Registration Dossier

Administrative data

Description of key information

In a subchronic toxicity study Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) was administered to 5 Sprague-Dawley rats/sex/dose via gavage at dose levels of 0, 15, 150, or 1000 mg/kg bw/day). 
Systemic changes in the lungs, mesenteric lymph node, stomach and duodenum occurred at the highest dose. A NOAEL of 150 mg/kg bw/day has been identified for systemic toxicity. A NOAEL of 1000 mg/kg bw/day has been identified for reproductive parameters.
This repeat dose/reproductive toxicity screening study in the rat is acceptable and satisfies the guideline requirement for a subchronic oral study OECD 422 in rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key 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 mammalian reproductive toxicity 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 subacute 28-day Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test Distilled Grade was administered to 5 Sprague-Dawley rats/sex/dose via oral gavage at dose levels of 0, 15, 150, or 1000 mg/kg bw/day). Changes in the lungs, mesenteric lymph node occurred at the highest dose of 1000 mg/kg bw/day resulting in a NOAEL of 150 mg/kg bw/day for systemic toxicity. A NOAEL of 1000 mg/kg bw/day has been identified for reproductive toxicity based on an absence of effects of the test substance on the relevant reproductive parameters. 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 does not result effects on mammalian reproductive toxicity parameters at an exposure dose of 1000 mg/kg bw/day.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no toxicologically significant deaths during the study.

Increased salivation was detected prior to dosing and up to 5 hours after dosing for animals of either sex treated with 1000 mg/kg bw/day from Day 9 onwards. One female treated with 150 mg/kg bw/day developed clinical signs consistent with inappropriate dosing on Day 5 and was subsequently terminated. One female treated with 1000 mg/kg bw/day had given birth to a number of pups of which the majority were found dead. Several clinical signs were observed in this animal, and the animal and litter were terminated.

BODY WEIGHT AND WEIGHT GAIN
A slightly reduced bodyweight gain was observed for 1000 mg/kg bw/day males during the first two weeks of the study. Reduced bodyweight gain was also observed for 1000 mg/kg bw/day females during the later stages of the gestation period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No adverse effect on dietary intake or food efficiency were detected.

FOOD EFFICIENCY
No adverse effect on dietary intake or food efficiency were detected.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
No intergroup differences were detected.

OPHTHALMOSCOPIC EXAMINATION
N/A

HAEMATOLOGY
Haematological assessments revealed elevated platelet counts in animals of either sex treated with 1000 mg/kg bw/day. Elevated haemoglobin, erythrocyte and haematocrit was also evident for males treated at 1000 mg/kg bw/day. No such effects were detected at 150 and 15 mg/kg bw/day.

CLINICAL CHEMISTRY
An increase in aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels were observed for 1000 mg/kg bw/day animals of either sex, together with elevated inorganic phosphorus, bilirubin and urea, and reduced cholesterol levels.

URINALYSIS
N/A

NEUROBEHAVIOUR
Open field arena observations revealed increased salivation for individual animals of either sex treated with 1000 mg/kg bw/day from Week 3.

ORGAN WEIGHTS
Females treated with 1000 mg/kg bw/day showed elevated liver weights.

GROSS PATHOLOGY
None

HISTOPATHOLOGY: NON-NEOPLASTIC
Groups of alveolar macrophages were seen with a higher incidence for females treated with 1000 mg/kg bw/day.
A higher incidence of sinus histiocytosis and/or foamy histiocytes was observed in relation to treatment with 1000 mg/kg bw/day.
Hyperkeratosis, frequently associated with acanthosis was seen in the forestomachs of animals of either sex treated with 1000 mg/kg bw/day. Focal ulceration of the forestomach epithelium was also seen in one high dose female.
Mucosal hypertrophy was seen in three males at the top dose group. A low incidence of mucosal hypertrophy was observed in females in all dose groups.

OTHER FINDINGS
MATING
No adverse effects on mating or fertility were observed.

OFFSPRING LITTER SIZE AND VIABILITY
No effects detected.

OFFSPRING GROWTH AND DEVELOPMENT
No effects detected.

LITTER OBSERVATIONS
No effects detected.

UTERINE EXAMINATION
No effects detected.
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Based on systemic changes in the lungs, mesenteric lymph node, stomach and duodenum.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No treatment effects occurred on reproduction or offspring development.
Critical effects observed:
not specified
Conclusions:
Changes in the lungs, mesenteric lymph node occurred at the highest dose of 1000 mg/kg bw/day resulting in a NOAEL of 150 mg/kg bw/day for systemic toxicity. A NOAEL of 1000 mg/kg bw/day has been identified for reproductive toxicity based on an absence of effects of the test substance on the relevant reproductive parameters. 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 does not result effects on mammalian reproductive toxicity parameters at an exposure dose of 1000 mg/kg bw/day.
Executive summary:

In a subacute 28-day Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test Distilled Grade was administered to 5 Sprague-Dawley rats/sex/dose via oral gavage at dose levels of 0, 15, 150, or 1000 mg/kg bw/day). Changes in the lungs, mesenteric lymph node occurred at the highest dose of 1000 mg/kg bw/day resulting in a NOAEL of 150 mg/kg bw/day for systemic toxicity. A NOAEL of 1000 mg/kg bw/day has been identified for reproductive toxicity based on an absence of effects of the test substance on the relevant reproductive parameters. 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 does not result effects on mammalian reproductive toxicity parameters at an exposure dose of 1000 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Read across justification - 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 Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) has been tested for 28 days via the oral route. No severe adverse signs of toxicity occurred. A similar conclusion is expected for Cashew Nutshell Extract, Decarboxylated, Distillation Residue (Distilled Residue Grade) based on the read-across justification.

A 28 day repeat dose oral study is available, therefore a further 28 day studies via the dermal and inhalation routes cannot be justified due to additional animal testing.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: duodenum; digestive: stomach; glandular: other; respiratory: lung

Justification for classification or non-classification

In an oral repeat dose study, the lowest no adverse effect level (NOAEL) associated with a reproducible effect is 150 mg/kg bw/day.