Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
184.4 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):
6
Dose descriptor starting point:
NOAEL
Value:
1 255 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 106.4 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. Starting point: NOAEL of 1255 mg/kg bw/day in a 1-year repeated dose 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 = 1255 * 1/0.38 m3/kg/8h * ABSoral-rat /ABSinhal-human * 6.7 m3(8h)/10 m3(8h) = 1255 * 1/0.38 m3/kg/8h * 50/100 * 6.7 m3(8h)/10 m3(8h) = (1255 /0.38) * 0.5 * (6.7/10) = 1106.4 mg/m3.

With ABS: Absorption, sRV: Standard Respiratory Volume; wRV: Worker Respiratory Volume;

ABSoral-rat /ABSinhal-human= 50/100= 0.5, 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:
1
Justification:
Data from chronic study
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:
3
Justification:
Difference in sensitivity among workers
AF for the quality of the whole database:
2
Justification:
Reliable studies used, data from substance analogue (read across)
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:
52.3 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):
24
Dose descriptor starting point:
NOAEL
Value:
1 255 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 255 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and dermal intake in the absence of evidence of the opposite.Correction dermal NOAEL: 1255 x 50/50a= 1255 mg/kg bw/day (a% oral/dermal absorption)

AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
1
Justification:
Data from chronic study
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:
3
Justification:
Difference in sensitivity among workers
AF for the quality of the whole database:
2
Justification:
Reliable studies used, data from substance analogue (read across)
AF for remaining uncertainties:
1
Justification:
No remaining differences
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:
54.6 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):
10
Dose descriptor starting point:
NOAEL
Value:
1 255 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
545.7 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 

= 1255 * 1/1.15 m3/kg * ABSoral-rat /ABSinhal-human

= 1255 * 1/1.15 m3/kg * 0.5 = 545.7 mg/m3

 

With ABS: Absorption, sRV: Standard Respiratory Volume; ABSoral-rat /ABSinhal-human= 50/100= 0.5, 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:
1
Justification:
No extrapolation needed, results from chronic study used
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:
2
Justification:
Reliable studies used, data from substance analogue (read across)
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:
31.4 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):
40
Dose descriptor starting point:
NOAEL
Value:
1 255 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 255 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and dermal intake in the absence of evidence of the opposite.Correction dermal NOAEL: 1255 x 50/50a= 810 mg/kg bw/day (a% oral/dermal absorption).

AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
1
Justification:
No extrapolation, data from chronic study
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 within general population
AF for the quality of the whole database:
2
Justification:
Reliable studies used, data from substance analogue (read across)
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:
31.4 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):
40
Dose descriptor starting point:
NOAEL
Value:
1 250 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Value is NOAEL
AF for differences in duration of exposure:
1
Justification:
No extrapolation, data from chronic study
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:
2
Justification:
Reliable studies used, data from substance analogue (read across)
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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