Skin eye irritation

Strategie di test per la valutazione di skin e eye irritation

Costanza Rovida

CAAT Europe

REACH mastery

[email protected]

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Skin corrosion/irritation

in vivo in vitro

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in vivo

in vitro

Eye corrosion/irritation

I risultati negativi di un test in vitro non sono accettati dagli enti regolatori e vanno obbligatoriamente sempre confermati in vivo

1.4. In vitro methods…….If the results obtained from the use of such in vitro methods do not indicate a certain dangerous property, the relevant test shall nevertheless be carried out at the appropriate tonnage level to confirm the negative result, unless testing is not required in accordance with Annexes VII to X or the other rules in this Annex.Such confirmation may be waived, if the following conditions are met:(1) results are derived from an in vitro method whose scientific validity has been established by a validation study, according to internationally agreed validation principles;(2) results are adequate for the purpose of classification and labelling and/or risk assessment; and(3) adequate and reliable documentation of the applied method is provided.

Other official documents

http://echa.europa.eu/documents/10162/21650280/oecd_test_guidelines_skin_irritation_en.pdf

Report EUR 26797 ENhttp://publications.jrc.ec.europa.eu/repository/handle/111111111/32662

OECD 404: Description of the evaluation

and testing strategy

• Step 1: Evaluation of existing human and animal data• Step 2: Analysis of structure activity relationships

(SAR)• Step 3: Physicochemical properties and

chemical reactivity• Step 4: Dermal toxicity• Step 5 and 6: Results from in vitro or ex vivo tests• Step 6 and 7: In vivo test in rabbits

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1. Human data:

a. Occupational exposure

b. (consumer exposure)

2. Old animal data:

a. Impurities

b. GLP

Valutazione dei dati esistenti

Raccolta di tutte le informazioni disponibili

• Step 3: Physicochemical properties and chemical reactivity

• Step 4: Dermal toxicity (and other data)

http://chem.sis.nlm.nih.gov/chemidplus/

Raccolta di tutte le informazioni disponibili

Analisi della structure activity relationships (SAR)

Proprietà chimico-fisiche e reattività chimica

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Skin irritation Eye irritationNot irritant Not irritantCategory 2 – H315Causes skin irritation

Category 2 – H319Causes serious eye irritation

Category 1 – H314Causes severe skin burns and eye damage

Category 1 – H318Causes serious eye damage

Category 1A / 1B / 1C (Packing group I, II, III)1

Skin irritation Eye irritationNot irritant Not irritantNot irritant Category 2 - H319

Causes serious eye irritation

Category 2 – H315Causes skin irritation

Category 2 - H319Causes serious eye irritation

Category 2 – H315Causes skin irritation

Category 1- H318Causes serious eye damage

Category 1 – H314Causes severe skin burns and eye damage

• I dati esistenti, le proprietà chimico-fisiche (sperimentali o stimate) e lo studio SAR permettono una previsione preliminare della possibilita per una sostanza di essere irritante o corrosiva per la pelle e per gli occhi.

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CORROSIVO? IRRITANTE?

TOP DOWN APPROACH(irritation category)

BOTTOM UP APPROACH

Top Down e Bottom up

Esempio di strategia

X

Esempio: Thioanisole

methyl phenyl sulphideEC 202-878-2 CAS 100-68-5

https://eurl-ecvam.jrc.ec.europa.eu/laboratories-research/predictive_toxicology/information-sources/qsar-document-area/Evaluation_of_Skin_Irritation_QSARs.pdf

Thioanisole and QSAR Toolbox

Thioanisole and similar substances:Anisole

EUH066 (repeated exposure may cause skin dryness or cracking) Observed in an in vivo skin irritation study.

Thioanisole: mild irritant?

As described in the ECHA database

Guideline B46: In Vitro Skin Irritation: Reconstructed Human Epidermis Model TestGLP StudyTest substance: 10 µL undilutedDuration of treatment:

15 minutes followed by washing and incubation for 42 hours at 37°CTest animal: humanSpecies and strain, number of animals: not relevantcontrol animals: Other, negative control tissues treated with PBS;

positive control tissues treated with 5% SDS

Results: The relative mean tissue viability obtained after 15 minutes treatmentcompared to the negative controls was 11% (< 50%)

H315: Causes skin irritation

Thioanisole: eye irritant?


OECD Guideline 437:Bovine Corneal Opacity and Permeability (BCOP)GLP StudyTest substance: 750 µL undilutedDuration of treatment: 10 minutesTest animal: BovineSpecies and strain, number of animals: not relevant

Results: IVS range from 2.9 and 4.8, average 3.9

H318: Causes eye irritation

I risultati del BCOP sono molto vicini alla non classificazione. Questo, in teoria, dovrebbe indurre nuovi test di valutazione.Tuttavia, questa sostanza è già classificata irritante per la pelle.

Thioanisole: corrosive?


Guideline B40: In Vitro Skin corrosion: In vitro Skin Corrosion: Human Skin Model Test GLP StudyTest substance: 50 µL undilutedDuration of treatment: 3 minutes and 1 hourTest animal: humanSpecies and strain: not relevantnumber of animals: 4 tissuesResults: 3 minutes: viability 50%

1 hour: viability 59%

Not Corrosive, Classification H315 confirmed

Conclusions

Considerare le richieste regolatorie

Non esiste una strategia universale: anche la valutazione più semplice va adattata alla sostanza (miscela) specifica e ad un determinato uso, nonchè ambito di applicazione.

La valutazione di una sostanza va fatta in modo globale, e non endpoint per endpoint

Le conclusioni sono una valutazione di tutti I dati disponibili, e non solo una mera somma delle conclusioni dei singoli studi.

Un occhio anche ai costi e alla semplificazione dell'approccio

Ancora troppo basata sul giudizio degli esperti

Skin eye irritation

Science

Transcript of Skin eye irritation