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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.37 mg/m³
Most sensitive endpoint:
effect on fertility
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:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
18.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

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): 1/2 (default)

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

Corrected NOAEC (inhalation) for workers:

= 15 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 18.5 mg/m3

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
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 49 days for females and 42 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:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

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 after oral route and the group of LCs do not show acute systemic toxicity after dermal exposure.

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:
0.105 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
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:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
21 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Modification into a correct starting point:

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

There are no relevant experimental data on repeated dermal exposure. A conservative approach is used assuming identical dermal and oral absorption values even though a low dermal absorption value can be expected due to the physico- chemical properties of the test item.

Corrected NOAEL (dermal) for workers:

= 15 mg/kg bw/day x 1.4

= 21 mg/kg bw/day

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
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 49 days for females and 42 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:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
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

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:

Two subacute repeated dose toxicity studies are available with the test item:

-      OECD 407 (28-d): NOAEL 300 mg/kg bw/d

-      OECD 422 (up to 49-d): NOAEL 15 mg/kg bw/d for reproductive performance and systemic toxicity (Read Across)

Although a repeated dose toxicity study is available for the test item, the NOAEL (15 mg/kg bw/d) of the Read Across substance was chosen for DNEL derivation as it is considered to reflect the worst case.

Step 1:PoD: NOAEL = 15 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): 1/2 (default)

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

Corrected NOAEC (inhalation) for workers:

= 15 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x 1.4

= 18.5 mg/m3

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 49 days for females and 42 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: 1
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.

In conclusion,long term systemic inhalation DNEL, workers = 0.37 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)

No data on respiratory irritation are available. 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 15 mg/kg bw/day derived from an OECD TG 422 study performed with the test item was used as the Point of Departure following the same considerations as for DNEL inhalation.

Step 1:PoD: NOAEL = 15 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.

There are no relevant experimental data on repeated dermal exposure. A conservative approach is used assuming identical dermal and oral absorption values even though a low dermal absorption value can be expected due to the physico- chemical properties of the test item.

Corrected NOAEL (dermal) for workers:

= 15 mg/kg bw/day x 1.4

= 21 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 49 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 = 0.105 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 not classified for skin irritation or skin sensitization. Therefore, no DNEL for short or long term local dermal exposure is required.

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:
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

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:
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

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:
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 for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population