Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Justification for type of information:
1.HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
The basis for the adoption of a category approach for the three grades of processed Cashew Nutshell Extract is 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. The ECHA Final Decisions on the Annex IX and X (mammalian toxicology, ecotoxicology and environmental fate) Testing Proposals for three grades confirmed the applicability of a category approach which involves reading data across from the source substances Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) and Cashew Nutshell Extract, Decarboxylated, Distillation Residue (Distillation Residue Grade) to the target substance Cashew Nutshell Extract, Decarboxylated (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”. Further details on the justification for using the interpolation based read-across approach are given in the attached document “Report on the grouping and read-across rationale for the three grades of processed Cashew Nutshell Extract”. The interpolation approach has been applied to the Annex IX OECD TG408 and TG414 testing on Distilled and Distillation Residue Grades. For the Annex VII and VIII endpoints a programme of testing has been carried out to provide comparative information for the three grades and develop a data matrix to support the category and read-across approaches. This has involved generating reliable data for all Annex VII and VIII physico-chemical and environmental fate endpoints and certain mammalian toxicity properties. However, based on the discussions surrounding the Final Decisions it was not considered necessary to apply this approach retrospectively to address all identified data gaps at Annexes VII and VIII. The original data used for the registration of a single substance (Cashew Nutshell Liquid, CAS Number 8007-24-7) was largely based on data for Distilled Grade since this was considered to be the most (eco) toxicologically active form, given the higher content of low molecular weight constituents (such as cardanol) and the low content of polymeric species. Therefore, based on the use of the category approach it is considered appropriate to read-across from the existing short-term mammalian toxicity data for Distilled Grade to the other two grades.
2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL)
For the skin sensitisation endpoint no test data is available for the registered substance Distillation Residue Grade. However data is available for the compositionally similar substance Distilled Grade which is part of the category of the three grades of CNSL. In a dermal sensitisation study with Distilled Grade in acetone/olive oil 4:1, four young adult CBA mice were tested using the LLNA method. Mild redness to the eyes and neck were observed in test animals. No other clinical signs of toxicity were noted and mortality did not occur. Bodyweights of treated animals were comparable to that of controls. Stimulation indexes of 29.29 and 30.90 were identified, for the two samples, respectively and Distilled Grade was considered to be a dermal sensitiser. It is considered appropriate to read-across from the data for Distilled Grade to Distillation Residue Grade with the result that it has been estimated that Distillation Residue Grade is a dermal sensitiser.
Parameter:
SI
Remarks on result:
other: Vehicle: N/A NX-4708: 29.29 NX-2023: 30.90
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: Vehicle: 4871.26 NX-4708: 142691.40 NX-2023: 150509.50

Table 1 Clinical observations, bodyweight and mortality data - preliminary screening test - NX-4708

Concentration (% v/v) in acetone/olive oil 4:1 Animal number  Bodyweight change (g) Day 
      1  6  1     2     3     4  6
      Pre dose  Post dose
Pre dose
 Post dose  Pre dose  Post dose              
100  S-1  20 
50  S-2  20 
25  S-3  17 
10  S-4  19  20 
Interpretation of results:
sensitising
Remarks:
Migrated information EU
Conclusions:
A positive result was obtained in a well-conducted LLNA, indicating that Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) is able to cause skin sensitisation. A similar conclusion is expected for Cashew Nutshell Extract, Decarboxylated, Distillation Residue (Distilled Residue Grade) based on the read-across justification.
Executive summary:

For the skin sensitisation endpoint no test data is available for the registered substance Distillation Residue Grade. However, data is available for the compositionally similar substance Distilled Grade which is part of the category of the three grades of CNSL. In a dermal sensitisation study with Distilled Grade in acetone/olive oil 4:1, four young adult CBA mice were tested using the LLNA method. Mild redness to the eyes and neck were observed in test animals. No other clinical signs of toxicity were noted and mortality did not occur. Bodyweights of treated animals were comparable to that of controls. Stimulation indexes of 29.29 and 30.90 were identified, for the two samples, respectively and Distilled Grade was considered to be a dermal sensitiser. It is considered appropriate to read-across from the data for Distilled Grade to Distillation Residue Grade with the result that it has been estimated that Distillation Residue Grade is a dermal sensitiser.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Read across justification

The read across substance is Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (“Distilled Grade”). A document which justifies the read–across from Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (“Distilled Grade”) to Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distillation Residue (“Distilled Residue Grade”) is attached.

Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled (“Distilled Grade”) has a higher proportion of lower molecular weight, more potentially toxicologically active components, (principally cardanol) and lower proportion of more inert polymeric species compared to Distillation Residue Grade. The relative typical proportions of the cardanol and polymeric species in Distilled and Distillation Residue Grades are 78% versus 35% and 2% versus 50% respectively. Therefore, it is considered that distilled grade has the potential to exert greater toxicity within the group of distilled, technical and distilled residue grades (see Section 3.1 - Technological Process) for endpoints relevant to human health and environmental effects. On this basis within the group of distilled, technical and distilled residue grades, the substance Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled represents the potentially most (eco)toxicologically active form.

In a dermal sensitization study with Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade), guinea pigs (20) were tested with in a guinea pig maximisation test. Positive reactions in 30% of test animals is required for a positive sensitising result in an adjuvant test. A positive response was elicited in 70% of animals when a 1% induction dose was applied and challenged with a 5% concentration. Therefore, according to guidelines, this substance is a sensitser.Greater than 60% of animals responded at a 1% intradermal induction dose, therefore sub-category 1A is appropriate.In a dermal sensitization study with distilled Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) in acetone/olive oil 4:1, four young adult CBA mice were tested using the LLNA method.  Mild redness to the eyes and neck were observed in test animals. No other clinical signs of toxicity were noted and mortality did not occur. Bodyweights of treated animals were comparable to that of controls. Stimulation indexes of 29.29 and 30.90 were identified, for NX-4708 and NX-2023, respectively.  In this study, distilled Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) is a dermal sensitiser.

EC3 value was not directly determined, however, 10% of test substance elicited a stimulation index of 30 (EC3 = % test substance required to elicit a stimulation index of 3).

The two studies indicate that Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) is a skin sensitiser category 1A. A similar conclusion is expected for Cashew Nutshell Extract, Decarboxylated, Distillation Residue (Distilled Residue Grade) based on the read-across justification.


Migrated from Short description of key information:
In a dermal sensitization study with Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade), guinea pigs (20) were tested with in a guinea pig maximisation test.

Positive reactions in 30% of test animals is required for a positive sensitising result in an adjuvant test. A positive response was elicited in 70% of animals when challenged with a 5% concentration. Therefore, according to guidelines, this substance is a sensitser.

In a dermal sensitization study with distilled CNSL in acetone/olive oil 4:1, four young adult CBA mice were tested using the LLNA method. Mild redness to the eyes and neck were observed in test animals. No other clinical signs of toxicity were noted and mortality did not occur. Bodyweights of treated animals were comparable to that of controls.
Stimulation indexes of 29.29 and 30.90 were identified, for NX-4708 and NX-2023, respectively. In this study, Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) is a dermal sensitiser. A similar conclusion is expected for Cashew Nutshell Extract, Decarboxylated, Distillation Residue (Distilled Residue Grade) based on the read across justification.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

In a guinea pig maximisation test, positive response was elicited in 70% of animals when a 1% induction dose was applied, and challenged with a 5% concentration. Therefore, according to guidelines, this substance is a demal sensitser.Greater than 60% of animals responded at a 1% intradermal induction dose, therefore sub-category 1A is appropriate.

In a LLNA, Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) gave stimulation indexes of 29.29 and 30.90 following administration of 10% dose, therefore is classed as a dermal sensitiser. The EC3 value was not directly determined, however, 10% of test substance elicited a stimulation index of 30 (EC3 = % test substance required to elicit a stimulation index of 3).

The two studies indicate that Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) is a skin sensitiser category 1A. A similar conclusion is expected for Cashew Nutshell Extract, Decarboxylated (Technical Grade) based on the read-across justification.