Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.7 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):
75
Modified dose descriptor starting point:
NOAEC
Value:
727 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 = 825 mg/kg bw/day/2 x (1 / sRVrat) x (ABSoral rat / ABSinhalation rat) x (ABSinhalation rat / ABSinhalation human) x (sRVhuman / wRVhuman) = 825/2 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)) = 727 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 825 mg/m3 to 727 mg/m3.
AF for differences in duration of exposure:
6
Justification:
from subacute 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:
27 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
Modified dose descriptor starting point:
NOAEL
Value:
8 250 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:
6
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 28 days feeding study in rats was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 825 ppm test substance in food (highest dose,subacute 28-day oral toxicity (gavage) study in the rat according to OECD 407 – 1991) measuredfor a structure analogue of 133-66-4 having CAS 16090-02-1. 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 = 825 mg/kg bw/day/2 x (1 / sRVrat) x (ABSoral rat / ABSinhalation rat) x (ABSinhalation rat / ABSinhalation human) x (sRVhuman / wRVhuman) = 825/2 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)) = 727 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 825 mg/m3to 727 mg/m3.

Thus, the corrected startingpoint for workers was 727 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 subacute to chronic) = (6)

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

3) intraspecies differences: worker (5);

Then, this results in an overall assessment factor of 75

The DNEL for long-term inhalative exposure, systemic effects is therefore 9,7 mg/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 POWis 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 8250 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) = (6)

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

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

3) intraspecies differences: worker (5);

 

Then, this results in an overall assessment factor of 300

The resulting DNEL for long-term dermal systemic effects is 27 mg/kg for workers.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 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
Modified dose descriptor starting point:
NOAEC
Value:
359 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:
6
Justification:
from subacute 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:
13.8 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
Modified dose descriptor starting point:
NOAEL
Value:
8 250 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 8250 mg/kg/d for dermal route.
AF for differences in duration of exposure:
6
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:
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:
1.4 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
Modified dose descriptor starting point:
NOAEL
Value:
825 mg/kg bw/day
AF for differences in duration of exposure:
6
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:
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 825 mg/kg observed in thesubacute 28-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, is 359 mg/m3

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

1) Exposure duration (from subacute to chronic) = (6)

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

3) intraspecies differences: general population (10);

 

Then, this results in an overall assessment factor of 150.

The DNEL for long-term inhalative exposure, systemic effects is therefore considered to be 2,4 mg/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 8250 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 subacute to chronic) = (6)

2) Interspecies 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 600

The DNEL for long-term dermal exposure, systemic effects is therefore considered to be 13,8 mg/kg.

 

Systemic, long-term, oral:

The NOAEL of 825 mg/kg observed in thesubacute 28-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 subacute to chronic) = (6)

2) Interspecies 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 600

The resultingDNEL for long-term oral,systemic effects of the substance is 1,4 mg/kg for general population