Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
18
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
176.32 mg/m³
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite.

Calculation dose descriptor starting point:

Starting point: NOAEL of 100 mg/kg bw/day in a 28-day repeated dose toxicity study in rat.

 Conversion of an oral NOAEL into a corrected NOAEC:

 For workers (8h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human * sRVhuman/wRV

 = 100 * 1/0.38 m3/kg/8h * ABSoral-rat /ABSinhal-human * 6.7 m3(8h)/10 m3(8h)

 = 100 * 1/0.38 m3/kg/8h * 1 * 6.7 m3(8h)/10 m3(8h)

 = 100 /0.38 * 1* (6.7/10) = 176.32 mg/m3.

 With ABS: Absorption, sRV: Standard Respiratory Volume; wRV: Worker Respiratory Volume; ABSoral-rat /ABSinhal-human= 100/100= 1, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure worker
AF for interspecies differences (allometric scaling):
1
Justification:
No correction for caloric demand for inhalation; included in dose descriptor starting point.
AF for other interspecies differences:
1
Justification:
No remaining differences.
AF for intraspecies differences:
3
Justification:
Difference in sensitivity among workers.
AF for the quality of the whole database:
1
Justification:
Reliable studies used.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.2 mg/kg bw/day
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
60
Dose descriptor starting point:
other: EC 1.6: 22%
Modified dose descriptor starting point:
LOAEL
Value:
132 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Corrected NOAEL = 22 % x 250 µg/cm2 = 5500 µg/cm2

The above is based on 22 µl of test substance applied onto 1 cm2area of a mouse ear, and a test substance density of 1.

Modification of the DNEL from µg/cm2to mg/kg bw/day:

Average mouse body weight: 30 g (TNO report V98.390)

Average total body surface mouse: 36 cm2 (TNO report V98.390)

Dose is applied on approximately 1 cm2of body surface.

5500 µg/cm2/day = 5.5 / (0.03/0.72) = 132 mg/kg bw/day

AF for dose response relationship:
2
Justification:
Value is a LOAEL.
AF for differences in duration of exposure:
1
Justification:
Duration of exposure is not a relevant parameter for skin sensitizing effect.
AF for interspecies differences (allometric scaling):
10
Justification:
Specific assessment factor for skin sensitization.
AF for other interspecies differences:
1
Justification:
No remaining differences.
AF for intraspecies differences:
3
Justification:
Difference in sensitivity among workers.
AF for the quality of the whole database:
1
Justification:
Reliable studies used.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
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:
2.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
86.96 mg/m³
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite. For the general population (24h exposure/day), the corrected inhalatory NOAEC = oral NOAEC * 1/sRVrat * ABSoral-rat /ABSinhal-human

= 100 * 1/1.15 m3/kg * ABSoral-rat /ABSinhal-human

= 100 * 1/1.15 m3/kg * 1 = 86.96 mg/m3

With ABS: Absorption, sRV: Standard Respiratory Volume; ABSoral-rat /ABSinhal-human= 100/100= 1, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:
1
Justification:
Value is NOAEL.
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure general population.
AF for interspecies differences (allometric scaling):
1
Justification:
No correction for caloric demand for inhalation; is included in dose descriptor starting point.
AF for other interspecies differences:
1
Justification:
No remaining differences.
AF for intraspecies differences:
5
Justification:
Difference in sensitivity within general population.
AF for the quality of the whole database:
1
Justification:
Reliable studies used.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

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:
1.32 mg/kg bw/day
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
100
Dose descriptor starting point:
other: EC 1.6 = 22%
Modified dose descriptor starting point:
LOAEL
Value:
132 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Corrected NOAEL = 22 % x 250 µg/cm2 = 5500 µg/cm2

The above is based on 22 µl of test substance applied onto 1 cm2area of a mouse ear, and a test substance density of 1.

Modification of the DNEL from µg/cm2to mg/kg bw/day:

Average mouse body weight: 30 g (TNO report V98.390)

Average total body surface mouse: 36 cm2(TNO report V98.390)

Dose is applied on approximately 1 cm2of body surface.

5500 µg/cm2/day = 5.5 / (0.03/0.72) = 132 mg/kg bw/day

AF for dose response relationship:
2
Justification:
Value is LOAEL.
AF for differences in duration of exposure:
1
Justification:
Duration of exposure is not a relevant parameter for skin sensitizing effect.
AF for interspecies differences (allometric scaling):
10
Justification:
Specific assessment factor for skin sensitization.
AF for other interspecies differences:
1
Justification:
No remaining differences.
AF for intraspecies differences:
5
Justification:
Difference in sensitivity within general population.
AF for the quality of the whole database:
1
Justification:
Reliable studies used.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
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:
DNEL (Derived No Effect Level)
Value:
0.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Value is NOAEL.
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
Correction for caloric demand from rat to human.
AF for other interspecies differences:
1
Justification:
No remaining differences.
AF for intraspecies differences:
5
Justification:
Difference in sensitivity among general population.
AF for the quality of the whole database:
1
Justification:
Reliable studies used.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/kg bw/day
DNEL related information
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population