Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.3 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
DNEL value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
881.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic effects in workers after long-term inhalation exposure to the test item was derived via route-to-route extrapolation from the lowest NOAEL obtained in the sub-chronic (90-day) oral repeated dose toxicity study in rats (1000 mg/kg bw/day) with the read-across substance bismuth subnitrate. To convert the oral NOAEL in rats to an inhalation NOAEC in humans, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38m3/kg bw/8h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-hour exposure period) and under conditions of light activity (wRV: 10 m3for an 8-hour exposure period); extrapolation from 50% bioavailability oral to 100% bioavailability inhalation. Therefore, inhalatory NOAEC = oral NOAEL*(1/sRVrat 8h)*(ABSoral/ABSinh)*(sRVhuman/wRV) OR 1000*(1/0.38)*(50/100)*(6.7/10) = 881.6 mg/m3. Therefore, DNEL = Corrected inhalation NOAEC (881.6 mg/m3)*(1/25{Overall AF}) = 35.3 mg/m3.

AF for dose response relationship:
1
Justification:
Not required as starting point is NOAEL
AF for differences in duration of exposure:
2
Justification:
Default for sub-chronic in animals to chronic in humans
AF for interspecies differences (allometric scaling):
1
Justification:
Not required when route to route extrapolation is conducted
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining differences
AF for intraspecies differences:
5
Justification:
Default factor for workers
AF for the quality of the whole database:
1
Justification:
Not required. Source study K1 and data confirmed in the 28-day toxicity study also
AF for remaining uncertainties:
1
Justification:
Not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 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):
100
Dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The DNEL for systemic effects in workers after long-term dermal exposure to the test item was derived via route-to-route extrapolation from the lowest NOAEL of 1000 mg/kg bw/day obtained in the sub-chronic (90-day) oral repeated dose toxicity study in rats with the read-across substance bismuth subnitrate. Therefore, DNEL = 1000 mg/kg bw/day*(1/2{exposure duration sub-chronic to chronic}*4{allometric scaling rat-human}*2.5{interspecies differences}*5{intraspecies differences-worker population}) = 10.0 mg/kg bw/day. This is considered to be the worst-case scenario assuming similar potential for dermal absorption compared to oral at this level.

AF for dose response relationship:
1
Justification:
Not required as starting point is NOAEL
AF for differences in duration of exposure:
2
Justification:
Conversion of sub-chronic in animals to chronic in humans
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to human
AF for other interspecies differences:
2.5
Justification:
Default factor for remaining differences
AF for intraspecies differences:
5
Justification:
Default factor for workers
AF for the quality of the whole database:
1
Justification:
Not required. Source study K1 and data confirmed in the 28-day toxicity study
AF for remaining uncertainties:
1
Justification:
Not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

The basis for the inhalation and dermal systemic DNELs for worker exposure to the test item is an oral sub-chronic 90-day repeated dose toxicity study in rats with the read-across substance, bismuth subnitrate, from which the lowest NOAEL was determined to be 1000 mg/kg bw/day. This dose level was the highest dose level tested and there were no changes considered to be related to treatment with the read-across test item. The lowest NOAEL (No Observed Adverse Effect Level) of 1000 mg/kg bw/day was used as the basis of the DNEL calculations using appropriate assessment factors for relevant indicators including route to route extrapolation, allometric scaling, exposure duration and study length.

For local effects it is considered that the systemic DNEL for inhalation exposure would be protective for this exposure in the absence of specific data. For dermal exposure the combination of phys-chem data and in vitro skin irritation studies with the target material, bismuth silicate, would indicate only a low hazard.

General Population - Hazard via inhalation 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
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