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Toxicological information

Skin irritation / corrosion

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Administrative data

Endpoint:
skin 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) an OECD TG 439 study (In Vitro Skin Irritation Reconstructed Human Epidermis Test Method) has been conducted on all three grades. However, inconclusive outcomes were recorded for all three grades due to the nature of the test substances (i.e. they were oily viscous liquids which caused staining). These primarily related to difficulties in removing the test substances from the viable tissues without causing superficial damage and also to the fact that the test substances that remained on the tissues affected the test measurements. These issues are likely to have affected the reliability of the results and the interpretation of the data with regard to a substances’ potential to cause skin irritation.
No further assessments of skin irritation/corrosion data have been made for Technical Grade and 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 skin irritant (see 7.3.1) in a previous primary dermal irritation study (FHSA Standard 16 CFR 1500.41), three young adult New Zealand white rabbits were exposed dermally to Distilled grade for 24 hours. Animals then were observed for 72 hours and irritation was scored by the method of Draize. 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 skin irritants a further skin irritation/corrosion 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 a skin 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

GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
erythema score
Remarks:
Sample 1500-1, animal 1
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
erythema score
Remarks:
Sample 1500-1, animals 2 and 3
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
3.5
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample 1500-1, animal 1
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
2.5
Max. score:
3
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample 1500-1, animals 2 and 3
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
erythema score
Remarks:
Sample AF6155, animals 1, 2 and 3
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample AF6155, animal 1
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
2
Max. score:
2
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample AF6155, animal 2
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
3.5
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample AF6155, animal 3
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
erythema score
Remarks:
Sample 1600-1, animals 1, 2 and 3
Basis:
mean
Time point:
other: 24 and 72
Score:
1.5
Max. score:
2
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample 1600-1, animal 1
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0.5
Max. score:
1
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample 1600-1, animal 2
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
1
Max. score:
1
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample 1600-1, animal 3
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
1.5
Max. score:
2
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
erythema score
Remarks:
Sample 1650-1, animals 1 and 3
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
1.5
Max. score:
2
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
erythema score
Remarks:
Sample 1650-1, animal 2
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
1
Max. score:
1
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample 1650-1
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0
Max. score:
0
Irritation parameter:
edema score
Remarks:
Sample 1650-1
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
1
Max. score:
1
Reversibility:
not fully reversible within: 72 hours
Irritation parameter:
edema score
Remarks:
Sample 1650-1
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
1.5
Max. score:
2
Reversibility:
not fully reversible within: 72 hours

Applicant's summary and conclusion

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Samples 1500-1 and AF6155 were irritating, however, samples 1600-1 and 1650-1 were not irritating.
Executive summary:

In a primary dermal irritation study, 3 young adult New Zealand white rabbits were dermally exposed to Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) for 24 hours. Animals then were observed for 72 hours. Irritation was scored by the method of Draize.

 

In this study, Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) is a dermal irritant. A similar conclusion is expected for Cashew Nutshell Extract, Decarboxylated (Technical Grade).