Disilver oxide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 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):

75

Dose descriptor starting point:

LOAEL

Value:

55.54 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

97.93 mg/m³

Explanation for the modification of the dose descriptor starting point:

Since the LOAEL via oral route is not directly comparable with inhalation hazard, a route-to-route extrapolation from oral to inhalation route was calculated.  According to ECHA guidance, the ratio between the absorption of rat via oral route and the absorption of human via inhalation must be taken into account. Considering the in-vivo toxicokinetic data and the MPPD model calculation of inhalation absorption (see Annex II) the absorption via oral route (3-5%) is higher than via inhalation route (~3%). Therefore, the ratio of Abs oral-rat (5%)/Abs inhalation human (~2%) is of 1.6. However, as it is an unusual to have a higher absorption via oral route than inhalation, it was decided to keep this ratio equal to 1, as indicated in equation below.

Corrected inhalation LOAEC = oral LOAEL x (1/sVRrat) x [(ABS oral-rat)/ (ABS inh-human)] x [(sRV human)/(wRV)]

Corrected inhalation LOAEC = 55.54 x (1/0.38) x [1/1)] x [6.7/10]

[1] sRV: standard Respiratory Volume; wRV: worker Respiratory Volume

AF for dose response relationship:

3

Justification:

For the difference in dose-response relationship, ECHA R.8. guidance indicates when the starting point for DNEL calculation is a LOAEL, it is suggested to use an assessment factor between 3 (as minimum/majority of cases) and 10 (as maximum /exceptional cases), considering the limited adverse effects (stomach mucosa necrosis only in F0 females) observed in the EOGRTS in limited number parental animals the AF of 3 was considered appropriate.

AF for differences in duration of exposure:

2

Justification:

For the difference in duration of exposure, default ECHA AF from sub-chronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Considered in the modification of starting point from oral rat to human inhalation.

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for the use for other interspecies differences as even though a lot is known about toxicokinetic of silver in laboratory animals, a direct extrapolation to human data is considered not enough conservative.

AF for intraspecies differences:

5

Justification:

ECHA Default AF for workers based on subpopulation not covering very young, very old and ill part of population, it covers human difference in sensitivity to toxic insults due to a multitude of biological factors covering genetic and/or environmental influence.

AF for the quality of the whole database:

1

Justification:

Good quality of the database (source of starting point Klimish score = 1)

AF for remaining uncertainties:

1

Justification:

No further uncertainties have been considered

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:

0.46 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):

120

Dose descriptor starting point:

LOAEL

Value:

55.54 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The starting point from oral route is considered justifiable to derive dermal DNEL due to the systemic toxicity of silver ion.

According to ECHA guidance the conversion from oral N(L)OAEL rat into dermal N(L)OAEL rat shall consider a correction for differences in absorption between routes and the differences in dermal absorption between rats and humans. Overall, the available data for soluble silver substances indicates dermal absorption rates well below 1% of the applied dose (see details in Annex IV). The oral absorption of disilver oxide has been extrapolated from silver acetate (worst-case) experimentally measured between 3 and 5% by Melvin et al. 202111. Based on the assumption that the human dermal absorption (<1%) is lower than the rat oral absorption (3-5%), no correction factor was applied to convert the LOAELoral-rat to LOAELdermal-human.

AF for dose response relationship:

3

Justification:

ECHA R.8. guidance indicates when the starting point for DNEL calculation is a LOAEL, it is suggested to use an assessment factor between 3 (as minimum/majority of cases) and 10 (as maximum/exceptional cases), considering the limited adverse effects (stomach mucosa necrosis only in F0 females) observed in the EOGRTS in limited number parental animals the AF of 3 was considered appropriate.

AF for differences in duration of exposure:

2

Justification:

Default ECHA AF from sub-chronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Interspecies differences: default ECHA AF from rat to human

AF for other interspecies differences:

1

Justification:

For other interspecies differences, since a low bioavailability and the moderate toxicity, it is acceptable to assume no substantial toxicokinetic and toxicodynamic differences between species via dermal route.

AF for intraspecies differences:

5

Justification:

ECHA default AF for workers based on subpopulation not covering very young, very old and ill part of the population, it covers human difference in sensitivity to toxic insults due to a multitude of biological factors covering genetic and/or environmental influences.

AF for the quality of the whole database:

1

Justification:

Good quality of the database

AF for remaining uncertainties:

1

Justification:

No further uncertainties have been considered.

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:

medium hazard (no threshold derived)

Additional information - workers

For details, please refer to separate report "CSR Annex 2_Derivation of DNEL for disilver oxide_2022" which is attached to the CSR in section 13.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.32 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):

150

Dose descriptor starting point:

LOAEL

Value:

55.54 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

48.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

Since the LOAEL via oral route is not directly comparable with inhalation hazard, a route-to-route extrapolation from oral to inhalation route was calculated.  According to ECHA guidance, the ratio between the absorption of rat via the oral route and the absorption of human via inhalation must be taken into account. Considering the in-vivo toxicokinetic data and the MPPD model calculation of inhalation absorption the absorption via oral route (3-5%) is higher than via the inhalation route (~2%). Therefore, the ratio of Abs oral-rat (5%)/Abs inhalation human (~2%) is of 2.5. However, as it is unusual to have a higher absorption via oral route than inhalation, it was decided to keep this ratio equal to 1.

Corrected inhalation LOAEC = oral LOAEL x (1/sVRrat) x [(ABS oral-rat)/ (ABS inh-human)] x [(sRV human)/(wRV)]

Corrected inhalation LOAEC = 55.54 x (1/1.15) 

AF for dose response relationship:

3

Justification:

ECHA R.8. guidance indicates when the starting point for DNEL calculation is a LOAEL, it is suggested to use an assessment factor between 3 (as minimum/majority of cases) and 10 (as maximum/exceptional cases), considering the limited adverse effects (stomach mucosa necrosis only in F0 females) observed in the EOGRTS in limited number parental animals the AF of 3 was considered appropriate.

AF for differences in duration of exposure:

2

Justification:

Default ECHA AF from sub-chronic to chronic.

AF for interspecies differences (allometric scaling):

1

Justification:

Considered in the modification of starting point from oral rat to human inhalation.

AF for other interspecies differences:

2.5

Justification:

Default ECHA AF for the use for other interspecies differences as even though a lot is known about toxicokinetics of silver in laboratoriy animals, a direct extrapolation to human data is not conservative.

AF for intraspecies differences:

10

Justification:

ECHA default AF sufficient to protect the lrager part of population as consumers and humans via environment (including e.g. children, pregnant women, elderly).

AF for the quality of the whole database:

1

Justification:

Good quality of the database.

AF for remaining uncertainties:

1

Justification:

No further assessment factor has been applied.

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:

0.23 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):

240

Dose descriptor starting point:

LOAEL

Value:

55.54 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The starting point from oral route is considered justifiable to derive dermal DNEL due to the systemic toxicity of silver ion.

According to ECHA guidance R.8. the conversion from oral N(L)OAEL rat into dermal N(L)OAEL rat shall consider a correction for differences in absorption between routes and the differences in dermal absorption between rats and humans. Overall, the available data for soluble silver substances indicates dermal absorption rates well below 1% of the applied dose (see details in Annex IV). The oral absorption of disilver oxide has been extrapolated from silver acetate (worst-case) experimentally measured between 3 and 5% by Melvin et al. 202111. Based on the assumption that the human dermal absorption (<1%) is lower than the rat oral absorption (3-5%), no correction factor was applied to convert the LOAELoral-rat to LOAELdermal-human.

AF for dose response relationship:

3

Justification:

For the difference in dose-response relationship, ECHA R.8. guidance indicates when the starting point for DNEL calculation is a LOAEL, it is suggested to use an assessment factor between 3 (as minimum/majority of cases) and 10 (as maximum/ exceptional cases), considering the limited adverse effects (stomach mucosa necrosis only in females) observed in the EOGRTS in limited number of parental animals the AF of 3 was considered appropriate.

AF for differences in duration of exposure:

2

Justification:

Default ECHA AF sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Interspecies differences: default ECHA AF from rat to human.

AF for other interspecies differences:

1

Justification:

For other interspecies differences, since a low bioavailability and the moderate toxicity, it is acceptable to assume no substantial toxicokinetic and toxicodynamic differences between species via dermal route.

AF for intraspecies differences:

10

Justification:

ECHA default AF sufficient to protect the larger part of population as consumers and humans via environment (including e.g. children, pregnant women, elderly).

AF for the quality of the whole database:

1

Justification:

Good quality of the database.

AF for remaining uncertainties:

1

Justification:

No further assessment factor has been applied.

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:

0.23 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):

240

Dose descriptor starting point:

LOAEL

Value:

55.54 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

No modification of the starting point as the starting point to derive oral DNEL for disilver oxide has been based on a long term oral data from silver acetate study, in  read-across approach.

AF for dose response relationship:

3

Justification:

For the difference in dose-response relationship, ECHA R.8. guidance indicates when the starting point for DNEL calculation is a LOAEL, it is suggested to use an assessment factor between 3 (as minimum/majority of cases) and 10 (as maximum/exceptional cases), considering the limited adverse effects (stomach mucosa necrosis only in females) observed in the EOGRTS in limited number parental animals the AF of 3 was considered appropriate.

AF for differences in duration of exposure:

2

Justification:

Default ECHA AF from sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Interspecies differences: default ECHA AF from rat to human.

AF for other interspecies differences:

1

Justification:

For other interspecies differences, since a low bioavailability and the moderate toxicity, it is acceptable to assume no substantial toxicokinetic and toxicodynamic differences between species via dermal route.

AF for intraspecies differences:

10

Justification:

ECHA default AF sufficient to protect the larger part of the population as consumers, and humans via environment (including e.g. children, pregnant women, elderly).

AF for the quality of the whole database:

1

Justification:

Good quality of the database.

AF for remaining uncertainties:

1

Justification:

No further assessment factor has been applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

For details, please refer to separate report "CSR Annex 2_Derivation of DNEL for disilver oxide_2022" which is attached to the CSR in section 13.