Bismuth citrate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.8 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

93.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of the dose descriptors is necessary, because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose the default respiratory volume for the rat corresponding to the daily duration of human exposure is considered in the first step, followed by a correction for the difference between respiratory rates of workers under standard conditions and under light activity in the second step. NAECcorr_inh = oral NOAEL (1000) x 1/0.38 m3/kg bw x 6.7 m3/10 m3 = 1763 mg/m3. Oral absorption is very low in rats and can per default be assumed at about 0.5 % (D’Souza and Francis, 1987). The estimated percentage of bismuth citrate absorbed via inhalation is in the range 5.0% to 9.4% (see Chapter 7.1 Toxicokinetics for explanation). Therefore, correction factor for differences in the rates of absorption for the oral and the inhalation routes in rats and humans is: ABS human-inhalation ÷ ABS rat-oral = 9.4/0.5 = 18.8. Therefore, NAECcorr_inh = 1763 mg/m3/18.8 = 93.8 mg/m3.

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for differences in duration of exposure:

2

Justification:

Default assessment factor for extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling required for inhalation route.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor

AF for intraspecies differences:

5

Justification:

Default assessment factor of 5 for workers

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

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:

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

There is a 90 day repeated dose oral toxicity study (OECD 408) available, which characterised the potential toxic effects of read-across substance, bismuth subnitrate. A NOAEL of 1000 mg/kg bw/day was established for bismuth subnitrate in this study based on the lack of toxicologically relevant effects at the highest dose tested. There is also a prenatal developmental toxicity study (OECD 414) available for the read-across substance, bismuth subnitrate. In this study, the NOEL for maternal toxicity was considered to be 1000 mg/kg bw/day. No treatment-related changes were detected in the offspring parameters measured therefore the NOEL for developmental toxicity was also considered to be 1000 mg/kg bw/day. The NOAEL from the 90 day study is selected as the starting point for DNEL derivation for long-term systemic effects via inhalation because this is the study with the longest duration. No dermal DNELs were derived as dermal absorption of bismuth is expected to be negligible and bismuth citrate was shown to be not irritating to the skin in an in vitro test. Local and acute inhalation DNELs were not derived because an acute inhalation study with read-across substance, dibismuth trioxide, in rats did not indicate any local or significant systemic effects up to the threshold of 5 mg/l air.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.9 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

46.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of the dose descriptors is necessary, because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose the default respiratory volume for the rat corresponding to the daily duration of human exposure is considered in the first step. NAECcorr_inh = oral NOAEL (1000) x 1/1.15 m3/kg bw = 869.6 mg/m3. Oral absorption is very low in rats and can per default be assumed at about 0.5 % (D’Souza and Francis, 1987). The estimated percentage of bismuth citrate absorbed via inhalation is in the range 5.0% to 9.4% (see Chapter 7.1 Toxicokinetics for explanation). Therefore, correction factor for differences in the rates of absorption for the oral and the inhalation routes in rats and humans is: ABS human-inhalation ÷ ABS rat-oral = 9.4/0.5 = 18.8. Therefore, NAECcorr_inh = 869.6 mg/m3/18.8 = 46.3 mg/m3.

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for differences in duration of exposure:

2

Justification:

Default assessment factor for extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling required for inhalation route.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor

AF for intraspecies differences:

10

Justification:

Default assessment factor of 10 for general population

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

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:

DNEL (Derived No Effect Level)

Value:

5 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation required. Assuming that oral absorption in rats = oral absorption in humans.

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC

AF for differences in duration of exposure:

2

Justification:

Default assessment factor for extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Factor for allometric scaling for rat

AF for other interspecies differences:

2.5

Justification:

Default assessment factor

AF for intraspecies differences:

10

Justification:

Default assessment factor for general population

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

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

There is a 90 day repeated dose oral toxicity study (OECD 408) available, which characterised the potential toxic effects of read-across substance, bismuth subnitrate. A NOAEL of 1000 mg/kg bw/day was established for bismuth subnitrate in this study based on the lack of toxicologically relevant effects at the highest dose tested. There is also a prenatal developmental toxicity study (OECD 414) available for the read-across substance, bismuth subnitrate. In this study, the NOEL for maternal toxicity was considered to be 1000 mg/kg bw/day. No treatment-related changes were detected in the offspring parameters measured therefore the NOEL for developmental toxicity was also considered to be 1000 mg/kg bw/day. The NOAEL from the 90 day study is selected as the starting point for DNEL derivation for long-term systemic effects via inhalation and long-term oral systemic effects because this is the study with the longest duration.

No acute oral systemic DNEL was derived because an acute oral toxicity study with read-across substance, bismuth subsalicylate, in rats did not indicate any systemic effects up to the threshold of 2000 mg/kg bw/day. No dermal DNELs were derived as dermal absorption of bismuth is expected to be negligible and bismuth citrate was shown to be not irritating to the skin in an in vitro test. Local and acute inhalation DNELs were not derived because an acute inhalation study with read-across substance, dibismuth trioxide, in rats did not indicate any significant systemic or local effects up to the threshold of 5 mg/L air; in addition, the general population is not expected to be at risk by this route of exposure.