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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.41 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
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
other: NOAEL
Value:
185.13 mg/m³
Explanation for the modification of the dose descriptor starting point:

In the derivation of the long-term inhalation DNEL for workers interspecies variation (rat to human) is accounted for by converting the rat NOAEL (No Observed Adverse Effect Level) to a human NAEL (No Adverse Effect Level) by applying a factor of 0.38 to account for the standard breathing volume of the rat for 8 hours, as per the ECHA Guidance (ECHA, 2012). An adjustment of x50/100% oral absorption/inhalation absorption (ABS) has been applied to account for assumed bioavailability via the inhalatory route compared with the oral route. Oral absorption is low since the substance has to pass into the blood stream from the intestines, whereas there is high inhalatory absorption straight from the lungs (ECHA, 2012).


An additional conversion for workers of 6.7m3/10m3 to account for caloric demand during light activity has been applied. The correction factors used to account for differences in the exposure conditions of experimental animals in a test study from those of human groups (EXPCOND) is 1.4 for workers (ECHA, 2012).

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
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:
2.1 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):
100
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
210 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The correction factors used to account for differences in the exposure conditions of experimental animals in a test study from those of human groups (EXPCOND) are 1.0 for the general population and 1.4 for workers (ECHA, 2012). Correction factors of 1.0 for differences in bioavailability (ABS) are applied for the human groups, whilst those for differences in respiratory volume (sRV) and light activity at work (WORKER) are not considered appropriate.

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for other interspecies differences:
10
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.3 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):
50
Dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Modified dose descriptor starting point:
other: NOAEL
Value:
65.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

 


In the derivation of the long-term inhalation DNEL for the general population an adjustment of x50/100% oral absorption/inhalation absorption (ABS) has been applied to account for assumed bioavailability via the inhalatory route compared with the oral route. Oral absorption is low since the substance has to pass into the blood stream from the intestines whereas there is high inhalatory absorption straight from the lungs (ECHA, 2012). In the derivation of the long-term inhalation DNEL for the general population, interspecies variation (rat to human) is accounted for by converting the rat NOAEL (No Observed Adverse Effect Level) to a human NAEL (No Adverse Effect Level) by applying a factor of 1.15 to account for the standard breathing volume of the rat for 24 hours, as per the ECHA Guidance (ECHA, 2012). The correction factors used to account for differences in the exposure conditions of experimental animals in a test study from those of human groups (EXPCOND) is 1.0 for the general population (ECHA, 2012). Differences in light activity at work (WORKER) are not considered appropriate for the DNEL calculation for the general population.

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.75 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:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The correction factors used to account for differences in the exposure conditions of experimental animals in a test study from those of human groups (EXPCOND) are 1.0 for the general population and 1.4 for workers (ECHA, 2012). Correction factors of 1.0 for differences in bioavailability (ABS) are applied for the human groups, whilst those for differences in respiratory volume (sRV) and light activity at work (WORKER) are not considered appropriate.

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for other interspecies differences:
10
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.75 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:
150 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The correction factors used to account for differences in the exposure conditions of experimental animals in a test study from those of human exposure groups (EXPCOND) are 1.0 for the general population and 1.4 for workers (ECHA, 2012). Correction factors of 1.0 for differences in bioavailability (ABS) are applied for the human exposure groups, whilst those for differences in respiratory volume (sRV) and light activity at work (WORKER) are not considered appropriate.

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
AF for other interspecies differences:
10
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

The available short- and long-term toxicological dataset for the source substances Distilled Grade and Distillation Residue Grade has been used to generate by interpolation the relevant Derived No Effect Levels (DNELs) for the target substance Technical Grade required for the risk characterisation exercise. The approach adopted is based on ECHA Guidance on information requirements and chemical safety assessment - Chapter R.8: Characterisation of dose [concentration]-response for human health (ECHA, 2012).


 


Longer-term repeated dose toxicity data for Distilled Grade and Distillation Residue Grade are available from two studies which provide data on key target groups, namely males, unmated females, mated (pregnant) females and their offspring. Data for mated females can be used to determine if pregnant females represent a group of concern that may need to be specifically addressed in the determination of DNELs. These studies comprise:


 



  1. OECD TG408 Repeated Dose Oral Toxicity studies in which males and unmated females are exposed to the test substance during a 90-day period of growth and maturation.


 



  1. OECD TG414 Prenatal Developmental Toxicity studies in which mated females are exposed to the test substance during pregnancy.


 


Based on the available No Observed Adverse Effect Levels (NOAEL) generated from the data and the identified routes of exposure it has been concluded that no DNELacute values need to be derived since no acute toxicity effects have been observed in OECD studies assessing exposure via the oral and dermal routes. In order to be able to assess all potential risks to humans (in terms of the general population and workers) DNELlong-term values have been derived for all possible routes of exposure (i.e. oral, dermal and inhalation). The general population and worker DNELlong-term values for the oral route have been derived directly from the most relevant test NOAEL values. In contrast, the oral NOAEL values have been corrected to achieve the starting point values for the derivation of the dermal and inhalation DNELlong-term values.


 


Based on the available data the DNELs derived for systemic exposure are sufficiently precautionary to provide adequate protection for the local histopathological effects on the stomach surface identified to varying degrees in both the OECD studies on the two grades.


In addition the derived DNEL for maternal toxicity in pregnant females based on the oral route of exposure is higher than the corresponding long-term DNEL for the general population indicating that they do not constitute a vulnerable population to Technical Grade.


The DNELs generated are considered to be conservative due to the use of the default assessment factors to cover issues such as interspecies differences, intraspecies differences, differences in duration of exposure, issues related to the dose-response relationship and the quality of the whole database in the absence of substance-specific data.

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