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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
The effect values for the prenatal developmental toxicity to mammals endpoint for the target substance Technical Grade have been generated by interpolation from the experimental test data on the source substances Distilled and Distillation Residue Grades. In this context interpolation is considered to be 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’ (ECHA 2008: Guidance on information requirements and chemical safety assessment. Chapter R.6: QSARs and grouping of chemicals).

Distilled and Distillation Residue Grades represent the two ends of the compositional spectrum of the three grades of CNSL with regard to the levels of the main component (the different forms of cardanol) and the polymeric content. Distilled Grade has the highest level of cardanol and a lowest level of polymeric content, whilst Distillation Residue Grade has the lowest level of cardanol and the highest level of the polymeric content. On a compositional basis the target substance Technical Grade lies between Distilled and Distillation Residue Grade.

Full details of the results of the OECD TG414 tests on Distilled Grade (EC Number 700-991-6) and Distillation Residue Grade (EC Number 941-212-1) are given in the relevant Registration Dossiers.

Data source

Materials and methods

Test material

1
Reference substance name:
Cashew Nutshell Extract, Decarboxylated (Technical Grade)
IUPAC Name:
Cashew Nutshell Extract, Decarboxylated (Technical Grade)

Test animals

Species:
rat

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related clinical signs of toxicological relevance (such as hunched posture, flat gait, rales, piloerection, ptosis, uncoordinated movements and/or pale appearance) may be evident for organisms exposed to Technical Grade at higher doses (500 to 1000 mg/kg bw/day) based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related body weight effects (as decreases in body weight gain before and after correction for uterus weight) may be evident for organisms exposed to Technical Grade at higher doses (500 to 1000 mg/kg bw/day) based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Endocrine findings:
no effects observed
Description (incidence and severity):
No test substance induced changes in triiodothyronine (T3) or thyroxine (T4) are expected in females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade. Increases in thyroid stimulating hormone (TSH), showing considerable inter-group variability, but which are largely consistent with the 95%ile limit for historical control data of the test laboratory, may be expected in females exposed to Technical Grade and surviving to necropsy based on interpolation from the data for Distilled and Distillation Residue Grades.
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No changes in behavior (functional findings) are expected in organisms which have been exposed to Technical Grade and survived to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No changes to thyroid weight (including thyroid /body weight ratios) are expected in organisms which have been exposed to Technical Grade and survived to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related gross pathological changes (namely increased incidence of irregular surface morphology of the non-glandular mucosa of the stomach and duodenum thickening) may be evident for organisms exposed to Technical Grade at higher doses (500 to 1000 mg/kg bw/day) based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related non-neoplastic histopathological findings (namely increased incidence of irregular surface morphology of the non-glandular mucosa of the stomach and duodenum thickening) may be evident for organisms exposed to Technical Grade at higher doses (500 to 1000 mg/kg bw/day) based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No neoplastic histopathological findings are expected in organisms which have been exposed to Technical Grade and survived to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.

Maternal developmental toxicity

Number of abortions:
not examined
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No treatment–related effects on pre- and post-implantation losses are expected in organisms which have been exposed to Technical Grade and survived to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No treatment–related effects on total litter losses are expected in organisms which have been exposed to Technical Grade and survived to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Early or late resorptions:
no effects observed
Description (incidence and severity):
No treatment–related effects on the number of early or late resorptions are expected in organisms which have been exposed to Technical Grade and survived to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Dead fetuses:
no effects observed
Description (incidence and severity):
No treatment–related effects on the number of dead fetuses are expected in organisms which have been exposed to Technical Grade and survived to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
No treatment–related effects on the changes in the number of pregnant females are expected in organisms which have been exposed to Technical Grade and survived to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: Maternal toxicity

Maternal abnormalities

Abnormalities:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related non-neoplastic histopathological findings (namely increased incidence of irregular surface morphology of the non-glandular mucosa of the stomach and duodenum thickening) may be evident for organisms exposed to Technical Grade at higher doses (500 to 1000 mg/kg bw/day) based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
No toxicologically significant changes are expected for the body weight of fetuses produced by adult females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No toxicologically significant changes are expected for the numbers of live offspring produced by adult females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No toxicologically significant changes are expected for the sex ratio of fetuses produced by adult females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No toxicologically significant changes are expected for the size and weights of offspring produced by adult females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade
Anogenital distance of all rodent fetuses:
no effects observed
Description (incidence and severity):
No toxicologically significant changes are expected for the anogenital distance of fetuses produced by adult females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
No toxicologically significant changes are expected for external malformations of fetuses produced by adult females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No toxicologically significant changes are expected for skeletal malformations of fetuses produced by adult females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.
Visceral malformations:
no effects observed
Description (incidence and severity):
No toxicologically significant changes are expected for visceral malformations of fetuses produced by adult females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.

Effect levels (fetuses)

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Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Tetratoxicity
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Fetotoxicity
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Embryotoxicity

Fetal abnormalities

Abnormalities:
no effects observed
Description (incidence and severity):
No toxicologically significant changes are expected for external, visceral and skeletal malformations of fetuses produced by adult females exposed to Technical Grade and surviving to necropsy based on interpolation from the results of tests on the source substances Distilled and Distillation Residue Grade.

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The effects values for the prenatal developmental toxicity to mammals endpoint for the target substance Technical Grade have been generated by interpolation from the experimental test data on the source substances Distilled and Distillation Residue Grades.

In the study on Distilled Grade all the animals at the highest dose of 1000 mg/kg bw/day had to be euthanized on animal welfare grounds in extremis on Days 12-18 post-coitum. At the mid dose of 300 mg/kg bw/day mild to moderate test substance-related local effects (as marked alterations to forestomach morphology) and systemic toxicity (as reduced bodyweight gains) were evident. In contrast, no effects relevant to maternal toxicity were evident at any of the doses (100, 300 and 1000 mg/kg bw/day) in the test on Distillation Residue Grade.

In both studies, no toxicologically significant changes were noted in any of the developmental parameters investigated in this study (i.e. litter size, post-implantation loss, sex ratio, fetal body weights, fetal anogenital distance, external, as well as visceral and skeletal malformations and developmental variations) were evident in animals surviving to necropsy (300 and 1000 mg/kg bw/day for Distilled and Distillation Residue Grades respectively).

For the target substance Technical Grade, based on the results obtained for Distilled and Distillation Residue Grades, the precautionary “worst case” NOAEL for the prenatal developmental toxicity to mammals endpoint (maternal toxicity) would be 100 mg/kg bw/day. This corresponds to the lowest toxicity value measured in the studies on the source substances and has been identified as the most scientifically defensible value be used for the derivation of the relevant DNEL and PNEC thresholds based on the analysis of the OECD TG414 data. This NOAEL also provides protection against the observed local effects on stomach morphology due to the know irritancy of the test substance. The corresponding NOAEL for developmental toxicity would be 300 mg/kg bw/day based on the responses in the tests on Distilled and Distillation Residue Grades.
Executive summary:

The effect values for the endpoint for the target substance Technical Grade have been generated by interpolation from the experimental test data on the source substances Distilled and Distillation Residue Grades. In this context interpolation is considered to be 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’ (ECHA 2008: Guidance on information requirements and chemical safety assessment. Chapter R.6: QSARs and grouping of chemicals). Distilled and Distillation Residue Grades represent the two ends of the compositional spectrum of the three grades of CNSL with regard to the levels of the main component (the different forms of cardanol) and the polymeric content. Distilled Grade has the highest level of cardanol and a lowest level of polymeric content, whilst Distillation Residue Grade has the lowest level of cardanol and the highest level of the polymeric content. On a compositional basis the target substance Technical Grade lies between Distilled and Distillation Residue Grade.


 


In valid (reliable without restrictions, Klimisch Code 1) OECD TG414 Prenatal Developmental Toxicity Studies on Distilled and Distillation Residue Grades groups of time-mated Wistar Han female rats were exposed to doses of 100, 300 and 1000 mg/kg bw/day by once daily oral gavage for 14 days from Day 6 to 20 post-coitum.


 


In the study on Distilled Grade severe toxicity of the test substance was observed in females treated at 1000 mg/kg bw/day and this complete high dose group was euthanized on animal welfare grounds in extremis on Days 12-18 post-coitum.  In these animals, slight to severe body weight loss (up to 20%) and/or strongly reduced body weight gain, strongly reduced food consumption (up to 50% lower than controls), severe macroscopic alterations of the stomach wall (irregular surface) and/or severe clinical signs. At the mid-dose 300 mg/kg bw/day treatment mild to moderate test substance-related effects were evident. Microscopy revealed ulceration/erosion, hyperplasia with keratosis and sub-epithelial inflammatory cell infiltrates. The forestomach findings are considered a local test substance-related effect, most likely caused by the known irritating properties of cardol and, to a lesser extent, cardanol constituents of the test substance. At this dose level body weight gain was slightly lower from Day 12 post-coitum onwards, reaching statistical significance on Days 18 and 20 post-coitum only (0.88x and 0.83x of controls, respectively). 


 


In the corresponding study on Distillation Residue Grade no maternal toxicity was observed in the 100, 300 and 1000 mg/kg bw/day groups, as no relevant endpoints showed significant differences in responses compared to the control animals.


 


No test substance-related microscopic observations in the thyroid glands of females were observed in animals surviving to necropsy in both studies as the recorded responses were within the range of normal background pathology encountered in rats of this age and sex for both grades. In both studies no test substance induced changes in triiodothyronine (T3) or thyroxine (T4) were evident in adult females surviving to necropsy (300 and 1000 mg/kg bw/day for Distilled and Distillation Residue Grades respectively). In both studies increases in thyroid stimulating hormone (TSH), showing considerable inter-group variability, but which are largely consistent with the 95%ile limit for historical control data of the test laboratory, were evident in adult females surviving to necropsy. Given that the possible adversity of these effects could not be assessed within this type of study the finding was not taken into account when determining the maternal NOAEL.


 


In both studies no toxicologically significant changes were noted in any of the developmental parameters investigated in this study (i.e. litter size, post-implantation loss, sex ratio, fetal body weights, fetal anogenital distance, external, as well as visceral and skeletal malformations and developmental variations) were evident in animals surviving to necropsy.


 


The data from the oral gavage OECD TG414 study on Distilled Grade is consistent with the data from the OECD TG408 studies and indicates that there is localised epithelial hyperplasia of the non-glandular mucosa (forestomach, squamous mucosa) in the stomach at higher exposure doses. The stomach findings were interpreted to be adverse due to the overall severity and concurrent presence of ulceration in some animals. This response is considered to be a result of the known irritancy of the test substance due to the presence of the constituents cardol, and to a lesser extent, cardanol. No comparable effects were observed in the OECD TG414 study on Distillation Residue Grade. In the study on Distillation Residue Grade gross lesions (dark red discoloration) were noted in the mesenteric lymph nodes for 3/22 females at 1000 mg/kg bw/day. However, no test substance-related microscopic findings were observed. No comparable effects were observed in the study on Distilled Grade.


 


For the target substance Technical Grade, based on the results obtained for Distilled and Distillation Residue Grades, the precautionary “worst case” NOAEL for the prenatal developmental toxicity to mammals endpoint (maternal toxicity) would be 100 mg/kg bw/day. This corresponds to the lowest toxicity value measured in the studies on the source substances and has been identified as the most scientifically defensible value be used for the derivation of the relevant DNEL and PNEC thresholds based on the analysis of the OECD TG414 data. This NOAEL also provides protection against the observed local effects on stomach morphology due to the know irritancy of the test substance. The corresponding NOAEL for developmental toxicity would be 300 mg/kg bw/day based on the responses in the test on Distilled Grade.

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