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Toxicological information

Eye irritation

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Endpoint:
eye irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
To provide data on the skin irritation of Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated (Technical Grade) OECD TG 437 - In vitro Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants) studies were conducted on all three grades. However, inconclusive outcomes were recorded for all three grades since the test materials as applied to the corneas were oily viscous liquids and it was not possible to remove all the test material from these tissues. A part of the test is to assess the opacity of the corneas by measuring the amount of light that passes through the cornea. In the tests the measured opacities of the corneas showed large variations within the replicates which suggest that the test material remaining on the corneas affected the opacity readings. The permeability readings were relatively low which suggests that the final mean in vitro irritancy score was not totally due to irritancy, but due to in part to adherence of the test material to the corneas.
No further assessments of skin irritation/corrosion data have been made for Technical Grade and the Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distillation Residue (Distillation Residue Grade) because it was not considered appropriate from an animal welfare standpoint. It is a legal and ethical duty under the Animals (Scientific Procedure) Act 1986 that the unnecessary use of animals is avoided, and that any testing which is likely to produce severe responses in animals is minimised. There is evidence that Distilled grade is an eye irritant (see 7.3.1). In a rabbit enucleated eye study Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) was instilled into three eyes of New Zealand White rabbits. The eyes were observed for 240 minutes. Irritation was scored by the method of McDonald-Shadduck. Moderate fluorescein uptake was noted in the test eyes 240 minutes following test material application. No fluorescein uptake was noted in the control eyes 240 minutes following treatment. Following assessment of the data for all endpoints, the test material was considered to have the potential to cause ocular irritancy in vivo. A similar conclusion is expected for Technical and Distillation Residue grades since it is postulated that the effects are due to cardol which is present in all the grades of processed cashew nutshell extract at concentrations of 5 to 13%. Studies by Keil et al. (1947), Schwartz et al. (1957), Rosen and Fordice (1994) and Diogenes et al. (1995, 1996) indicate that cardol is considered to act as a skin and eye irritant when present above threshold concentrations (of 1 to 2%). This is because the different forms of the substance share a common molecular skeleton with forms of urushiol an oily organic allergen found in plants of the family Anacardiaceae especially Toxicodendron spp. (e.g. poison oak, poison ivy, poison sumac) or Anacardium occidentale (Cashew Nut tree). Given that the three grades are considered to be eye irritants a further eye irritation test for Technical grade has not been conducted and relevant data has been generated by read-across from the source substances Distilled and Distillation Residue grade.
Under Annex XI of the REACH Regulation “General rules for adaptation of the standard testing regime set out in Annexes VII to X”, in addition to the specific rules set out in Column 2 of Annexes VII to X, a registrant may adapt the standard testing regime in accordance with the general rules set out in Section 1 of the Annex. One approach that may be used is the grouping of substances and the read-across approach (Section 1.5 of Annex XI). An overall grouping and read-across rationale has been developed for the three grades of cashew nutshell extract. This has involved using data for two source substances Distilled and Distillation Residue grades to read-across the required data for Technical grade by interpolation. In this context interpolation is “the estimation of a value for a member of the group using measured values from other members on both sides of that member within the defined group spectrum”.
The justification for the read-across approach results from the commonality of the constituents and functional groups in the three grades and the common modes of action for specific localised endpoints that are manifest in physico-chemical, environmental fate and toxicological properties that are similar or follow a regular pattern as a result of structural similarity. Further details on the justification for using the interpolation based read-across approach are given in the accompanying document “Report on the development of an updated grouping and read-across rationale for the three grades of processed Cashew Nutshell extract”. The following points are relevant:
• The three grades are manufactured using a common process in which the unprocessed cashew nutshell extract is heated, which produces Technical grade. Subsequent distillation does not result in the formation of any new constituents in the resulting Distilled and Distillation Residue grades, but rather changes in the proportion of certain constituents relative to those present in Technical grade.

• In all the three grades the proportions of three out of the five key constituents namely the low boilers, C17 phenolics and high boilers (cardol and 2-methylcardol) are similar. Whilst the lightest, lower molecular weight non-polymeric constituents (such as cardanol) and the highest molecular weight polymeric constituents vary between the grades, Technical grade compositionally lies between Distilled and Distillation Residue grades.

• For all the physico-chemical parameters for which measured data are available (relative density, vapour pressure, water solubility, octanol-water partition coefficient, flash point and flammability) the values estimated for the target substance Technical grade from the results generated in tests on the source substances Distilled and Distillation Residue grade are consistent with the actual measured values for Technical grade. The consistency of the estimated and measured values for these endpoints for Technical grade indicate that the read-across approach is appropriate and that reliable results can be generated by interpolation from the source substances (Distilled and Distillation Residue grades). In particular, there is consistency for the key physico-chemical parameters which influence toxicological behaviour of the three grades of processed cashew nutshell extract, namely: water solubility, octanol-water partition coefficient (logKow) and vapour pressure.

• Based on mammalian toxicity studies conducted with the Distilled grade, the following points can be concluded regarding the substance. Systemic effects following repeated dosing indicate that Distilled grade is absorbed via the gastro-intestinal tract. The rate and extent of absorption cannot be elucidated from the data available. Only local effects were observed from an acute dermal toxicity study, and also a skin irritation and sensitisation studies. It is likely that the skin barrier will be compromised by the irritation/sensitisation observed following application of Distilled grade, and that some absorption via this route will occur. Systemic effects in the lung, mesenteric lymph nodes, stomach and duodenum were observed, indicating that Distilled grade is distributed throughout the body, however, the extent of such distribution is unknown. There is no data available regarding metabolism or excretion of the Distilled grade.
The conclusions discussed above suggest similar local and systemic toxicity profiles for all the three substances. The use of data from two source substances Distilled and Distillation Residue grades to read-across to Technical grade is considered to provide greater confidence in the predicted data for the target substance, as testing at the two ends of the compositional spectrum will reveal the toxicity or lack of toxicity of all the key constituents (including those of their degradation products) which are present in the Technical grade. On this basis Technical grade is considered to be an eye irritrant.
References

Dióegenes, M.J.N., Morais, S.M.D.E and Carvalho, F.F. (1995) Perioral Contact Dermatitis by Cardol. International Journal of Dermatology, 34(1), 72-73.
Dióegenes, M.J.N., Morais, S.M.D.E. and Carvalho, F.F. (1996) Contact Dermatitis among Cashew Nut Workers. Contact Dermatitis, 35(2), 114-115.
Keil, H., Wasserman, D. and Dawson, D.R. (1945) The relation of hypersensitivity to poison ivy and to the pure ingredients in cashew nut shell liquid and related substances. Industrial Medicine and Surgery, 14, 825-830.
Rosen, T. and Fordice, D.B. (1994) Cashew Nut Dermatitis. Southern Medical Journal, 87(4), 543-546.
Scharwtz, L. Tulipan, L. and Peck, S.M. (1957) Occupational Disease of the Skin, 2nd Edition. Lea and Febiger Publishers, Philadelphia, pp638-647.

Category: Cashew Nutshell Extract category

Data source

Materials and methods

Test material

Reference
Name:
Unnamed

Results and discussion

In vivo

Results
Irritation parameter:
cornea opacity score
Remarks:
Maximum fluorescein uptake > = 4; Mean corneal swelling > = 25%
Time point:
other: 240 minutes
Score:
>= 4
Max. score:
4
Irritant / corrosive response data:
The data for all endpoints was assessed and an estimate of the test material ocular irritancy potential was made based on the following cut-off values:

REET Parameter REET cut-off value
Maximum Corneal Opacity > = 4
Maximum fluorescein uptake > = 4
Mean corneal swelling > = 25%
Corneal epithelium observations Any pitting, mottling or sloughing

Any other information on results incl. tables

Moderate loss of transparency was noted in all test eyes during the study.

Corneal swelling of the test eyes was considerably greater than that observed in the control eyes over the same period.

Pitting and sloughing of the corneal epithelium was noted in all test eyes during the study.

Moderate fluorescein uptake was noted in the test eyes 240 minutes following test material applicaiton. No fluorescein uptake was noted in the control eyes 240 minutes following treatment.

Applicant's summary and conclusion

Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) causes severe irritation to eyes. A similar conclusion is expected for Cashew Nutshell Extract, Decarboxylated (Technical Grade).
Executive summary:

In a rabbit enucleated eye study 0.1 ml of Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) was instilled into three eyes of New Zealand White rabbits.  The eyes were observed for 240 minutes. Irritation was scored by the method of McDonald-Shadduck.

 

Severe eye irritation was observed.  In this study, Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) is a severe eye irritant. A similar conclusion is expected for Cashew Nutshell Extract, Decarboxylated (Technical Grade).