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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
some minor deviations
GLP compliance:
yes
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled, oligomerisation products with 1-chloro-2,3-epoxypropane
Cas Number:
68413-24-1
Molecular formula:
C24H36O2
IUPAC Name:
Cashew (Anacardium occidentale) Nutshell Extract, Decarboxylated, Distilled, oligomerisation products with 1-chloro-2,3-epoxypropane
Test material form:
liquid
Details on test material:
- Name of test material (as cited in study report): CARDOLITE NC-513
- Physical state: liquid
- Batch no.: GH-0129
- Expiry date: 13.07.2014
- Storage condition of test material: room temperature 20 ± 5 °C, keep away from humidity
- Other: the test item was previously considered as 'Cashew, nutshell liq., oligomeric reaction products with 1-chloro-2,3-epoxypropane' (EC number 500-210-7).

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sandhofer Weg 7 97633 Sulzfeld, Germany
- Age at study initiation: 11-12 weeks
- Weight at study initiation: 259 g – 296 g (males); 173 g – 196 g (females) (at acclimatisation)
- Fasting period before study: no information
- Housing: Clean conventional housing
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6-9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 10 cycles/hour
- Photoperiod (hrs dark / hrs light): 12h/12h

Administration / exposure

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

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test item is not soluble in water in concentrations necessitated for this study. Formulations prepared with the vehicle are suitable for oral administration as it is the anticipated route of human exposure to the test item.
- Concentration in vehicle:
- Amount of vehicle (if gavage): Treatment volume was 5 mL/kg body weight in all groups
- Lot/batch no. (if required): N83746634
Details on mating procedure:
- Proof of pregnancy: vaginal plug and sperm in vaginal smear
- M/F ratio per cage: 1/1
- After successful mating each pregnant female was caged (how): single
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
males: 48 -61 days
females: >= 46 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
62.5 mg/kg bw/day (actual dose received)
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Control
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: preliminary study
Positive control:
none

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
- Cage side observations: Viability and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: at least once weekly

OTHER: see study record under 'Repeated dose toxicity'
Sperm parameters (parental animals):
Parameters examined in male parental generation:
testis weight, epididymis weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, weight gain

GROSS EXAMINATION OF DEAD PUPS: no
Postmortem examinations (parental animals):
Sacrifice: Animals were euthanised when found to be moribund or when the adequate number of litters according to guideline OECD 422 was achieved. All animals were sacrificed humanely by asphyxiation in a CO2 atmosphere.

Organ weights: The body weight of all animals killed at the end of the treatment period was recorded before sacrifice, and the organs specified in the Tissue Procedure Table were weighed wet as soon as possible after dissection. The ratio of organ weight to body weight (recorded immediately before sacrifice) was calculated.

Macroscopic post-mortem examination: A complete macroscopic post-mortem examination was performed on all study animals. This included examination of the external surfaces, all orifices, the cranial cavity, the external surfaces of the brain and spinal cord, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the neck with its associated organs and tissues.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mild discomfort throughout the whole application period was observed for the animals treated with the high and the medium dose of the test item (wiping of nose and mouth through the cage bedding, salivation after application, bleeding of mucous membranes at nose and mouth, respirators sounds). Moreover, some male animals of the high dose group became lethargic after application of the test item on individual days. A biological and particularly toxicological relevance of these observations could not be excluded.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Regarding the body weight and the body weight gain, no significant differences were observed between all test item treated animals (male and female) and their respective vehicle control animals. Occasional differences observed for the females were assumed to be of natural origin based on the pregnancy status of the animals.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Regarding the body weight and the body weight gain, no significant differences were observed between all test item treated animals (male and female) and their respective vehicle control animals. Occasional differences observed for the females were assumed to be of natural origin based on the pregnancy status of the animals.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Regarding the body weight and the body weight gain, no significant differences were observed between all test item treated animals (male and female) and their respective vehicle control animals. Occasional differences observed for the females were assumed to be of natural origin based on the pregnancy status of the animals.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No relevant test item induced effects on any haematology or clinical biochemistry parameter
could be detected
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No relevant test item induced effects on any haematology or clinical biochemistry parameter
could be detected
Endocrine findings:
not examined
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No alterations regarding general behaviour of the rats were observed during in-life phase
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
The type, incidence and severity of all microscopic findings observed did not indicate a relationship to the treatment with the test item. The repeated oral administration of the test item did not produce any evidence of pathomorphological findings that are considered to be due to a toxic effect of the test item.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

ORGAN WEIGHTS (PARENTAL ANIMALS)
For females of the high dose group (1000 mg/kg bw) ovary weight was increased.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
other: No adverse effects observed

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
A statistical significant decrease in the amount of pups born alive was detected for the animals of the high and medium dose groups
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Details on results (F1)

The total amount of live pups born is statistically significant reduced in the test item treated groups when compared to the vehicle control animals. A total of 11 animals of the high dose group gave birth to 69 pups (mean: 6,3). Ten animals of the medium dose group gave birth to 82 pups (mean: 8,2) and 9 animals of the low dose group gave birth to 77 pups (mean: 8,6). In contrast, 12 animals of the vehicle control group gave birth to 124 pups (mean: 10,3). The data were analysed additionally by Dunnett’s post-hoc t-test after One-Way ANOVA. Analysis revealed a statistically significant reduced amount of live born pups in the animals treated with the high and the medium dose of the test item. Regarding the loss of offspring it is striking, that six animals of the high dose group, eight animals of the medium dose group and seven animals of the low dose group had three or more pre-implantation losses (difference between corpora lutea and implantation sites), whereas only three animals of the vehicle control group had more than three pre-implantation losses (see table 10). Moreover, the mean amount of pre-implantation losses is about 30 to 50 % higher in the test item treated animals (High dose: 4,5; Medium dose: 3,9; Low dose: 4,1) when compared to the vehicle control animals (3,0).
No further abnormalities were detected during gestation and lactation phase. In summary, an increase in pre- implantation losses and a corresponding decrease in the amount of pups born alive was detected in all dose groups compared to the vehicle control group. However, pup growth and development, as far as monitored, was normal for all test item treated animals when compared to the vehicle control animals. No further differences were observed regarding reproduction success (achievement and duration of pregnancy, post- implantation losses, survival rate of pups, development of pups) for all test item treated animals when compared to the vehicle control animals. In the absence of another test item related effect the reduced amount of live born could not be rated as clear evidence for a toxic effect. Nonetheless, a test item related effect could not be excluded.

Effect levels (F1)

open allclose all
Dose descriptor:
NOAEL
Remarks:
Development
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Pup growth and development (day 0 and day 4 post-partum) were normal for all test item treated animals when compared to the vehicle control animals
Dose descriptor:
NOAEL
Remarks:
Embryo-/fetotoxicity
Generation:
F1
Effect level:
62.5 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: number of pups born alive

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of the present study, CARDOLITE NC-513 did not cause toxic changes and did not influence male and female reproductive performance (gonad function, mating behavior, conception, pregnancy, parturition) in parental male and female Wistar rats after repeated dose oral administration at 62.5, 250 or 1000 mg/kg bw/day.
The number of pups born alive was lower with respect to control at 250 and 1000 mg/kg bw/day.
Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as follows:
NOAEL (F0 systemic) females/males: 250 mg/kg bw/day
NOAEL (F0 reproduction) females/males: >=1000 mg/kg bw/day
NOAEL (F1 embryo-/fetotoxicity) 62.5 mg/kg bw/day
NOAEL (F1 development): >=1000 mg/kg bw/day (pup growth and development (day 0 and day 4 post-partum) were normal for all test item treated animals when compared to the vehicle control animals)
Executive summary:

 


In a GLP-study according to OECD Tes Guideline 422 the toxic effects of the test item CARDOLITE NC-513 at doses of 62.5, 250 and 1000 mg/kg body weight on the subacute toxicity and the development and reproduction of Wistar rats after oral administration were under examination.The substance was at least applied for 46 days daily to rats of both sexes. The following observations were made.


 


General and detailed clinical signs:


Mild discomfort throughout the whole application period was observed for the animals treated with the high and the medium dose of the test item (wiping of nose and mouth through the cage bedding, salivation after application, bleeding of mucous membranes at nose and mouth, respirators sounds). Moreover, some male animals of the high dose group became lethargic after application of the test item on individual days. A biological and particularly toxicological relevance of these observations could not be excluded.


 


Body weight, food and water consumption: Regarding the body weight and the body weight gain, no significant differences were observed between all test item treated animals (male and female) and their respective vehicle control animals. Occasional differences observed for the females were assumed to be of natural origin based on the pregnancy status of the animals.


No test item related tendencies regarding food and water consumption of all test item treated animals (male and female) could be observed throughout the whole study phase when compared to their respective vehicle control animals. All fluctuations observed were most likely of natural origin.


 


Haematology and clinical biochemistry: no effects


 


Reproduction and Development:


A statistical significant decrease in the amount of pups born alive was detected for the animals of the high and medium dose groups. This was not statistically significant for the animals of the low dose group. The increase in pre-implantation losses was not significant for any dose group. Pup growth and development (day 0 and day 4 post-partum) were normal for all test item treated animals when compared to the vehicle control animals. No further findings regarding reproduction success (achievement and duration of pregnancy, post- implantation losses, survival rate of pups, development of pups) were observed in animals of any test item treated group when compared to the vehicle control group.


 


Necropsy:


The determination of organ weights, as part of the necropsy, showed a statistically significant increase of the liver weight (male; absolute and relative), a statistically significant decrease of the prostate weight (absolute and relative), a statistically significant increase of the brain weight (female; absolute), and a statistically significant weight increase of the right ovary (absolute and relative) within the animals treated with the high dose of the test item. However, the changed organ weights were not accompanied by structural changes (see below 'Histology'). Moreover, with increasing dose levels the amount of male animals having slightly developed mammary glands declined. Besides some further individual findings, heterogeneously distributed over all dose groups, no further apparent observations were made that could be related to the administration of the test item.


 


Histology: no effects


 


Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as follows:


NOAEL (F0 systemic) females/males: 250 mg/kg bw/day
NOAEL (F0 reproduction) females/males: >=1000 mg/kg bw/day
NOAEL (F1 embryo-/fetotoxicity) 62.5 mg/kg bw/day
NOAEL (F1 development): >=1000 mg/kg bw/day (pup growth and development (day 0 and day 4 post-partum) were normal for all test item treated animals when compared to the vehicle control animals)