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Toxicological information

Eye irritation

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Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
other: expert statement
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: expert statement

Data source

Reference
Reference Type:
publication
Title:
The Draize Eye Test and in vitro alternatives; a left-handed marriage?
Author:
Prinsen M.K.
Year:
2006
Bibliographic source:
Toxicology in Vitro 20 (2006) 78–81

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Principles of method if other than guideline:
Discussion of variability in the middle range of irritancy in the Draize Eye Test when testing sticky pastes and solids
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals / tissue source

Species:
rabbit

Test system

Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
contact time may vary from a couple of minutes to 24 h, because rinsing the eye is not allowed before the 24-h reading (only recently changed
to 1 h for solids in the 2002 update of OECD TG 405).
Observation period (in vivo):
not applicable
Number of animals or in vitro replicates:
not applicable

Results and discussion

In vivo

Results
Remarks on result:
other: For solids and sticky pastes, the Draize Eye Test is of limited relevance for the prediction of eye irritation potential in humans as the kind of entrapment of solids in the conjunctival cul-de-sac of the rabbit eye is highly unlikely to occur in humans.

Any other information on results incl. tables

Results from the Draize Eye Test may be highly variable especially in the middle range of irritancy and thus not necessarily be predictive of eye irritation potential in humans. One of the factors contributing to this variability is based on the unrealistic exposure conditions of the Draize Eye Test, i.e., instillation in the conjunctival cul-de-sac of the rabbit eye, compared to potential human exposure.

For hydrophilic substances instillation of 0.1 mL in the conjunctival cul-de-sac of the rabbit and holding of the eye-lids closed for 1 s, will result in a rapid removal of the material within seconds/minutes through blinking with the nictitating membrane. The situation is different for solids and sticky pastes: "Even if applied as a 0.1 mL equivalent (the content of the cul-de-sac), the actual amount of a powder/solid that stays in contact with the eye is unpredictable. More importantly, the contact time may vary from a couple of minutes to 24 h, because rinsing the eye is not allowed before the 1 h reading" (for solids). "In the case of poorly water-soluble solids with distinct cytotoxic properties, the entrapped solid can rapidly cause a considerable and increasing degree of swelling of the conjunctivae, making it even more difficult for the animal to remove the material. If, at the 1-h observation, the lower eye-lid is not pulled away far enough by the observer, it can stay unnoticed that a bulk of test material lays deeply hidden in the conjunctival cul-de-sac. Often, this forced continuous exposure for the next 24 h results in a complete closure of the eye-lids by the abundant production of colloidal discharge which often forms a sealing crust. Upon opening these sealed eyelids, purulent discharge, and other inflammatory debris are released. The degree of swelling of the conjunctivae can be sufficiently severe such that removal of any remains of the test substance is hardly possible anymore. In the majority of these cases, the eye is permanently damaged or can only be saved by applying special care, such as regular daily cleaning and rinsing of the eye and eye-lids, often including cutting off the eye-lashes to prevent further sealing. In general, keeping the eye-lids open is essential for the recovery process, otherwise the enclosed inflammatory exudate will further damage the cornea. If no further extensive remedial treatment is given to the animal, the described exposure conditions can easily cause an initial opacity score of 1 or 2 to develop into a score of 3 or 4. Also, the eye can become vulnerable to microbiological infection (the so-called secondary inflammatory process), causing initial mild to moderate effects during the first days after exposure developing into more severe and prolonged effects during the 21 day observation period."

Applicant's summary and conclusion

Interpretation of results:
other: the kind of entrapment of solids in the rabbit eye has little relevance, because it is highly unlikely to occur in humans
Conclusions:
For solids and sticky pastes, the Draize Eye Test is of limited relevance for the prediction of eye irritation potential in humans as the kind of entrapment of solids in the conjunctival cul-de-sac of the rabbit eye is highly unlikely to occur in humans.
Executive summary:

Based on the high variability in results, especially in the middle range of irritancy, the standard in vivo test for eye irritation according to OECD Guideline 405 is of limited relevance for the prediction of eye irritation potential of solids and sticky pastes in humans. One of the factors contributing to this variability is based on the unrealistic exposure conditions of the Draize Eye Test, i.e., instillation in the conjunctival cul-de-sac of the rabbit eye, compared to potential human exposure.

Poorly water-soluble solids may become entrapped and may cause a considerable and increasing degree of swelling of the conjunctivae, making it even more difficult for the animal to remove the material. If the eye ist not thoroughly rinsed at the 1 h observation, the forced continuous exposure to teh residual material for the next 24 h results in a complete closure of the eye-lids by the abundant production of colloidal discharge which often forms a sealing crust. Upon opening these sealed eyelids, purulent discharge, and other inflammatory debris are released. The degree of swelling of the conjunctivae can be sufficiently severe such that removal of any remains of the test substance is hardly possible anymore. In the majority of these cases, the eye is permanently damaged. If no further extensive remedial treatment is given to the animal, the described exposure conditions can easily cause an initial opacity score of 1 or 2 to develop into a score of 3 or 4. Also, the eye can become vulnerable to microbiological infection (the so-called secondary inflammatory process), causing initial mild to moderate effects during the first days after exposure developing into more severe and prolonged effects during the 21 day observation period.

The author concludes that "such data will be unsuitable for the use as benchmarking data in the validation of in vitro methods. Apart from that, the kind of entrapment of solids in the rabbit eye has little relevance, because it is highly unlikely to occur in humans, accidentally or intentionally."