Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.4 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):
50
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
370 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
4
Justification:
Since the OECD 422 Guideline study was conducted up to 63 days for females and 28 days for males and the study provides additional information on fertility and developmental toxicity in comparison to a OECD 407 Guideline study, an assessment factor of 4 ist justified.
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

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
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):
200
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
4
Justification:
Since the OECD 422 Guideline study was conducted up to 63 days for females and 28 days for males and the study provides additional information on fertility and developmental toxicity in comparison to a OECD 407 Guideline study, an assessment factor of 4 ist justified.
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:
medium hazard (no threshold derived)

Additional information - workers

Considering the Guidance on information requirements and chemical safety assessment, R.8 Characterisation of dose [concentration]-response for human health (May 2008) DNEL acute and DNEL long-term might be relevant for the chemical safety assessment.

 

Acute, systemic DNELs

The test item is not classified for acute systemic toxicity according to Regulation (EC) No 1272/2008 based on the available study results after oral exposure. No acute systemic toxicity after dermal exposure is to be expected based on the Category Approach with structural analogue compounds which belong to the same chemical class. Since no peak exposure is to be expected, the DNEL for acute sytemic (inhalation) is covered by the long term DNEL (systemic, inhalation). Thus, no hazard is identified for acute systemic exposure after inhalation and no DNEL has to be derived.

 

Acute/long term DNELs for local effects

 

Skin irritation/corrosion: The test item is not classified for skin irritation/corrosion according to Regulation (EC) No 1272/2008. Therefore, no hazard was identified.

 

Eye irritation: The test item is classified for eye irritation cat. 2 and labelled with H319 according to Regulation (EC) No 1272/2008. Therefore, the test item is allocated to the moderate hazard band according to the ECHA Guidance Document, Part E: Risk Characterisation (Ver. 3.0, May 2016).

 

Skin sensitization: The test item is not classified for skin sensitization according to Regulation (EC) No 1272/2008. Therefore, no hazard was identified.

 

Respiratory irritation: No experimental data on respiratory irritation are available. According to ECHA Guidance Doc R.7a, the term "respiratory tract irritation" is often used to indicate either or both of two different toxicological effects. These are i) cytotoxic effects in the affected tissue, and ii) sensory irritation. Cytotoxic effects in the respiratory tract are comparable to dermal and eye irritation. "Sensory irritation" refers to the local and central reflex interaction of a substance with the autonomic nerve receptors, which are widely distributed in the mucosal tissues of the eyes and upper respiratory tract.

Since the test item is classified for eye irritation according to Regulation (EC) No 1272/2008, the test item is allocated to the moderate hazard band according to the ECHA Guidance Document, Part E: Risk Characterisation (Ver. 3.0, May 2016).

 

Long term systemic DNEL - inhalation

a) Relevant dose descriptor - starting point

A sub-acute oral toxicity study in rats according to OECD 422 Guideline is available. The NOAEL was determined to be 300 mg/kg bw/d.

b) Modification of starting point

Since no experimental data on the relevant route of exposure are available, route-to-route extrapolation (oral to inhalative) has to be conducted taking into account the following parameters:

 

Standard respiratory volume rat (sRVrat) for 8 hours: 0.38 m3/kg bw/d

Standard respiratory volume of humans (sRVhumans) for 8 hours: 6.7 m3

Standard respiratory volume of workers (wRV) with light physical activity for 8 hours: 10 m3

Exposure conditions (rat): 7 days per week

Exposure conditions (worker): 5 days per week

Furthermore, a factor of 2 is applied for the potential higher bioavailability via inhalation compared to oral route (ABSoral-rat/ABSinhal-human = 50%/100% = 0.5) according to Guidance on information requirements and chemical safety assessment, chapter R.8.

Corrected NOAEC (inhal) for workers = 300 mg/kg bw/d * (1/0.38 m3/kg bw/d) * (6.7 m3/10 m3) * 0.5 * (7 d/5 d) = 370 mg/m3.

 

c) Assessment factors: 50

Dose response relationship: 1 (default)

Duration of exposure: 4

Interspecies differences (allometric): 1 (default)

Other interspecies differences: 2.5 (default)

Intraspecies differences: 5 (default)

 

By applying an assessment factor of 50, the inhalatory DNEL for workers is considered to be 7.4 mg/m3.

 

Long term systemic DNEL - dermal

 

a) Relevant dose descriptor - starting point

A sub-acute oral toxicity study in rats according to OECD 422 Guideline is available. The NOAEL was determined to be 300 mg/kg bw/d.

b) Modification of starting point

Since no experimental data on the relevant route of exposure are available, route-to-route extrapolation (oral to dermal) has to be conducted taking into account the following parameters:

 

Exposure conditions (rat): 7 days per week

Exposure conditions (worker): 5 days per week

 

For oral-to-dermal extapolation a default factor of 1 (ABSoral-rat/ABSdermal-human) was used as in general dermal absorption will not be higher than oral absorption (Guidance on information requirements and chemical safety assessment, chapter R.8).

Corrected NOAEL (dermal) for workers = 300 mg/kg bw/d * 1 * (7 d/5 d) = 420 mg/kg bw/d

 

c) Assessment factors: 200

Dose response relationship: 1 (default)

Duration of exposure: 4

Interspecies differences (allometric): 4 (default)

Other interspecies differences: 2.5 (default)

Intraspecies differences: 5 (default)

 

By applying an assessment factor of 200, the DNEL (dermal) for workers is considered to be 2.1 mg/kg bw/d.

 

References

1) Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7a: Endpoint specific guidance, Version 6.0, July 2017, ECHA-17 -G-18 -EN

2) Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, Nov 2012, ECHA-2010 -G-19 -EN

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
DNEL related information
Justification:
Default (DNEL calculator)
Justification:
Default (DNEL calculator)
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