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EC number: 281-897-8
CAS number: 84057-80-7
Skin irritation: not irritating (OECD 404, GLP)
Eye irritation: not corrosive/not severe irritant to the eye (OECD 437 & OECD 405; GLP)
Table 1: Results after 240 minutes
Opacity value = Difference (t240 – t0) of opacity
Permeability at 490 nm (OD490)
In vitro irritation score
Mean in vitro irritation score
Proposed in vitro irritation scale
Non corrosive / non severe irritant
Corrosive / severe irritant
* corrected values
- With the negative control (0.9% (w/v) NaCl
in deionised water) neither an increase of opacity nor permeability of
the corneae could be observed (mean in vitro irritation score 2.44).
- The positive control (10% (w/v)
Benzalkonium chloride in 0.9% (w/v) NaCl in deionised water) showed
clear opacity of the corneae (mean in vitro irritation score 180.94)
corresponding to a classification as corrosive /severe irritant to the
eye (CLP/EPA/GHS (Cat 1)).
Table 2: Historical data
Mean in vitro Irritation Score
Values of 138 studies with solid test items
performed until November 2012
One reliable in vivo study described by Hansen (2013) (OECD 404; GLP compliant) is considered to be reliable without restrictions. The substance was determined not to be irritating to the skin.
The data requirements as laid down in the REACH regulation Annex VII and VIII, foresee a sequential testing strategy for the endpoint skin irritation. According to Annex VII, an in vitro study for skin corrosion and skin irritation shall be performed, before further in vivo tests according to Annex VIII are conducted. For the conduct of the in vitro skin corrosion and skin irritation properties, the human skin model system is recommended for the assessment of both endpoints (OECD 431 and 439 respectively).
During the conduct of the sequential testing for skin corrosion and skin irritation by another registrant also using metal substances (salts with organic and inorganic anion/ligand of high water solubility, Cobalt, borate neodecanoate complexes, Cobalt di(acetate) and Cobalt dichloride), it became obvious that a high number of false positive test results were received. Six supporting study records for three substances are attached to the waiving statement for in vitro skin irritation in section 7.3.1 of the IUCLID file. The studies represent three in vitro studies with the human skin model test system and a subsequently conducted in vivo skin irritation study in rabbits. These results raised doubt on the suitability of the in vitro skin model test systems for metal substances.
It was therefore decided by the registrant to deviate from the suggested in vitro human skin model test for skin irritation and skin corrosion testing, with reference to the,
Not to cause unnecessary suffering in experimental animals by exposing them to corrosive substances, an alternative testing strategy to assess the skin corrosive properties for zirconium propionate was developed. The alternative testing strategy was tailored to the properties of zirconium propionate, comprising the following steps:
1) Collect information on pH shifts during water solubility testing (according to OECD 105), a pH value of <3 or >11.5 is indicative for skin corrosive properties.
2) Assess the potential of oxidising properties of the anion or the cation individually. Agents with oxidising properties are likely to react with biological membranes and exert irritating or corrosive properties.
3) Assess corrosive effects on the bovine cornea via BCOP test (according to OECD 437).
4) In case pH shifts, oxidising properties or the BCOP test results indicate a potential for skin corrosive/irritating properties, tiered testing should be performed:
5) In case pH shifts, oxidising properties or the BCOP test results indicate a lack of skin corrosive/irritating properties, in vivo skin irritation testing (according to OECD 404) should be performed.
The in vivo skin irritation testing does not breach the last resort principle, since the data requirements of regulation (EC) 1907/2006 at the time of dossier preparation (before 1st June 2013) foresaw the conduct of an in vivo skin irritation study (Annex VIII, Section 8.1.1 Column 1). Since the substance zirconium propionate had to fulfil the data requirements inter alia laid down in Annex VIII, the conduct of an in vivo skin irritation study was statutory.
Further details on the testing strategy for skin irritation/corrosion testing and the findings with zirconium propionate are presented in the report in attached to the waiving statement for in vitro skin irritation in section 7.3.1 of the IUCLID file.
One reliable in vivo study described by Pooles (2013) (OECD 405; GLP compliant) is considered to be reliable without restrictions. The substance was determined to be neither corrosive nor severely irritating to the eye.
Furthermore, a reliable in vitro study described by Heppenheimer (2012) (OECD 437; GLP compliant) is considered to be reliable without restrictions. The substance was determined to be neither corrosive nor severely irritating to the eye.
Reference Hansen (2013) is considered as the key study for in vivo skin irritation and will be used for classification. The skin irritation was scored according to the Draize scale. The mean score (24, 48, 72 h) for erythema and oedema for all three animals were as follows:
Erythema: 0 for all animals
Oedema: 0 for all animals
Thus, according to Regulation (EC) 1272/2008 and subsequent amendments the substance will not be classified as irritating to the skin.
Reference Pooles (2013) is considered as the key study for in vivo eye irritation and will be used for classification. During the study the test item was applied to one eye of two animals each and the eye irritation was scored according to the Draize scale. The following mean scores (24, 48 and 72 hours) were obtained for the two animals:
cornea: 0 for both animals
iris: 0 for both animals
conjunctival redness: 1.67 and 1.0
chemosis:1.33 and 0.67
The ocular effects were fully reversible within 7 days. Thus, according to Regulation (EC) 1272/2008 and subsequent amendments the substance will not be classified as irritating to the eyes.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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