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Description of key information

Key value for chemical safety assessment

Skin sensitisation

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Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
1. HYPOTHESIS FOR THE READ-ACROSS APPROACH (ENDPOINT LEVEL)
The data used for the toxicological hazard assessment of bulk silver and nanosilver are not restricted to studies referring to only these individual substances as test items. Instead, a more generic approach for the toxicological assessment of “silver” in general is adopted by also including information/data generated with other inorganic silver substances such as silver acetate.
The basic assumption for this is that the systemic toxicity of any of the inorganic silver substances is driven by the silver ion (Ag+), which is considered the primary relevant species of silver for the hazard assessment. It is noted that many silver substances have a low if not negligible solubility and are thus considered to be of low bioavailability in the human (or animal) body. Once dissolved to any relevant extent, the other moieties or ions released from silver salts, such as chloride, sulfate etc. are not considered further in the hazard assessment, since these are typically either ubiquitous ions in a physiological environment, or generally not known to cause any particular concern regarding their toxicology. On the other hand, a separate assessment is considered if a substance is shown to cause local effects, such as the soluble and corrosive silver nitrate. The approach of conducting a common hazard assessment for silver substances where possible has the overall aim of avoiding unnecessary new animal studies.
To justify this generic approach, the published literature on toxicological effects of silver was assessed, as well as collected proprietary studies from the joint members of the silver REACH registration dossiers. Furthermore, the EPMF is currently performing the following toxicological studies which will supplement the Ag mammalian toxicity database:
• An in vivo toxicokinetics study with several test substances (silver acetate, silver nitrate, metallic silver (tested as a powder), nanosilver) to strengthen the basis for read-across. The read-across approach for mammalian toxicity endpoints will be updated based on the outcome of this study.
• An EOGRTS (OECD guideline 443) with silver acetate. Testing outcomes from a study utilising silver acetate are anticipated to be fully applicable to ionic silver (Ag+) irrespective of the donor silver substance forming this ion, i.e. being applicable to freely soluble salts such as silver nitrate, sparingly soluble compounds including disilver(I) oxide, and metallic silver including nanosilver forms.
The hazard assessment is supplemented by a separate report titled “Derivation of DNELs - silver substances“, which is attached to the CSR and the technical dossier in the endpoint summary of section 7. The hazard assessment and DNEL derivation for silver substances distinguishes between the following substance categories:
I. soluble/bioavailable silver substances (examples: silver nitrate, -sulfate, -acetate). These substances are characterised by water solubilities in the range ca. 8 g/L to >2,000 g/L, which is assumed to facilitate their bioavailability, and
II. poorly soluble/poorly bioavailable silver substances (such as silver oxide, iodide, chloride, bromide), including silver metal and nanosilver. The solubilities of the substances in this group are typically in the low mg/L range or even below (some are considered “practically insoluble”) rendering them poorly accessible to dissolution processes under physiological conditions.
Further, conventional read-across grouping would usually also consider aspects of bioaccessibility (i.e., solubility in surrogate physiological media) as well as in vivo toxicokinetic data for validation purposes. The former aspect has been studied for silver substances (please refer to the endpoint summary of the toxicokinetics; IUCLID section 7.1), but with the observation that the intrinsic chloride content in these in vitro test media coupled with the poor water solubility of silver chloride obviously is a limiting factor, rendering this testing of limited use for “silver”. Conversely, the toxicokinetic database for silver substances including non-nano sized silver metal with respect to differences in bioavailability is scarce. Hence the importance and relevance of the ongoing in vivo toxicokinetics study referred to above.
For this reason, the dossier often refers to data on silver metal nanomaterials for the assessment of silver metal (for a lack of substantial data on non-nanosized silver powder forms) and beyond this for the group of poorly soluble silver substances, albeit recognising that this often constitutes a conservative read-across.

2. READ-ACROSS APPROACH JUSTIFICATION (ENDPOINT LEVEL)
Based on a weight-of-evidence assessment (studies included in the REACH dossier as Endpoint Study Records), it is concluded that silver substances do not elicit skin sensitising effects:
• Two reliable in vivo animal studies on standard skin sensitisation tests are available with silver containing products/preparations (plus supporting data on a nanosilver product):
o Dermal sensitisation study (Buehler Method) in guinea pigs, with a biocidal product (aq. solution) containing 2438 ppm Ag+ ions, besides other ingredients (Moore 1999).
o Sensitization study in guinea pigs (maximization test) with a liquid plant preservative preparation containing 18 g/L of silver thiosulfate in aqueous solution, besides other ingredient (Prinsen 1995).
• Supporting human data: overall, very few publications are available (literature search report available as attachment to the endpoint summary on sensitisation; IUCLID Section 7.4) and no specific concern for sensitising properties of silver (compounds) could be identified based on human data.
For the silver nanoforms covered under REACH (Nano 8.1 and Nano 34.2), read across is done from above in vivo animal studies.

For further information and data matrix see 'CSR Annex 10 - Read Across Justification Nanosilver HH_SUMMARY_200706' attached in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Positive control results:
Induction Phase:
Very faint to severe erythema (0.5-3) was noted
Challenge Phase:
Eight of ten positive control animals exhibited signs of a sensitization response (faint to moderate rythema [1-2] 24 and /or 48h after challenge
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50 % w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
very faint erythema (0.5)
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 50 % w/w. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: very faint erythema (0.5).
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50 % w/w
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
very faint erythema (0.5)
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50 % w/w. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: very faint erythema (0.5).
Reading:
1st reading
Hours after challenge:
24
Group:
other: naive control group
Dose level:
50 % w/w
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
very faint erythema (0.5)
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: naive control group. Dose level: 50 % w/w. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: very faint erythema (0.5).
Reading:
2nd reading
Hours after challenge:
48
Group:
other: naive control group
Dose level:
50 % w/w
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
very faint erythema (0.5)
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: naive control group. Dose level: 50 % w/w. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: very faint erythema (0.5).
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
0.04% DNCB in acetone
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
faint to moderate erythema (1-2)
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: 0.04% DNCB in acetone. No with. + reactions: 8.0. Total no. in groups: 10.0. Clinical observations: faint to moderate erythema (1-2).
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
0.04% DNCB in acetone
No. with + reactions:
7
Total no. in group:
10
Clinical observations:
faint to moderate erythema (1-2)
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 0.04% DNCB in acetone. No with. + reactions: 7.0. Total no. in groups: 10.0. Clinical observations: faint to moderate erythema (1-2).
Reading:
1st reading
Hours after challenge:
24
Group:
other: positive naive control group
Dose level:
0.04% DNCB in acetone
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
very faint erythema (0.5)
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: positive naive control group. Dose level: 0.04% DNCB in acetone. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: very faint erythema (0.5).
Reading:
2nd reading
Hours after challenge:
48
Group:
other: positive naive control group
Dose level:
0.04% DNCB in acetone
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
no irritation
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: positive naive control group. Dose level: 0.04% DNCB in acetone. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: no irritation.
Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
Based on these findings and on the evaluation system used, Axenohl is not considered to be a contact sensitizer.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
1. HYPOTHESIS FOR THE READ-ACROSS APPROACH (ENDPOINT LEVEL)
The data used for the toxicological hazard assessment of bulk silver and nanosilver are not restricted to studies referring to only these individual substances as test items. Instead, a more generic approach for the toxicological assessment of “silver” in general is adopted by also including information/data generated with other inorganic silver substances such as silver acetate.
The basic assumption for this is that the systemic toxicity of any of the inorganic silver substances is driven by the silver ion (Ag+), which is considered the primary relevant species of silver for the hazard assessment. It is noted that many silver substances have a low if not negligible solubility and are thus considered to be of low bioavailability in the human (or animal) body. Once dissolved to any relevant extent, the other moieties or ions released from silver salts, such as chloride, sulfate etc. are not considered further in the hazard assessment, since these are typically either ubiquitous ions in a physiological environment, or generally not known to cause any particular concern regarding their toxicology. On the other hand, a separate assessment is considered if a substance is shown to cause local effects, such as the soluble and corrosive silver nitrate. The approach of conducting a common hazard assessment for silver substances where possible has the overall aim of avoiding unnecessary new animal studies.
To justify this generic approach, the published literature on toxicological effects of silver was assessed, as well as collected proprietary studies from the joint members of the silver REACH registration dossiers. Furthermore, the EPMF is currently performing the following toxicological studies which will supplement the Ag mammalian toxicity database:
• An in vivo toxicokinetics study with several test substances (silver acetate, silver nitrate, metallic silver (tested as a powder), nanosilver) to strengthen the basis for read-across. The read-across approach for mammalian toxicity endpoints will be updated based on the outcome of this study.
• An EOGRTS (OECD guideline 443) with silver acetate. Testing outcomes from a study utilising silver acetate are anticipated to be fully applicable to ionic silver (Ag+) irrespective of the donor silver substance forming this ion, i.e. being applicable to freely soluble salts such as silver nitrate, sparingly soluble compounds including disilver(I) oxide, and metallic silver including nanosilver forms.
The hazard assessment is supplemented by a separate report titled “Derivation of DNELs - silver substances“, which is attached to the CSR and the technical dossier in the endpoint summary of section 7. The hazard assessment and DNEL derivation for silver substances distinguishes between the following substance categories:
I. soluble/bioavailable silver substances (examples: silver nitrate, -sulfate, -acetate). These substances are characterised by water solubilities in the range ca. 8 g/L to >2,000 g/L, which is assumed to facilitate their bioavailability, and
II. poorly soluble/poorly bioavailable silver substances (such as silver oxide, iodide, chloride, bromide), including silver metal and nanosilver. The solubilities of the substances in this group are typically in the low mg/L range or even below (some are considered “practically insoluble”) rendering them poorly accessible to dissolution processes under physiological conditions.
Further, conventional read-across grouping would usually also consider aspects of bioaccessibility (i.e., solubility in surrogate physiological media) as well as in vivo toxicokinetic data for validation purposes. The former aspect has been studied for silver substances (please refer to the endpoint summary of the toxicokinetics; IUCLID section 7.1), but with the observation that the intrinsic chloride content in these in vitro test media coupled with the poor water solubility of silver chloride obviously is a limiting factor, rendering this testing of limited use for “silver”. Conversely, the toxicokinetic database for silver substances including non-nano sized silver metal with respect to differences in bioavailability is scarce. Hence the importance and relevance of the ongoing in vivo toxicokinetics study referred to above.
For this reason, the dossier often refers to data on silver metal nanomaterials for the assessment of silver metal (for a lack of substantial data on non-nanosized silver powder forms) and beyond this for the group of poorly soluble silver substances, albeit recognising that this often constitutes a conservative read-across.

2. READ-ACROSS APPROACH JUSTIFICATION (ENDPOINT LEVEL)
Based on a weight-of-evidence assessment (studies included in the REACH dossier as Endpoint Study Records), it is concluded that silver substances do not elicit skin sensitising effects:
• Two reliable in vivo animal studies on standard skin sensitisation tests are available with silver containing products/preparations (plus supporting data on a nanosilver product):
o Dermal sensitisation study (Buehler Method) in guinea pigs, with a biocidal product (aq. solution) containing 2438 ppm Ag+ ions, besides other ingredients (Moore 1999).
o Sensitization study in guinea pigs (maximization test) with a liquid plant preservative preparation containing 18 g/L of silver thiosulfate in aqueous solution, besides other ingredient (Prinsen 1995).
• Supporting human data: overall, very few publications are available (literature search report available as attachment to the endpoint summary on sensitisation; IUCLID Section 7.4) and no specific concern for sensitising properties of silver (compounds) could be identified based on human data.
For the silver nanoforms covered under REACH (Nano 8.1 and Nano 34.2), read across is done from above in vivo animal studies.

For further information and data matrix see 'CSR Annex 10 - Read Across Justification Nanosilver HH_SUMMARY_200706' attached in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Species:
guinea pig
Reading:
1st reading
Hours after challenge:
24
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No skin reactions were observed in test or control animals following the challenge application in the main study after 24 hours.

Range finding for intradermal induction: Three animals were intradermal treated with 100%, 30%, 10% and 3% concentrations of the test substance. Scores were obtained 24 hours after application. Slight to moderate irritation was observed in all concentrations tested. From the 30% concentration upward necrosis was observed as well. No irritation was observed after topical induction with 30% and 100% test substance concentrations in three animals. Challenge: No skin reactions were observed in test or control animals following the challenge application in the main study after 24 hours.

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
On the basis of the results obtained it was concluded that, under the conditions of this study and according to the EC-standards silver thiosulphate is not a sensitizer.
Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Based on a weight-of-evidence assessment, it is concluded that silver substances do not elicit skin sensitising effects:

Human data:

Long term industrial experience does not raise any concern on skin sensitisation attributable to silver substances (personal communication, members of the Silver Work Group of the Precious Metals and Rhenium Consortium, 2010-07-27). Furthermore, a literature search has been conducted to check whether published literature is available which would provide further information on the potential occurrence or absence of skin sensitisation effects of silver substances, specifically in occupational settings. A report on this literature search is attached to the endpoint summary on sensitisation in the technical dossier. As a result, only a limited number of case reports dealing with skin sensitisation could initially be identified. However, upon close inspection, in several of these silver was not the potential cause. For example, one study investigated skin effects in workers with a range of precious metal compounds and found that silver compounds were not causing allergic skin reactions (Bruevich et al 1980). In other cases, “silver” was mentioned but not in the context of sensitisation by silver, but e. g. where thiourea contained in a silver polish was identified as a sensitiser (Dooms-Goossens, 1988).

Overall, very few publications are available and no specific concern for sensitising properties of silver (compounds) could be identified based on human data.

 

Animal data:

Two reliable studies on standard skin sensitisation tests are available with silver containing products/preparations:

Moore, G.E. (1999): Dermal sensitisation study (Buehler Method) in guinea pigs, with a biocidal product (aqueous solution) containing 2438 ppm Ag+ ions, besides other ingredients.

Prinsen, M.K. (1995): Sensitization study in guinea pigs (maximization test) with a liquid plant preservative preparation containing 18 g/L of silver thiosulfate in aqueous solution, besides other ingredients.

As a third source of information, the data published by Kim et al. (2012) on a guinea pig maximisation test are presented. Kim et al. studied the sensitising properties of a nano-silver product (in 1% citrate solution) in close agreement with OECD TG 406. Whereas this publication is of limited reliability since no test concentrations are stated and the use of a positive control is not reported, the clear negative outcome (no skin sensitisation) is in agreement with other information.

 

Conclusion:

Neither human nor animal data show any specific concern for skin sensitising properties of silver or silver substances. Based on a weight-of-evidence assessment it is concluded that classification for skin sensitisation is not required and that further experimental verification is not justified.


Migrated from Short description of key information:
Neither human nor animal data show any specific concern for skin sensitising properties of silver or silver substances. Based on this weight-of-evidence assessment, it is concluded that classification for skin sensitisation is not required and that further experimental verification is not justified (see discussion).

Justification for selection of skin sensitisation endpoint:
Weight-of-evidence assessment based on human and animal data.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Neither human nor animal data show any specific concern for skin sensitising properties of silver or silver substances. Based on this weight-of-evidence assessment, it is concluded that classification for skin sensitisation is not required and that further experimental verification is not justified. In consequence, classification for skin sensitisation is not required for silver substances.

Similarly, based on a complete absence of any indication of respiratory sensitisation in the public domain, classification is not required.