Bismuth oxide salicylate

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:

95.8 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 of bismuth 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 subsalicylate absorbed via inhalation is in the range 2.9% to 9.2% (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 = 9.2/0.5 = 18.4. Therefore, NAECcorr_inh = 1763 mg/m3/18.4 = 95.8 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:

DNEL (Derived No Effect Level)

Value:

2.9 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):

17.5

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal absorption of bismuth is considered to be very low, however, salicylates are absorbed dermally (see toxicokinetics summary). It is conservatively assumed that the oral absorption in dogs is equal to the dermal absorption in humans.

AF for dose response relationship:

1

Justification:

Default assessment factor when starting pont for DNEL calculation is NOAEL

AF for differences in duration of exposure:

1

Justification:

Chronic study

AF for interspecies differences (allometric scaling):

1.4

Justification:

Allometric factor for dogs as compared to humans

AF for other interspecies differences:

2.5

Justification:

Default assessment factor

AF for intraspecies differences:

5

Justification:

Default assessment factor 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

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 the inhalation route because this study has a longer duration than the prenatal developmental study and it provided the lowest DNEL value (following correction for route to route extrapolation and application of assessment factors). The repeated dose studies using the read-across substances, methyl salicylate, sodium salicylate and acetylsalicylic acid, all provided lower NOAEL values, however, the derived DNEL values were higher than the DNEL values calculated using the NOAEL for the repeated dose bismuth subnitrate study.

The NOAEL from the repeated dose toxicity study in dogs with read-across substance, methylsalicylate, was used to derive the long-term systemic dermal DNEL because this NOAEL value provided the lowest DNEL value (following application of assessment factors). The developmental/reproductive toxicity studies with salicylates in animals were not considered for DNEL derivation because published studies in human pregnancy (reliability = Klimisch 2) indicate that low doses of the structurally related read-across substance, aspirin (acetylsalicylic acid), are not associated with adverse effects in human pregnancy (Koser et al, 2003, CLASP 1995, Kaandorp et al 2009). Acute dermal DNELs were not derived because bismuth subsalicylate has been shown to be non irritating to the skin and no significant adverse effects were observed in an acute dermal toxicity study with read-across substance, salicylic acid. In addition, bismuth is poorly absorbed by the dermal route.

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, read-across substance, methyl salicylate, showed no evidence of local effects when tested by inhalation at a concentration of 700 mg/m3 (effectively saturated) for 7 hours per day for four weeks in rats.

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:

47.3 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 subsalicylate absorbed via inhalation is in the range 2.9% to 9.2% (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 = 9.2/0.5 = 18.4. Therefore, NAECcorr_inh = 869.6 mg/m3/18.4 = 47.3 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 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

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:

DNEL (Derived No Effect Level)

Value:

1.4 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):

35

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal absorption of bismuth is considered to be very low, however, salicylates are absorbed dermally (see toxicokinetics summary). It is conservatively assumed that the oral absorption in dogs is equal to the dermal absorption in humans.

AF for dose response relationship:

1

Justification:

Default assessment factor when starting pont for DNEL calculation is NOAEL

AF for differences in duration of exposure:

1

Justification:

Chronic study

AF for interspecies differences (allometric scaling):

1.4

Justification:

Allometric scaling factor for dogs as compared to humans

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 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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.4 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):

35

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:

1

Justification:

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

AF for differences in duration of exposure:

1

Justification:

Chronic study

AF for interspecies differences (allometric scaling):

1.4

Justification:

Factor for allometric scaling for dog as compared to humans

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 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

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 the inhalation route because this study has a longer duration than the prenatal developmental study and it provided the lowest DNEL value (following correction for route to route extrapolation and application of assessment factors). The repeated dose studies using the read-across substances, methyl salicylate, sodium salicylate and acetylsalicylic acid, all provided lower NOAEL values, however, the derived DNEL values were higher than the DNEL values calculated using the NOAEL for the repeated dose bismuth subnitrate study.

The NOAEL from the repeated dose toxicity study in dogs with read-across substance, methylsalicylate, was used to derive the long-term systemic oral DNEL and the long-term systemic dermal DNEL because this NOAEL value provided the lowest DNEL values (following application of assessment factors). The developmental/reproductive toxicity studies with salicylates in animals were not considered for DNEL derivation because published studies in human pregnancy (reliability = Klimisch 2) indicate that low doses of the structurally related read-across substance, aspirin (acetylsalicylic acid), are not associated with adverse effects in human pregnancy (Koser et al, 2003, CLASP 1995, Kaandorp et al 2009). Acute dermal DNELs were not derived because bismuth subsalicylate has been shown to be non irritating to the skin and no significant adverse effects were observed in an acute dermal toxicity study with read-across substance, salicylic acid. In addition, bismuth is poorly absorbed by the dermal route.

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, read-across substance, methyl salicylate, showed no evidence of local effects when tested by inhalation at a concentration of 700 mg/m3 (effectively saturated) for 7 hours per day for four weeks in rats.

An acute oral DNEL was not derived because an acute oral toxicity study with bismuth subsalicylate, in rats did not indicate any systemic effects up to the threshold of 2000 mg/kg bw/day.