Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
13 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
25.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
335 mg/m³
AF for differences in duration of exposure:
3.4
Justification:
Minimal toxicological profile justifies factor of 3.4 to extrapolate from sub-acute to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable for inhalation
AF for other interspecies differences:
2.5
AF for intraspecies differences:
3
AF for the quality of the whole database:
1
Justification:
Multiple reliable guideline studies are available with consistent results
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
102
Modified dose descriptor starting point:
NOAEL
DNEL value:
400 mg/kg bw/day
AF for differences in duration of exposure:
3.4
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
3
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:
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

DNELs for Acute (local and systemic) and Repeated exposure (Local):

These DNELs are not relevant for this substance. The acute toxicity values are in excess of 21000 mg/m3 (inhalation) and 7000 mg/kg bw (oral and dermal) and in the acute inhalation toxcity study (and repeated dose inhalation study) there was no evidence of narcotic effects at any dose level. As such acute exposure scenarios for this substance are not considered relevant. In addition, the substance is not irritating to the eyes, skin or respiratory tract and therefore there are no data on which to base DNELs for local effects.

DNELs Repeated dose inhalation and dermal

Key study selection:

In the repeated dose toxicity section there are 2 available studies - the first a 28 day oral study that was not performed specifically to the OECD guideline, but had a specific focus on testicular toxicity. The second an inhalation study according to the standard OECD guideline for the 28 -day stdy. In the oral study, although the study was not to the specific guideline, it was thorough in its assessment of systemic toxicity and reported a NOEL of 200 mg/kg bw/day.

In the inhalation study the NOEC was the mid dose of 500 mg/m3 for the females and the high dose of 1500 mg/m3 for the males. In the high dose females the only change was a temporary drop in bodyweight that was not considered to be a significant adverse effect.

For the purposes of calculating the DNELs the NOELs from both studies were used to determine the 'adjusted starting point' for the inhalation DNEL.

based on the inhalation study, the adjusted starting point = 500 mg/m3 * 6.7/10 = 335 mg/m3

based on the oral study, the adjusted starting point = 200/0.38 * 6.7/10 = 352 mg/m3

Given the consistency between the 2 adjusted Inhalation starting points, the inhalation study NOEC of 500 mg/m3 will be chosen as the starting point for the inhalation DNELs and the oral study for the dermal DNELs (since route to route extrapolation from oral to dermal is marginally more reliable than inhalation to dermal).

Inhalation DNEL, repeated exposure, systemic toxicity:

Revised starting point = 335 mg/m3

Assessment factors:

Allometric scaling = not applicable

'Other differences' = 2.5

Duration = 3.4 - based on the publication from Batke et al 2011 (Toxicology Letters 205, 122 -129) an analysis of repeated dose toxicity studies demonstrates that a factor of 3.4 is acceptable in the majority of cases to extrapolate from a sub acute study to the chronic exposure situation. Given the minimal toxicological profile of this substance, deviating from the ECHA default is justified in this case.

Worker variability = 3 - Given the minmial toxicological profile for this substance and the absence of any significant findings in the available studies, a deviation from the ECHA default factor of 5 to the value used by SCOEL and proposed by ECETOC is justified.

quality of database = 1 - multiple reliable guideline studies are available with consistent results.

Total factor: 25.5

Inhalation DNEL = 335 / 25.5 = 13 mg/m3

Dermal DNEL, repeated exposure, systemic toxicity

Revised starting point = 400 mg/kg bw (assuming 50% dermal penetration and 100% oral absorption)

Assessment factors:

Allometric scaling = 4

'Other differences' = 2.5

Duration = 3.4 - based on the publication from Batke et al 2011 (Toxicology Letters 205, 122 -129) an analysis of repeated dose toxicity studies demonstrates that a factor of 3.4 is acceptable in the majority of cases to extrapolate from a sub acute study to the chronic exposure situation. Given the minimal toxicological profile of this substance, deviating from the ECHA default is justified in this case.

Worker variability = 3 - Given the minmial toxicological profile for this substance and the absence of any significant findings in the available studies, a deviation from the ECHA default factor of 5to the value used by SCOEL and proposed by ECETOC is justified.

quality of database = 1 - multiple reliable guideline studies are available with consistent results.

Total factor = 102

Dermal DNEL = 400/102 = 4 mg/kg bw (rounded up)

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

No consumer DNELs calculated due to the lack of consumer or general population exposure scenarios.