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178User Guide for Thresholds and ClassificationsStep Parameter Findings ConclusionsNo5aIs a valid in vitro test available to assesssevere damage to eyesNo Go to step 65bIn vitro test for severe eye irritationEye corrosive Category 8.3ANot a severe eye irritant6 Is a valid in vitro test foreye irritation availableNoBut in vitro test forsevere eye irritancywas negativeGo to step 8YesIn the absence ofany in vitro testGo to step 76aIn vitro eye irritation testEye irritant Category 6.4ANo indication of eye irritant properties7 Experimentally assess skin corrosionpotential (see Table 11.1 in chapter 11)Skin corrosiveNo evaluation of effects on eyes,deemed to be category 8.3ANot corrosive8 One-rabbit eye testEye corrosive Category 8.3ANot corrosive9 One or two further rabbits Eye irritantCategory 6.4ANot an eye irritantNot classifiedJanuary 2012 EPA0109
179User Guide for Thresholds and ClassificationsNotes: See also Table 11.1 in chapter 11.Step 1:Step 2:Step 3:Step 4:Step 5:Step 6:Step 7:Step 8:Step 9:Data relating to historical human or animal experience: pre-existing information on eye irritation and skincorrosion are shown separately because evaluation of skin corrosion has to be considered if there is noinformation on local effects on eyes. Analysis of pre-existing experience with the chemical may identifyserious eye damage, corrosion, and irritation potential for both skin and eye effects.i Step 1a: Reliable determination of eye irritancy based on human or animal experience – Dependson expert judgement. In most cases human experience is based on accidental events, so the localeffects detected after an accident have to be compared with classification criteria created forevaluation of animal test data.ii. Step 1b: Evaluation of data on skin corrosivity – Skin corrosive substances should not be instilledinto the eyes of animals; such substances should be considered as leading to eye corrosion as well(category 8.3A).Structure activity relationships (SARs)/structure property relationships (SPRs) for eye irritation and skincorrosion are shown separately but in reality would probably be done in parallel. This stage should becompleted using validated and accepted SAR/SPR approaches. The SAR/SPR analysis may identifyserious eye damage, corrosion, and irritation potential for both skin and eye effects.i. Step 2a: Reliable determination of eye irritancy only by theoretical evaluations – In most cases itwill be appropriate only for substances that are homologous to agents with very well-knownproperties.ii. Step 2c: Theoretical evaluation of skin corrosivity – Skin corrosive substances should not beinstilled into the eyes of animals; such substances should be considered as leading to eyecorrosion as well (category 8.3A).pH extremes (≤ 2 and ≥11.5) may indicate strong local effects, especially in combination withassessment of acid or alkaline reserve, substances exhibiting such physico-chemical properties shouldbe considered as leading to eye corrosion (category 8.3A).All attainable information should be used, including human experience. But this information should berestricted to that which pre-exists (for example, the results of a skin median lethal dose (LD50) test orhistorical information on skin corrosion).These must be alternative methods for the assessment of eye irritation or corrosion (for example,irreversible corneal opacity) that have been validated in accordance with internationally agreed principlesand criteria.This step seems not to be achievable in the near future. Validated alternative methods for the reliableassessment of (reversible) eye irritation need to be developed.In the absence of any other relevant information, it is essential to obtain this using an internationallyrecognised corrosion or irritation test before proceeding to a rabbit eye irritation test. This must beconducted in a staged manner. If possible, this should be achieved using a validated, accepted in vitroskin corrosivity assay. If this is not available, then the assessment should be completed using animaltests (see section 11.1 in chapter 11).Staged assessment of eye irritation in vivo – If in a limit test with one rabbit eye corrosion is detected, nofurther testing is neededOnly two animals may be used for irritation testing (including the one used for evaluating possibleserious effects), if these two animals give concordant clearly irritant or clearly non-irritant responses. Inthe case of different or borderline responses, a third animal is needed. Depending on the result of thisthree-animal test, classification may be required or not.12.1.2. Weight of evidenceThe best quality data should be used as the fundamental basis for classification. Preferably, classificationshould be based on primary data sources. It is essential that test conditions are clearly and completelyarticulated.January 2012 EPA0109
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