Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEC
Value:
250 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
176 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are reliable experimental data on repeated exposure by inhalation. No route to route extrapolation is needed, but an adaptation of the inhalation human NOAEC to the experimental design was performed (see also discussion).
AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
6
Justification:
Default value for time extrapolation from sub-acute to chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not necessary as no route to route extrapolation is applied and doses expressed as concentrations are assumed to be already scaled
AF for other interspecies differences:
1
Justification:
No evidence for other interspecies differences
AF for intraspecies differences:
5
Justification:
The default value for "worker" is used
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and reliable (GLP Guideline study)
AF for remaining uncertainties:
1
Justification:
Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

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:
4.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEL
Value:
145 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No repeated dose toxicity study with dermal application is available. Therefore an inhalation-to-dermal extrapolation is done.
AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
6
Justification:
Default value for time extrapolation from sub-acute to chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not necessary as those differences are already applied during route-to-route extrapolation.
AF for other interspecies differences:
1
Justification:
No evidence for other interspecies differences
AF for intraspecies differences:
5
Justification:
The default value for "worker" is used
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and reliable (GLP Guideline study)
AF for remaining uncertainties:
1
Justification:
Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1
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

Occupational exposure to the test substance occurs mainly by dermal as well as inhalation exposure. Therefore two long-term DNELs are calculated for workers.

Inhalation long-term exposure – systemic effects:

The systemic NOAEC from a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test in rats via inhalation conducted according to OECD 422 (BASF SE 2015) was identified as the appropriate starting point for a systemic DNEL derivation for long-term exposure following inhalation. The NOAEC for general, systemic toxicity of the test substance was 250 mg/m³/d for rats which was the mid dose tested.

This point of departure was modified to get the corrected starting point for DNEL derivation as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, v 2.1, Nov. 2012":

The inhalation rat NOAEC was converted into the corrected inhalation human NOAEC:

No difference in bioavailability between humans and rats are assumed, same route of exposure.

- Differences in exposure conditions (6 h/day in rat inhalation study versus occupational exposure 8 h/day): factor 6/8 = 0.75

- Differences in exposure conditions (7 d/week in rat inhalation study versus weekly occupational exposure 5 d/week): factor 7/5 = 1.4

- Differences in respiratory volumes between experimental animals (at rest) and humans (light activity): respiratory volume in humans during 8 h at rest is 6.7 m³ versus 10 m³ for 8 h at light activity in workers; factor 6.7/10 = 0.67

 

NOAEC x 0.75 x 1.4 x 0.67 = 250 mg/m³ x 0.7035 = 176 mg/m³

 

The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 176 mg/m³/d.

 

Afterwards, the assessment factors were applied according to the "Guidance on information requirements and chemical safety assessment", Chapter R.8, v 2.1, Nov. 2012.

 

Dermal long-term exposure – systemic effects:

The systemic NOAEC from a combined repeated dose toxicity study with the reproduction / developmental toxicity screening test in rats via inhalation conducted according to OECD 422 (BASF SE 2015) was identified as the appropriate starting point for a systemic DNEL derivation for long-term exposure following inhalation. The NOAEC for general, systemic toxicity of the test substance was 250 mg/m³/d for rats which was the mid dose tested.

This point of departure was modified to get the corrected starting point for DNEL derivation as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, v 2.1, Nov. 2012":

The inhalation rat NOAEC was converted into the dermal human NOAEL, which was calculated using the default respiratory volume reflecting the daily exposure period of the rats during the study (6 h). The double absorption rate was assumed for the inhalation (rat) compared to the dermal route (human) in the following approach.

 

NOAEL (dermal-rat) = NOAEC x (sRVrat) x (ABSinhal-rat/ABSdermal-human)= 250 mg/m³ x (0.29 m³/kg bw/d) x (2/1) = 145 mg/kg bw/d

- Standard dose descriptor (NOAEC): 250 mg/m³

- Standard respiratory volume of the rat (sRVrat) for 6 hours: 0.29 m³/kg bw/d

- Inhalation absorption of the rat/dermal absorption of humans (ABSinhal-rat)/ABSdermal-human): 2/1

 

Afterwards, the assessment factors were applied according to the "Guidance on information requirements and chemical safety assessment", Chapter R.8, v 2.1, Nov. 2012.

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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:
no hazard identified
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

Not applicable; the test substance is only used in industrial settings.