Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
Reliable test data has been generated for a source substance for Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) in which no mortality was observed up to the limit dose of 2000 mg/kg bw in an acute dermal toxicity study (OECD TG402). This result is consistent with the predictions of low acute dermal toxicity for the different forms of cardanol and cardol (monoene, diene, triene and saturated side chain) using the OECD QSAR Toolbox which range from 1610 to 1770 mg/kg bw (see accompanying “Report on the development of an updated grouping and read-across rationale for the three grades of processed Cashew Nutshell extract”). These constituents typically comprise 88% of Distilled grade.

No measured acute dermal toxicity data have been derived for Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated (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 irritant (see 7.3.1) in a primary dermal irritation study (FHSA Standard 16 CFR 1500.41) carried out with rabbits. It is postulated that the effects are due to the presence of cardol, which is present in all three 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 an acute dermal 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 have low acute dermal toxicity.
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

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
Deaths did not occur during the study.
Clinical signs:
Systemic toxicity was not observed.
Body weight:
Three females showed bodyweight decrease or no gain in bodyweight during the first week with expected gain in bodyweight during the second week. One female showed expected gain in bodyweight during the first week with bodyweight decrease during the second week. All males and one female showed expected gains in bodyweight over the study period.
Gross pathology:
No abnormalities were noted.
Other findings:
Very slight or well-defined erythema was noted at the test sites of all animals. Other signs of dermal irritation noted were thickening of the skin, haemorrhage of dermal capillaries, hardened light brown or dark brown/black coloured scab, small superficial scattered scabs, scab undulating, scab cracking and scab lifting at edges to reveal bleeding, dried blood, glossy skin or further deep scabbing. Adverse reactions prevented accurate evaluation of erythema and oedema at all test sites during the study.

Any other information on results incl. tables

Table 2: Number of animals dead [and with evident toxicity] [and time range within which mortality occurred]

 

Dose
(mg/kg bw)

Conc.
in vehicle (%)*

Mortality (# dead/total)

Time range of deaths (hours)

Number with evident toxicity (#/total)

Male

Female

Combined

Male

Female

Combined

2000

 

 0/5

 0/5

0/10 

 -

 5/5

 5/5

10/10

 

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Deaths did not occur in an acute dermal toxicity test in rats at 2000 mg/kg bw, therefore Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) is of low acute dermal toxicity. Severe skin reactions were observed in all animals at the test substance application site.
Executive summary:

In an acute dermal toxicity study, groups of Sprague-Dawley rats (5/sex) were given a single dermal dose of Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) at 2000 mg/kg bw and observed for 14 days.

No mortality occurred in this limit test, therefore an LD50 has not been determined.

This acute study is classified as acceptable. It satisfies the guideline requirement for an acute dermal study in the rat.