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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
78.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance, ECETOC Technical Report No. 110 and Batke et al (2011)
Overall assessment factor (AF):
4.5
Modified dose descriptor starting point:
NOAEC
Value:
352.63 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used.
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:
1.5
Justification:
An extrapolation factor based on experimental data is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
An additional factor for "remaining interspecies differences" is scientifically not justified and arbitrary since the allometric scaling factor fully accounts for interspecies differences
AF for intraspecies differences:
3
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
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 aassessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.11 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, ECETOC Technical Report No. 110 and Batke et al (2011)
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by dermal absorption. Based on the physiochemical properties it is assumed that the test item absorption corresponds to a worst case of 100 % of the oral uptake.
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:
1.5
Justification:
An extrapolation factor based on experimental data is used: subchronic (starting point) to chronic (end point).
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:
An additional factor for "remaining interspecies differences" is scientifically not justified and arbitrary since the allometric scaling factor fully accounts for interspecies differences
AF for intraspecies differences:
3
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
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 aassessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)

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 REACH Guidance (2010), ECETOC (2010) and Batke et al (2011).In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1.

 

Long term exposure- systemic effects

Inhalation exposure

In order to derive the worker DNEL (long- term inhalation exposure), the NOAEL assessed in the key 90-day repeated dose oral toxicity study was used as relevant dose descriptor (NOAEL = 200 mg/kg bw/day).The oral NOAEL was converted to an inhalation NOAEC, assuming 100 % absorption via the lung and via the oral route.

 

Inhalation NOAEC = oral NOAEL x 1/sRV (rat) x ABS oral (rat)/ ABS inhalation (human) x sRV (human)/ wRV (human)

 

Correction of the dose descriptor

Oral NOAEL: 200 mg/kg bw/ day

sRV(rat): 0.38 m3/kg bw (8 hours) [standard respiratory volume of the rat]

ABSoral(rat)/ABSinhalation(human): 1 [ratio of oral absorption in the rat to inhalative absorption in the human]

sRV (human)/ wRV (human): 6.7 m3/ 10 m3[ratio of human standard respiratory volume to worker respiratory volume]

The oral NOAEL= 200 mg/kg bw/ day is converted in an inhalation NOAEC= 352.63 mg/ m3

 

Calculation of the worker DNEL

Corrected inhalatory NOAEC for worker: 352.63 mg/ m³

Assessment factor for exposure duration (subchronic to chronic): 1.5

Assessment factor for intraspecies differences (worker): 3

Worker DNEL (inhalation exposure) = 352.63 mg/ m3/ (1 x 1.5 x 1 x 3 x 1 x 1 x 1) = 352.63 mg/ m3/ 4.5 = 78.36 mg/ m3

  

Dermal exposure

In order to derive the worker DNEL (long-term dermal exposure), the NOAEL assessed in the 90-day repeated dose oral toxicity study is identified as the relevant dose descriptor. Considering the appropriate modification and assessment factors, the worker DNEL (long-term dermal exposure) is calculated as follows:

 

Relevant dose descriptor of relevant study: 200 mg/kg bw/ day (assuming 100 % dermal absoprtion)

Route to route extrapolation (oral to dermal): 1

Exposure duration factor (subchronic-to-chronic): 1.5

Allometric scaling factor (rat-to-human): 4

Assessment factor for intraspecies differences (worker): 3

Worker DNEL (long-term dermal exposure): 200 mg/kg bw/day / (1 x 1.5 x 4 x 3 x 1 x 1 x 1) = 200 / 18 = 11,11 mg/kg bw/day

 

Acute exposure- systemic effect

A short-term DNEL systemic is not required as the acute oral, inhalation and dermal toxicity of the test item is considered to be very low and no classification and labelling was required according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).

 

Acute/ long term exposure- local

Skin irritation/corrosion: A long-term and acute DNEL local is not required as the local toxicity of the the test item is not classified for skin irritation/corrosion according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).

Eye irritation: The test item is not classified for eye irritation according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). Thus, no local DNEL was derived.

Skin sensitization: The test item is not classified as a skin sensitizer according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).

Respiratory irritation: As no eye and skin irritation/ corrosion properties were identified in the available studies and uptake via inhalation is unlikely to occur, no DNEL was derived. In addition, in an acute inhalation study, no local respiratory irritation was observed.

 

References

(not included as endpoint study record)

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.Version 2. ECHA-2010 -G-19 –EN.

- ECETOC (2010). Technical Report 110.Guidance on assessment factors to derive a DNEL.

according to Annex VI of Regulation EC 1272/2008 (CLP).

- Batke (2011). Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205, 122– 129

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance, ECETOC Technical Report No. 110 and Batke et al (2011)
Overall assessment factor (AF):
7.5
Modified dose descriptor starting point:
NOAEC
Value:
150 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used.
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:
1.5
Justification:
An extrapolation factor based on experimental data is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
An additional factor for "remaining interspecies differences" is scientifically not justified and arbitrary since the allometric scaling factor fully accounts for interspecies differences
AF for intraspecies differences:
5
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
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 aassessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.67 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, ECETOC Technical Report No. 110 and Batke et al (2011)
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by dermal absorption. Based on the physiochemical properties it is assumed that the test item absorption corresponds to a worst case of 100 % of the oral uptake.
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:
1.5
Justification:
An extrapolation factor based on experimental data is used: subchronic (starting point) to chronic (end point).
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:
An additional factor for "remaining interspecies differences" is scientifically not justified and arbitrary since the allometric scaling factor fully accounts for interspecies differences
AF for intraspecies differences:
5
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
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 aassessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.67 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):
30
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary since a repeated dose oral toxicity study is available.
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:
1.5
Justification:
An extrapolation factor based on experimental data is used: subchronic (starting point) to chronic (end point).
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:
An additional factor for "remaining interspecies differences" is scientifically not justified and arbitrary since the allometric scaling factor fully accounts for interspecies differences
AF for intraspecies differences:
5
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
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 aassessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA REACH Guidance (2010), ECETOC (2010) and Batke et al (2011). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1.

 

Long term exposure- systemic effects

Inhalation exposure

The derived general population DNEL (long-term inhalation exposure) is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected). The NOAEL assessed in the 90-day repeated dose oral toxicity study is identified as the relevant dose descriptor.

 

Modification of the starting point

Relevant dose descriptor (NOAEL): 200 mg/kg bw/ day

Allometric scaling: 4

Body weight: 60 kg

Standard respiratory volume of humans (sRV human) for 24 hours: 20 m³

Oral absorption of the rat / inhalation absorption of humans (ABS oral-rat / ABS inh- human): 1  

Corrected inhalatory NOAEC for general population: (200 mg/kg bw/day / 4) × 60 kg/ 20 m3/ day × 1 = 150 mg/ m³  

 

Calculation of the general population DNEL

Corrected inhalatory NOAEC for general population: 150 mg/m³

Assessment factor for exposure duration (subchronic to chronic): 1.5

Assessment factor for intraspecies differences (general population): 5  

General population DNEL (long-term inhalation exposure) = 150 mg/m³ / (1x 1.5 x 1 x 1 x 5 x 1 x 1 ) = 150 mg/m³ / 7.5 = 20 mg/m³

 

Dermal exposure

In order to derive the general population DNEL (long-term dermal exposure), the NOAEL assessed in the 90-day repeated dose oral toxicity study is identified as the relevant dose descriptor. Considering the appropriate modification and assessment factors, the general population DNEL (long-term dermal exposure) is calculated as follows:  

Relevant dose descriptor of relevant study: 200 mg/kg bw/ day (assuming 100 % dermal absoprtion)

Route to route extrapolation (oral to dermal): 1

Exposure duration factor (subchronic-to-chronic): 1.5

Allometric scaling factor (rat-to-human): 4

Assessment factor for intraspecies differences (general population): 5

General population DNEL (long-term dermal exposure): 200 mg/kg bw/day / (1 x 1.5 x 4 x 5 x 1 x 1 x 1) = 6.67 mg/kg bw/ day

 

Oral exposure

In order to derive the general population DNEL (long-term oral exposure), the NOAEL assessed in the 90-day repeated dose oral toxicity study is identified as the relevant dose descriptor. Considering the appropriate modification and assessment factors, the general population DNEL (long-term oral exposure) is calculated as follows:

 

Relevant dose descriptor (NOAEL): 200 mg/kg bw/ day

Exposure duration factor (subchronic-to-chronic): 1.5

Allometric scaling factor (rat-to-human): 4

Assessment factor for intraspecies differences (general population): 5

General population DNEL (long-term dermal exposure) = 200 mg/kg bw/day / (2 x 4 x 5 x 1 x 1 x 1) = 6.67 mg/kg bw/day

 

Acute/ short-term- systemic effects

Short-term DNELs are not required as there is no acute toxicity of the test item. It is not classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral, dermal and inhalation toxicity.

 

Acute/ long-term- local effects

Skin and eye irritation/corrosion: The test item is not classified for skin and eye irritation based on the results of the skin and eye irritation studies available. Therefore, no DNEL was derived.

Skin sensitisation: The test item is not classified as a skin sensitizer based on the results of the skin sensitisation study available. Therefore, no DNEL was derived.

Respiratory irritation: As no eye and skin irritation/ corrosion properties were identified in the available studies and uptake via inhalation is unlikely to occur, no DNEL was derived. In addition, in an acute inhalation study, no local respiratory irritation was observed.

 

References

(not included as endpoint study record)

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.Version 2. ECHA-2010 -G-19 –EN.

- ECETOC (2010). Technical Report 110.Guidance on assessment factors to derive a DNEL.

according to Annex VI of Regulation EC 1272/2008 (CLP).

- Batke (2011). Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205, 122– 129

 

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