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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted to OECD guidelines and to GLP.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD 422
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Cashew nutshell liquid (distilled grade)
- Physical state: liquid
- Lot/batch No.: AZ0192
- Storage condition of test material: room temperature in the dark
- Other: dark brown slightly viscous liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited
- Age at study initiation: 8 weeks
- Weight at study initiation: males, 290-335g; females 191-215g
- Housing: Initially in groups of 5 in polypropylene cages with stainless steel grid floors and tops, suspended over polypropylene trays lined with absorbant paper. During mating cages held one male and one female. Males were returned to their original cages and females were housed individually.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): 55%
- Air changes (per hr): 15/hour
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Storage temperature of food: 4°C

VEHICLE
- Justification for use and choice of vehicle (if other than water): arachis oil BP

Details on mating procedure
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear
- After successful mating each pregnant female was caged (how): individually in wire mesh cages

Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear
- After successful mating each pregnant female was caged (how): individually in wire mesh cages

Duration of treatment / exposure:
Up to 54 consecutive days.
Frequency of treatment:
Daily
Duration of test:
28 days up to 54 day.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 15, 150, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results o f a preliminary range-finder study.
- Rationale for animal assignment (if not random): Random based on stratified bodyweights

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily



DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before and after dosing, and one and five hours after dosing during the working week; before and after dosing, and one hour after dosing during the weekend.


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly for males; weeks 1, 2 and 3 and days 1 and 4 post partum for females.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data:


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations:


OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Day 13, females at day 5 post-partum
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals:5 males and 5 females/dose group


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:Day 13, females at day 5 post-partum
- Animals fasted: No data
- How many animals:5 males and 5 females/dose group

URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine:
- Animals fasted:


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: End of mating phase, 5 males/dose group; Day 4 post-partum, 5 females/dose group
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: No

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
Fetal examinations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead. GROSS NECROPSY
- Gross necropsy consisted of external appearance


Statistics:
ANOVA, incorporating Levene's test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparisons were conducted using Dunnett's test. Where Levene's test showed unequal variances the data were analysed using non-parametric methods: Kruskal-Wallis, ANOVA and Mann-Whitney 'U' test.
Indices:
Mating index, pregnancy index, parturition index, live birth index, viability index, sex ratio, pre-implantation loss, post-implntation loss

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
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.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No effects occurred.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

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 in the endpoint summary.

Applicant's summary and conclusion

Conclusions:
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.

Executive summary:

In a subchronic toxicity study Cashew Nutshell Extract, Decarboxylated, Distilled (Distilled Grade) as 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.The NOAEL is 150 mg/kg bw/day.

 

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.