an overall assessment factor of 200

The DNEL for long-term dermal exposure, systemic effects is therefore considered to be 50 mg/kg.

 

Systemic, long-term, oral:

The NOAEL of 1000 mg/kg observed in thesubchronic 90-day oral toxicity (gavage) study in ratswas used as starting point to derive this DNEL.

For the overall assessment factor evaluation the following factors have to be taken into account for the final DNEL calculation:

1) Exposure duration (from subchronic to chronic) = (2)

2) Intraspecies differences (from rat to human) (4)

2) remaining interspecies differences – allometric scaling (2.5);

3) intraspecies differences: general population (10);

 

Then, this results in an overall assessment factor of 200

The resulting DNEL for long-term oral,systemic effects of the substance is 5 mg/kg for general population