Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
17.5
Dose descriptor starting point:
NOAEL
Value:
57.4 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
50.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

For the inhalation route there is no animal study available. Therefore, oral rat data are used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a default factor of 2 is recommended according to ECHA Guidance (November 2012) R.8.4.2. According to Figure Figure R. 8-3 in the Guidance Document R.8 (ECHA, 2012) additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral NOAEL * 0.5 * 1/0.38 m³ per kg and day * 6.7 m³/10 m³ (based on the oral NOAEL of 57.4 mg/kg bw /day for parental toxicity obtained in a 2-generation study on rats with subchronic oral exposure the starting point is calculated with 50.6 mg/m³).

AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to ECHA Guidance (November 2012), R.8.4.3.1 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
1.4
Justification:
Difference in the experimental exposure duration (= subchronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to ECHA Guidance (November 2012) Chapter R. 8. Table R.8-5. The suggested factor of 2 for extrapolation of exposure duration subchronic to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in the Guidance Document R.8 (ECHA, 2012).
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in the Guidance Document R.8 (ECHA, 2012)
AF for intraspecies differences:
5
Justification:
According to ECHA Guidance (November 2012) Chapter R.8.4.3.1 the default AF to be applied for intraspecies differences in workers is 5.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by the Guidance Document R8 (ECHA, 2012)
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:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
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:
57.4 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
25 mg/m³
Explanation for the modification of the dose descriptor starting point:

For the inhalation route there is no animal study available. Therefore, oral rat data are used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a default factor of 2 is recommended according to ECHA Guidance (November 2012) R.8.4.2. According to Figure Figure R. 8-3 in the Guidance Document R.8 (ECHA, 2012) additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral NOAEL * 0.5 * 1/1.15 m³ per kg and day (based on the oral NOAEL of 57.4 mg/kg bw/day for parenal toxicity obtained in a 2-generation study on rats with subchronic oral exposure the starting point is calculated with 25 mg/m³).

AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to ECHA Guidance (November 2012), R.8.4.3.1 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
2
Justification:
Difference in the experimental exposure duration (= subchronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to ECHA Guidance (November 2012) Chapter R. 8. Table R.8-5. The suggested factor for extrapolation of exposure duration subchronic to chronic is 2.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in the Guidance Document R.8 (ECHA, 2012).
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in the Guidance Document R.8 (ECHA, 2012)
AF for intraspecies differences:
10
Justification:
According to ECHA Guidance (November 2012) Chapter R.8.4.3.1 the default AF to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by the Guidance Document R8 (ECHA, 2012)
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:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 mg/kg bw/day
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 000
Modified dose descriptor starting point:
other: LOEL
Value:
70.7 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Oral data from the rat are used to decide on a corresponding oral dose for humans. Therefore a route-to-route extrapolation is not necessary.

AF for dose response relationship:
5
Justification:
As the starting point for the DNEL calculation is a LOEL according to ECHA Guidance (November 2012), R.8.4.3.1 the default assessment factor for dose response relationship is 5.
AF for differences in duration of exposure:
2
Justification:
Difference in the experimental exposure duration (= subchronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to ECHA Guidance (November 2012) Chapter R. 8. Table R.8-5.
AF for interspecies differences (allometric scaling):
4
Justification:
According to ECHA Guidance (November 2012) R.8, Table R.8-3 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in the Guidance Document R.8 (ECHA, 2012)
AF for intraspecies differences:
10
Justification:
According to ECHA Guidance (November 2012) Chapter R.8.4.3.1 the default AF to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by the Guidance Document R8 (ECHA, 2012)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

The DNEL derived above for ‘long-term, systemic, oral exposure of the General Population’ is based on effects on the reproductive oestrus cycle in female rats seen in a 2-Generation Study that had no influences on reproductive performance. As such, starting with the LOEL of 70.7 mg/kg bw a DNEL of 0.07 mg/kg bw/day is calculated that should be considered as worst-case consideration.

If the overall NOAEL for general parental toxicity of the 2-Generation study is taken forward for DNEL derivation the starting dose is 57.4 mg/kg bw/day. The respective DNEL derivation is given below:

Oral NOAEL (rat) from a 2-Gen study (subchronic) toxicity study: 57.4 mg/kg bw/day

- Justification for route to route extrapolation:

Oral data from the rat are used to decide on a corresponding oral dose for humans. Therefore a route-to-route extrapolation is not necessary.

AF for dose response relationship: 1

- As the starting point for the DNEL calculation is a NOAEL according to ECHA Guidance (November 2012), R.8.4.3.1 the default assessment factor for dose response relationship is 1.

AF for difference in duration of exposure: 2

- Difference in the experimental exposure duration (= subchronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to ECHA Guidance (November 2012) Chapter R. 8. Table R.8-5.

AF for interspecies differences rat vs. human (allometric scaling): 4

According to ECHA Guidance (November 2012) R.8, Table R.8-3 the allometric scaling factor for the rat when compared with humans is 4.

AF for other interspecies differences: 2.5

- A factor of 2.5 for remaining interspecies differences is suggested in the Guidance Document R.8 (ECHA, 2012)

AF for intraspecies differences in workers: 10

- According to ECHA Guidance (November 2012) Chapter R.8.4.3.1 the default AF to be applied for intraspecies differences in the general population is 10.

AF for the quality of the whole database: 1

- Default assessment factor for good/standard quality of database as suggested by the Guidance Document R8 (ECHA, 2012)

Overall factor: 200 (2 x 4 x 2.5 x 10)

General Population

DNELlong-term, systemic for oral exposure: 0.29 mg/kg bw/day (57.4 mg/kg : 200)