hydronium;iron(3+);hexahydroxide;disulfate

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation, other

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Remarks:

Valid and conclusive guideline study under Quality Assurance according to US standards

Justification for type of information:

The Reporting Format for the Chemical Category According to ECHA (2008) Guidance R.6.2.6.2 can be found in the Endpoint Summary of Toxicokinetics, metabolism and distribution.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

EPA OPP 81-6 (Skin Sensitisation)

Deviations:

yes

Remarks:

report does not include results of a positive control

GLP compliance:

yes

Remarks:

Quality Assurance according to 40 CFR §160.12 (United States of America)

Type of study:

Buehler test

Justification for non-LLNA method:

At the time of the study conduction, the LLNA was not yet a recognized test method (adopted by the Organization for Economic Co-operation and Development (OECD) as a standalone method (OECD 429) in 2002).

Specific details on test material used for the study:

Beige granules of the product Ferri-Floc were used in the test. The material is composed of 35 % weight ferric sulphate, anhydrous and 65 % inert ingredients.

Species:

guinea pig

Strain:

not specified

Remarks:

albino

Sex:

not specified

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Cam Research Lab Animals
- Age at study initiation: Young adults
- Weight at study initiation: 366 to 392 g

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Remarks:

The test item was moistened only, not dissolved

Concentration / amount:

0.5 g test item was moistened with 0.25 mL vehicle (normal saline)

Day(s)/duration:

0.25

Adequacy of induction:

highest technically applicable concentration used

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Remarks:

The test item was moistened only, not dissolved

Concentration / amount:

0.5 g test item was moistened with 0.25 mL vehicle (normal saline)

Day(s)/duration:

0.25

Adequacy of challenge:

other: Same concentration as during induction

No. of animals per dose:

10

Details on study design:

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: 6 h, then test site rinsed with warm water if necessary
- Test groups: 1
- Control group: 1

- Frequency of applications: There was one induction treatment per week, over a period of three weeks for a total induction treatments.
- Duration: 1 week
- Concentrations: 0.5 g test item was moistened with 0.25 mL normal saline

B. CHALLENGE EXPOSURE
- No. of exposures: 1, on virgin sites
- Day(s) of challenge: 1
- Exposure period: 6 h, then test site rinsed with warm water if necessary
- Test groups: 1
- Control group: 1
- Concentrations: 0.5 g test item was moistened with 0.25 mL normal saline
- Evaluation (hr after challenge): 24

Positive control substance(s):

yes

Remarks:

p-Phenylenediamine (CAS 106-50-3)

Positive control results:

The results of the positve control study were not reported.

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.5 g test item was moistened with 0.25 mL normal saline

No. with + reactions:

3

Total no. in group:

10

Clinical observations:

Very slight erythema on virgin sites; 24 h after induction treatment #1 2/10, #2 3/10 and #3 7/10 animals showed very slight erythema on induction sites.

Remarks on result:

no indication of skin sensitisation

Interpretation of results:

not sensitising

Remarks:

Migrated information 24 h after induction #1, in 2/10 very slight erythema; 24 h after induction #2, in 3/10 very slight erythema; 24 h after induction #3, in 7/10 very slight erythema; 24 h after challenge, in 3/10 very slight erythema (on virgin sites) Criteria used for interpretation of results: US EPA pesticides

Conclusions:

The test item was found not sensitizing in vivo.

Executive summary:

In vivo sensitizing effects of the test item ferric sulphate in the form of beige granules (composed of 35 % (weight) ferric sulphate, anhydrous (CAS 10028-22-5) and 65 % (weight) inert ingredients) in albino guinea pigs were investigated using the Buehler test according to the EPA OPP 81-6 protocol. The full study report was unavailable, but secondary source data provided sufficient details. Thus the experiment is deemed valid, relevant, adequate, conclusive and suitable for assessment with restrictions due to the fact that the test item was not pure and read-across to the submission item applies. Accordingly it was was rated „reliable with restrictions“, i.e. “Klimisch 2” according to the scale of Klimisch et al. (1997).

An amount of 0.5 g test item was moistened with 0.25 mL vehicle (normal saline) and applied to the exposure site of 10 test animals under a non-allergenic pad and wrapped with elastic bandage. A control and a positive control with p-Phenylenediamine (CAS 106-50-3) were also included. The exposure time was 6 h, and then the test site was rinsed with warm water if necessary. Readings were generally made 24 h after start of exposure. There was one induction treatment per week, over a period of three weeks for a total of 3 induction treatments. Then the challenge exposure was executed on virgin sites.

After induction treatment #1 2/10, #2 3/10 and #3 7/10 animals showed very slight erythema on induction sites, while only 3/10 showed very slight erythema after challenge.

In conclusion the test item was found not sensitizing in vivo.

• Klimisch HJ, Andreae M, Tillmann U (1997). A Systematic Approach for Evaluating the Quality of Experimental Toxicological and Ecotoxicological Data. DOI 10.1006/rtph.1996.1076 PMID 9056496 Regul Toxicol Pharmacol 25:1-5.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

This endpoint is covered by the category approach for dissociating, inorganic and non-toxic iron compounds (please see the section on toxicokinetics, metabolism and distribution for the category justification/report format).

• Animal data:

Stizinger (2010) performed a LLNA assay conducted according to OECD 429 and GLP using up to 50 % of the test item in acetone/olive oil (4:1 v/v). The test item was a 42.6 % solution of FeSO4 in water (plus some impurities). Therefore the final concentration of FeSO4 was about 21.3 % w/w in the applied test solution. Nevertheless this test is regarded suitable for read across to the other iron salts as generally the bioavailability of ferrous iron is higher, while it is rather quickly oxidised in watery solutions to ferric iron and therefore can function as surrogate for the latter. Only for FeCl3 information from two secondary sources (that most probably have the same primary source given the results reported) is available showing an ambiguous picture. As these sources are very unreliable this result is disregarded.

 • Human data

For human data two case reports and a human patch test with 31 volunteers are available. Baer (1973) reports contact sensitization to iron and a positive patch test to a 2 % ferric chloride (FeCl3) solution for a 66-year old white male tool maker. The patient's 5 -year history of allergic contact dermatitis was not associated with any other exposure to metals.

Nater (1960) describes a 44 year old male with eczema-type reactions on his skin in areas that were exposed to steel particles during his job using high pressure cleaning equipment to remove steel particles from construction elements. After testing against 16 other metal salt present in low concentrations in the steel (including nickel and cobalt) and comparing the results to 30 volunteer control people ferric chloride (FeCl3) was identified as the substance triggering sensitising reactions.

Oshima (1991) conducted a human patch test with metals salts from all metals used in a dental clinic. 30 volunteers from the staff of the clinic were tested. All were negative for skin sensitisation effects from the metal salts tested.

• Summary

The available animal data is limited but a fully reliable study on FeSO4 is deemed valid for read across for the other salts of the iron salt category. The available human data are limited. Two cases of skin sensitisation reactions against ferric chloride are reported for two workers that have been highly exposed occupationally through frequent contact with steel products. Nevertheless in one study in 30 individuals no comparable effects were seen. This is in line with the findings of the third available human study where 31 employees of a dental clinic were tested for contact allergy reactions against the metals that they are occupationally exposed to. They were all negative for reactions against metal salts. Finally iron additives are in widespread use as nutritional supplements. If iron ions had a high potency for causing sensitisation this would most probably be realised by now.

Finally it is concluded that in rare cases the development of sensitisation against iron salt is possible. Nevertheless in general iron salts are deemed not to have a potential to cause sensitisation that is relevant for classification.

Migrated from Short description of key information:
Not sensitising; read across from FeSO4 to all other iron salts of this category

Justification for selection of skin sensitisation endpoint:
The study was performed according to OECD TG 429

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

No specific information on respiratory sensitisation is available. In absence of skin sensitisation and in view of the long occupational use of soluble iron salts, a respiratory sensitisation potential seems unlikely.

Migrated from Short description of key information:
No data indicating sensitisation are available

Justification for classification or non-classification

Skin sensitisation

Pure grades

Based on the above stated assessment of the skin sensitisation potential of iron salts, none of the members of the iron salt category needs to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) or according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

Thus no classification for pure grades of the submission item is required.

Nickel impurity

Possible impurity-triggered classification may however be required depending on the Nickel content: In Annex VI of the 1st ATP to the CLP-Regulation (Commission Regulation (EC) No 790/2009 of 10 August 2009) “nickel sulfate” EC 232-104-9, CAS 7786-81-4, Index no. 028-009-00-5 (Tables 3.1 and 3.2 on pages L 235/11 and 243, respectively) and “nickel dichloride” EC 231-743-0, CAS 7718-54-9 Index no. 028-011-00-6 (Tables 3.1 and 3.2 on pages L 235/135 and 354, respectively) are listed with a specific concentration limit of ≥ 0.01 % w/w triggering classification as skin sensitizing class 1 according to directive 67/548/EWG. The risk phrase R43 (symbol Xi, the indication of danger “Irritant”) or the hazard statement H317 is required according to DSD and CLP, respectively.

Table: Skin sensitisation label elements for category 1 (CLP, 5th ATP, Annex I, 3.4.4.1, Table 3.4.7)

Element		Type
GHS Pictogram		GHS07 exclamation mark
Signal Word		Warning
Hazard Statement		H317: May cause an allergic skin reaction
Precautionary Statements	Prevention	P261, P272, P280
	Response	P302 + P352, P333 + P313, P321, P362 + P364 (4th ATP change)
	Storage	none
	Disposal	P501

Respiratory sensitisation

As no data on respiratory sensitisation is available for iron salts a classification is not possible according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.