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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
OECD 422
Type of information:
other: read-across from supporting substances (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
only Japanese translation available

Data source

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

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:
no
GLP compliance:
yes

Test material

Constituent 1
Test material form:
solid
Details on test material:
at room temperature appears as a yellow waxy paste
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: lot number 308251 from Taiyo Kagaku (Mie)
- Purity: 99.93%

STABILITY AND STORAGE CONDITIONS:
- Storage condition of test material:
stored under cool and dark condition (2 to 6°C)
- Storage condition of vehicle: corn oil stored in a cold place (2-6 °C), tightly closed under lighy shielding until use

It was confirmid that the test substance under storage conditions and dosage form was stable

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan (Kanagawa)
- Females (if applicable) nulliparous and non-pregnant: [yes]
- Age at study initiation: 10 weeks
- Weight at study initiation: The mean body weight for male 372 (352 to 426) g and for female 224 (192 to 249) g
- Housing: wire mesh cage and raised with solid feed (Lab MR Stock, Nippon Nogyo Sangyo). Females after mating confirmation were placed in a polycarbonate cage containing nest-making material (White Flake, Japan Charles River).
- Diet: ad libitum
- Water: ad libitum
- Recovery period: 14 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.1°C - 23.2°C
- Humidity (%): 48-61%

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
Nacalai Tesque
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosage of the test sustance is prepare as a solution with a concentration to give prescribed dose by using solvent oil (Nacalai Tesque) as a solvent

DIET PREPARATION
- Type of food: solid food

VEHICLE
- Justification for use and choice of vehicle (if other than water): 9-cis-octadecenoic acid (2,3-dihydroxypropyl) ester is insoluble in water but is soluble in food oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Method of administration:using a syringe fitted with Teflon stomach sonde, once a day (in the morning), Males were administered for 42 days, starting two weeks before mating. Females were administered staring two weeks before mating, during mating, pregnancy and until 4 days post-partum. Males and the female satellite group were orally administered for 42 days. Corn oil was similarly administered to the control group.
Frequency of treatment:
daily in the morning
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
5 animals for each dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: As a dose setting test, the test substance was repeatedly administered orally at doses of 0, 100, 300, and 1000 mg / kg for 14 days to 5 rats of each group. Weight and food consumption measurements, hematology and blood biochemical examination, necropsy and measurement of organ weights were carried out. As results, toxic effects due to administration were not observed. Therefore, the dose in this study was 1000 mg / kg / day as the highest dose, then 3 doses of 300 and 100 mg / kg / day.
- Post-exposure recovery period: was set in 14 days.

Examinations

Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: On the day before the start of administration and then once a week
- Parameters checked: ease of withdrawal from the cage, ease of handling when exiting the cage, body tension (relaxation - tonic), skin (color), coat, piloerection, ocular secretion, eyelid closure state, eyes projection, lacrimation, mouth nose stains (dirt), salivation, urine contamination of the lower abdomen coat, stains around the anus, vocalization, respiration, posture, convulsions, tremor, search behavior (arousal level), alertness, locomotor activity abnormal behaviors (self bite, retrograde walking, etc.), stereotyped (excessive hair repair, repeated swiveling motion, etc.), consciousness failure (confusion, catalepsy, coma), limb muscle tone degree, urination, and excretion.

BODY WEIGHT: Yes
- Time schedule for examinations: once a week and on the date of slaughter

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
The consumption of food was measured once a day for 24 hours on a daily basis.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 5pm (during administration period and the day after the completion of the recovery perid)
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- Parameters checked: red blood cells count, hemoglobin amount, hematocrit, MCV, MCH,MCHC, white blood cells count, platelet count prothrombin time, total protein, albumin, A/G ratio, glucose, triglyceride, total cholesterol, total bilirubin, urea nitrogen, creatinine, AST,
ALT, g-GTP, ALP, LDH, cholinesterase, calcium and inorganic phosphorus, sodium, potassium and chlorine

URINALYSIS: Yes /
- Metabolism cages used for collection of urine: Yes
Animals were housed in a metabolism cage for 40 days (males) and on 8 days on recovery for satellites.
- Parameters checked: observation of appearance, Qualitative inspection of pH, occult blood, protein, sugar, ketone bodies, bilirubin, urobilinogen and examination of sediment. Further, for urine obtained by storing for 18 hours, urine volume, specific gravity and sodium and potassium.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examamination: Males were administered 41 days after females, once during feeding period, and on the final administration day and recovery day 13 for males and females of the satellite group
- Battery of functions tested: sensory activity / grip strength / motor activity / other: the landing foot width, grip strength of forelimb and hindlimb, spontaneous momentum ( males for 30 minutes and 60 minutes, females for 30 minutes). Spontaneous momentum of female of satellite group was also measured for 60 minutes. Males in the final administration day, females once during the feeding period, males and females of the satellite group were examined about receive auditory reaction, visual reaction, tactile reaction, ear response Injection, pain sensation response, pupillary reflex, ipsilateral flexor reflex, eyelid reflex and right flank reflex.
Oestrous cyclicity (parental animals):
For females, vaginal plaque smears by Giemsa staining were prepared and examined by microscopic examination to study the sexual cycle stages until mating. It was confirmed following the acclimatization / quarantine period.
The mean periodicity was defined as the average number of days after the estrus late period where only keratinocytes are scattered or agglomerated.
Sperm parameters (parental animals):
not specified
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes

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

Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [4 of the attached background material] were prepared for microscopic examination and weighed, respectively.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No change due to administration of the test substance was observed during the administration period and during the recovery period.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
A small tumor was confirmed in the lower abdomen after 40 days of administration in one female of the 300 mg / kg group.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There was no significant change in body weight and weight gain during the administration period. (for results see Fig.1, 2.1 and 2.2 in the attachment)
During the recovery period, body weight gain of a male in the 1000 mg / kg group showed a significant high value, but this was due to the low value trend of weight gain of the control group rather
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No change due to administration of the test substance was observed during the administration period and during the recovery period.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No change due to administration of the test substance was observed. (for results see table 2 in the attachment)
There was a somewhat lower value overall compared to the control group, and a significant difference was observed in the 100 mg / kg group and the 300 mg / kg group, but no dose correlation was observed in the change.
In the examination at the end of the recovery period, no significant change was observed in each examination item.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the administration period, significant levels of inorganic phosphorus were observed in females at 300 mg / kg group and 1000 mg / kg group. These values correspond to the control group. Although dose correlation was not clear. (for results see table 3 in the attachement).
In the examination at the end of the recovery period female cholinesterase in the 1000 mg / kg group showed a significant high value.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No change due to administration of the test substance was observed during the administration period and during the recovery period. (for results see table 1 in the attachment)
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No significant change was observed in each examination item in the examination at 6 weeks of administration and 2 weeks of recovery.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No change due to administration of the test substance was observed. (for results see tables 5 and 6 in the attachment)
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No change due to administration of the test substance was observed. (for results see tables 5 and 6 in the attachment)

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
In the sexual cycle examination from the day after grouping to before mating, each individual regained estrus at 3.7 to 5.0 days, and the average periodicity of each administration group including the control group shows 4.0 to 4.1 days. No significant change was observed.
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
copulation rate: a pair of mating failed was found in the 1000mg/kg group. and one pair that did not became pregnant were established in the control group. Mating was established in all the other cases. There was no significant change in the number of days required for establishment, mating and conception rate.
Females that failed to copulate had a good sex cycles.
Number of corpus luteum, number of implantation and implantation rate not show significant changes.

Details on results (P0)

Regarding visceral mutation, one thoracic residual in the thymus in the control group (expression rate 0.6 One (0.5%) in the 300 mg / kg group and two (1.3%) in the 1000 mg / kg group, 1 left (0.5%) in the left umbilical artery remains 100 mg / kg group and 1000 Two animals (1.3%) in the mg / kg group, serpentine urine One tube (0.6%) at 100 mg / kg, three animals (2.0%) in the 300 mg / kg group and two animals (1.1%) in the 1000 mg / kg group, with pelvic extension 300 mg / kg group One (0.7%), ureter dilation 100 1 (0.6%) in the mg / kg group and 2 (1.4%) in the 300 mg / kg group. One animal (0.6%) in the control group, three animals with the visceral mutation in the 100 mg / kg group (1.8 %), 5 (3.3%) in the 300 mg / kg group and 6 (3.8%) in the 1000 mg / kg group. The expression rates by type of visceral mutation above and the animal's animal with any visceral mutation There was no significant difference in the expression rate between the control group and the test substance administration group. Changes in the sexual female cycle, mating period, mating rate, conception rate, pregnancy period, luteinum number, implantation rate, birth rate and delivery rate were not observed in relation to the reproductive ability of the parent animal.
No abnormality was found in the condition of feeding and nursing.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
histopathology: non-neoplastic
histopathology: neoplastic
reproductive function (oestrous cycle)
reproductive performance
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: P1 (second parental generation)

Effect levels (P1)

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
urinalysis
organ weights and organ / body weight ratios
histopathology: non-neoplastic
histopathology: neoplastic
reproductive function (oestrous cycle)
reproductive performance

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
there were no significant changes in the total number of births per litter, delivery rate, neonatal number and body weight at nursing 0 and 4, birth rate, sex ratio and survival rate on 4th day of nursing. There was no changes in the general condition of the newborns.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
there was no significant change in the total number of births per litter, delivery rate, sex ratio and survival rate on 4th day of nursing. There was no changes in the general condition of the newborns.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
there was no significant change in the body weight at nursing 0 and 4 and survival rate on 4th day of nursing. There was no changes in the general condition of the newborns.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
no significant changes were observed.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
a small number of visceral mutations were observed, but all are within the normal range (0 to 6.4%) ofa background data.
Other effects:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

No changes was observed in the total number of births, newborns , sex ratio, weight, morphology and nursing 4 -day survival rate in relation to the development of infant animals. In addition, the expression rates of infants with some internal visceral mutation are all within the normal range (0 to 6.4%) of background data, and the teratogenicity it was judged that it is not suggestive change.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
histopathology: non-neoplastic
histopathology: neoplastic

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

Changes in the sexual cycle (female), mating period, mating rate, conception rate, pregnancy period, luteinum number, implantation rate, birth rate and delivery rate were not observed in relation to the reproductive ability of the parent animal
No abnormality was found in the condition of feeding and nursing.

Applicant's summary and conclusion

Conclusions:
NOAEL= 1000 mg/kg/day.
Executive summary:

From the above results,  it was concluded that non-toxic level of reproductive capacity in male and female parents is 1000 mg/kg/day.