Registration Dossier

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
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:
other company data
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crl:CD (SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: BioLASCO Taiwan Co., Ltd., Taipei, Taiwan
- Age at study initiation: randomization x 8~9 wks; mating x 11 wks
- Weight at study initiation: Males: 283-339 g; Females: 195-227 g
- Housing: Animals were housed individually in stainless steel wire mesh cages firstly, then each presumed pregnant female was caged in a polycarbonate cage.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2℃
- Humidity (%): 50±20%
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
0, 10, 30, 100 mg/mL
Duration of treatment / exposure:
Males: 28 days
Females: 41 ~48 days
Frequency of treatment:
Once daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Control animals:
yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

Food consumption
No definitively test article-related changes were identified. Statistically significant increase of fodd consumptions relative to control group was observed on male and female rats at 1000 mg/kg/day in the second week of pre-mating period and on pregnant females at 100 and 1000 mg/kg/day in the pre-mating period. The findings were incidental and were no corresponding changes in body weight.

Maternal rats and pups examinations
During mating period, no test article related changes in the period of cohabitation were observed. One unsuccessful pairing was found in animals at 300 mg/kg/day. The finding was incidental and was not considered as test article-related. In females, all study females showed evidence of copulation. The conceiving days were within 5 days, which was corresponded to the period of one estrus cycle.
There were no test article related changes in the female fertility index, the period of gestation, performance of maternal rats in lactation period, the loss in pre-implantation, pre-natal/post-implantation and post-natal. The fertility index was 10/10, 8/10, 9/10 and 10/10 in control, low, mid, high dose group, respectively. The length of gestation was 22 or 23 days. The above parameters were not dose-dependent and within the normal range.

Gross lesions
All the study animals survived to the day of scheduled sacrifice. In gross examination, there were no test article-related gross changes in the study animals examined.

Organ weights
There were no treatment-related organ weight changes in tests or epiddidymides of the study animals examined.

Histopathology examination
There were no test article-related microscopic changes in the tests, epididymides or ovaries of the study animals examined. In tests, minimal cytoplasmic vacuolation of the Sertoli cells was noted in 2 males at 1000 mg/kg/day and once of which also had minimal segmental hyphplasia/atrophy in the seminiferous tubules, characterized by segments of seminiferous tubules lined by primarily Setoli cells with or without cytoplasmic vacuolation and few germ cells. There were no gross or organ weight correlations for these findings, and adjacent seminiferous tubules as well as epididymal sections were within normal limits. These findings were occasionally observed in male control rats in toxicity studies and considered spontaneous background changes in this species.

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:
mortality
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
histopathology: non-neoplastic
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed

Details on results (F1)

Pup examiniation
After delivery, all dams had live pups and no significant changes in sex ratio of pups per dam were observed. There were obvious changes in numbers of live pups per dam between P0 and P4. Although pups death/missing and slight abnormality on body surface were noted during 4-day lactation period, that had no dose-dependence and considered to be caused by the subsequent maternal behavior after delivery.

Effect levels (F1)

Key result
Dose descriptor:
dose level: pups were not treated with the test substance.
Generation:
F1
Effect level:
other: pups were not treated with the test substance.
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
Remarks on result:
other: pups were not treated with the test substance.

Overall reproductive toxicity

Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
no
Relevant for humans:
not specified

Any other information on results incl. tables

Table 1.  Mortality and Clinical Signs
Items   Dose level   (mg/kg/day)   Total incidence (n/n)
Male                   
Mortality 0a 0/10
100 0/10
300 0/10
1000 0/10
Clinical signs
Wound 0a 1/10
100 0/10
300 1/10
1000 0/10
Hair loss 0a 1/10
100 0/10
300 0/10
1000 1/10
Female         
Mortality 0a 0/10
100 0/10
300 0/10
1000 0/10
Clinical signs
Hair loss 0a 2/10
100 1/10
300 0/10
1000 1/10
Wound 0a 1/10
100 1/10
300 0/10
1000 0/10
Chromodacryorrhea 0a 0/10
100 0/10
300 1/10
1000 0/10
         
a: WFI
n/n: Total number of abnormal or dead animals observed/Total number of animals examined

Applicant's summary and conclusion

Conclusions:
Up to 1000 mg/kg/day oral administration of Everzol Orange ED-G, no adverse effects were observed at rats prior to mating, during the mating, post-mating, gestation and lactation.
Executive summary:

The study was conducted to evaluate the potential effects of the test article “Everzol Orange ED-G Crude” on the reproduction of Sprague-Dawley (SD) rats via oral administration.

The animals were randomized into four groups consisting of 10 males and 10 females each group. The animals at age of 8 to 9 weeks were used for starting dosing and at 11 weeks old used for mating. Groups of 20 SD rats received single oral doses of 0, 100, 300 or 1000 mg/kg/day test article. Following parameters were assessed: body weight and food consumption, mating behavior; fertility index; gestation length; uterus examination; pups examination including number, sex, live birth , litter weights and gross abnormalities; necropsy examination and specific organs histopathology examination.

During the study period, no mortalities were observed in male and female rats dosed with Everzol Orange ED-G Crude at 100, 300 or 1000 mg/kg/day. There were no test article treatment-related changes in clinical observation, body weight, food consumption, mating, behavior, fertility index and gestation length. No toxic effects on reproduction, offspring and post-natal growth. No macro- and microscopic findings in testes and epididymides of males, as well as ovaries of females.