Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.16 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):
25
Dose descriptor starting point:
NOAEL
Value:
145 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
178.96 mg/m³
Explanation for the modification of the dose descriptor starting point:

Due to the low vapour pressure of the test substance acute exposure hazard via inhalation is unlikely for humans. Therefore a route-to -route extrapolation from an oral repeated dose study in rats (90 days) as a worst case is justified. The oral NOAEL of 145 mg/kg bw/day was corrected for exposure days per week (7d/w to 5d/w; factor *7/5), absorption (assumption according to ECHA Guidance R.8: 50% absorbed oral, 100 % absorbed via inhalation; factor: 1/2), respirator volume (factor *1/0.38) and respiratory volume for light activity within 8h (6.7m3/10m3; factor * 6.7/10).

corrected NOAEC = 145 mg/kgbw/d / 0.38 m3/kg bw * (6.7 / 10) m3/d * 1/2 * 7d/5d = 168.96 mg/m3.

A corrected NOAEC of 178.96 mg/m3 is derived.

AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling is integrated in the corrected starting point
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
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:
0.66 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
87.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
65.63 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Long-term systemic DNEL for dermal route has been derived from the NOAEL of 87.5 mg/kg bw established in the dermal 3-month study in rats (NTP, 2012). The substance is systemically available by the oral and dermal route and caused decreased body weights and body weight gains and dermal irritation in the treated animals in the two highest dose groups (175 and 350 mg/kg bw). Treatment-related lesions of the skin were limited to the site of application. There were increased incidences of epidermal hyperplasia, hyperkeratosis, chronic active inflammation, epidermal necrosis, and sebaceous gland hypertrophy in dosed groups of males and females. The substance produced no changes in haematology or clinical chemistry. As seen in the acute dermal study in rats, the substance was not systemically toxic by the dermal route and it has also been shown to be of lower systemic toxicity after prolonged exposure with the skin. The starting point for the DNEL derivation is the dermal NOAEL.

This NOAEL is corrected for the duration of exposure (6 h in animal test vs. 8 h exposure for workers):

87.5 mg/kg bw/day * 6 h/8 h = 65.63 mg/kg bw/day

AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
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)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

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:
1.26 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:
145 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
63.04 mg/m³
Explanation for the modification of the dose descriptor starting point:

Due to the low vapour pressure of the test substance acute exposure hazard via inhalation is unlikely for humans. Therefore a route-to -route extrapolation from an oral repeated dose study ( 90 days) as a worst case is justified. The oral NOAEL of 145 mg/kg bw/day was corrected for absorption (assumption according to ECHA Guidance R.8: 50% absorbed oral, 100 % absorbed via inhalation; factor: 1/2), respiratory volume (factor *1/0.38) and respiratory volume for within 24 h (factor * 1/1.15).

corrected NOAEC = 145 mg/kg bw/d / 1.15 m3/kg bw * 1/2 = 63.04 mg/m3.

A corrected NOAEC of 63.04 mg/m3is derived.

AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling is integrated in correction of starting point
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The acute toxicity is sufficiently covered by the DNEL for the long-term toxicity.

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:
DNEL (Derived No Effect Level)
Value:
78.13 µg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
87.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
15.63 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Long-term systemic DNEL for dermal route has been derived from the NOAEL of 87.5 mg/kg bw established in the dermal 3-month study in rats (NTP, 2012). The substance is systemically available by the oral and dermal route and caused decreased body weights and body weight gains and dermal irritation in the treated animals in the two highest dose groups (175 and 350 mg/kg bw). Treatment-related lesions of the skin were limited to the site of application. There were increased incidences of epidermal hyperplasia, hyperkeratosis, chronic active inflammation, epidermal necrosis, and sebaceous gland hypertrophy in dosed groups of males and females. The substance produced no changes in haematology or clinical chemistry. As seen in the acute dermal study in rats, the substance was not systemically toxic by the dermal route and it has also been shown to be of lower systemic toxicity after prolonged exposure with the skin. The starting point for the DNEL derivation is the dermal NOAEL.

This NOAEL is corrected for the duration of exposure (6 h in animal test vs. 24 h exposure for workers; 5 d/week in animal test and 7 days/week for general population):

87.5 mg/kg bw/day * 6 h/24 h * 5 d/7 d= 15.63 mg/kg bw/day

AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The acute toxicity is sufficiently covered by the DNEL for the long-term toxicity.

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
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:
0.725 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:
145 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
145 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The oral rat NOAEL of 145 mg/kg bw derived in a subchronic study (NTP 2012) served as the starting point for the DNEL derivation. The NOAEL was not modified (oral absorption rat = oral absorption human), since no substance- and route specific information on absorption is available.

AF for dose response relationship:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for differences in duration of exposure:
2
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for interspecies differences (allometric scaling):
4
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for other interspecies differences:
2.5
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for intraspecies differences:
10
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for the quality of the whole database:
1
Justification:
in accordance with the principles given in ECHA R8 (2010)
AF for remaining uncertainties:
1
Justification:
no remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The acute toxicity is sufficiently covered by the DNEL for the long-term toxicity.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population