Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 012 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):
12.5
Dose descriptor starting point:
NOAEL
DNEL value:
50 307 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
25 153 mg/m³
Explanation for the modification of the dose descriptor starting point:

To the starting point, adjustments are applied for study duration (6 hr/day) and normal workday schedule (8 hr/day), and normal human to worker respiratory volume correction for light activity (6.7 m3/10 m3) per REACH guidance R.8.4.2.  With these two factors, 6/8 and 6.7/10, the starting point modification is 0.50.

AF for dose response relationship:
1
Justification:
NOAEL is available from the 90-day inhalation study and therefore the default AF, i.e., 1, is used, given the determination of NOAEL didn't fall into the specific cases described in REACH guidance R.8.4.3.1.
AF for differences in duration of exposure:
1
Justification:
The default AF of 2 (to address the difference in duration of exposure when converting from a 90-d inhalation study [subchronic] to worker life-time [chronic] exposure) per REACH guidance R.8.4.3.1 is not needed. Instead, the use of an AF of 1 is supported by the existence of a two-generation rat inhalation reproductive toxicity study. In this study, exposure to 12,500 ppm for ~130 days (6 hrs/day, 7 days/week) resulted in 2 (out of 30) male deaths and 0 (out of 30) female deaths (overall mortality rate of 3.3%). This is comparable to or even less adverse than 3 (out of 20) male deaths and 0 (out of 20) female deaths (overall mortality rate of 7.5%) in the 90-day inhalation study after ~65 exposures (6 hrs/day, 5 days/week) to 15,000 ppm. The critical effect (mortality) as noted in the 90-day inhalation study was not adversely impacted by longer exposure duration (i.e., increasing the frequency and duration of exposure did not adversely affect the incidence or severity of the critical effect). Therefore, an assessment factor of 1 is an appropriate value for study duration per REACH guidance R.8.4.3.1. 
AF for interspecies differences (allometric scaling):
1
Justification:
Since the starting point is an inhalation study in animals, no further assessment factor for allometric scaling is necessary for inhalation to inhalation route of exposure extrapolation per REACH guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
An assessment factor of 2.5 is appropriate to adjust for the variation in the sensitivity of species due to differences in toxicodynamics per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
A default factor of 5 for workers is appropriate according to REACH guidance in R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
A robust database exists for the substance . An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 249 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
NOAEC
DNEL value:
97 930 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
165 334 mg/m³
Explanation for the modification of the dose descriptor starting point:

To the starting point, adjustments are applied for normal human to worker respiratory volume correction for light activity (6.7 m3/10 m3) per REACH guidance R.8.4.2.  

AF for dose response relationship:
1
Justification:
NOAEC is available from the acute inhalation study and therefore the default AF, i.e., 1, is used, given the determination of NOAEC didn't fall into the specific cases described in REACH guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
1
Justification:
Since the starting point is an inhalation study in animals, no further assessment factor for allometric scaling is necessary for inhalation to inhalation route of exposure extrapolation per REACH guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
An assessment factor of 2.5 is appropriate to adjust for the variation in the sensitivity of species due to differences in toxicodynamics per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
A default factor of 5 for workers is appropriate according to REACH guidance in R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
NOAEC was derived from a GLP, guidelined study. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

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:
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
359 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):
25
Dose descriptor starting point:
NOAEL
DNEL value:
50 306 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
8 981 mg/m³
Explanation for the modification of the dose descriptor starting point:

To the starting point, adjustments are applied to convert study duration (6 hr/day, 5 day/week) to whole day & week exposure (24 hr/day, 7 day/week) per REACH guidance R.8.4.2.  With these two factors, 6/24 and 5/7, the starting point modification is 0.1786.

AF for dose response relationship:
1
Justification:
NOAEL is available from the 90-day inhalation study and therefore the default AF, i.e., 1, is used, given the determination of NOAEL didn't fall into the specific cases descibed in REACH guidance R.8.4.3.1.
AF for differences in duration of exposure:
1
Justification:
The default AF of 2 (to address the difference in duration of exposure when converting from a 90-d inhalation study [subchronic] to general population life-time [chronic] exposure) per REACH guidance R.8.4.3.1 is not needed. Instead, the use of an AF of 1 is supported by the existence of a two-generation rat inhalation reproductive toxicity study. In this study, exposure to 12,500 ppm for ~130 days (6 hrs/day, 7 days/week) resulted in 2 (out of 30) male deaths and 0 (out of 30) female deaths (overall mortality rate of 3.3%). This is comparable to or even less adverse than 3 (out of 20) male deaths and 0 (out of 20) female deaths (overall mortality rate of 7.5%) in the 90-day inhalation study after ~65 exposures (6 hrs/day, 5 days/week) to 15,000 ppm. The critical effect (mortality) as noted in the 90-day inhalation study was not adversely impacted by longer exposure duration (i.e., increasing the frequency and duration of exposure did not adversely affect the incidence or severity of the critical effect). Therefore, an assessment factor of 1 is an appropriate value for study duration per REACH guidance R.8.4.3.1. 
AF for interspecies differences (allometric scaling):
1
Justification:
Since the starting point is an inhalation study in animals, no further assessment factor for allometric scaling is necessary for inhalation to inhalation route of exposure extrapolation per REACH guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
An assessment factor of 2.5 is appropriate to adjust for the variation in the sensitivity of species due to differences in toxicodynamics per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
A default factor of 10 for general population is appropriate according to REACH guidance in R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
A robust database exists for the substance. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.
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
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