Registration Dossier
Registration Dossier
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EC number: 226-378-9 | CAS number: 5384-21-4
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of 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:
- data from handbook or collection of data
- Justification for type of information:
- Weight of evidence based on the information of data of test chemical.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- Approximately 68 days
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Justification for type of information:
- Data is from a J-check report
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 422 (Combined Repeated and Reproductive Toxicity Screening Test)
- Principles of method if other than guideline:
- The above experiment was performed to evaluate and assess the effects of the test chemical on the reproductive parameters of the test animals.
- GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- - Name of test material (as cited in study report):6,6'-di-tert-Butyl-2,2'-methylenedi-p-cresol
- Molecular formula (if other than submission substance):C23H32O2
- Molecular weight (if other than submission substance):340.51 g/mole
- Substance type:organic
- Physical state:solid
- Impurities (identity and concentrations):1.8%(identity and concentration not given) - Species:
- rat
- Strain:
- other: Crj: CD (SD) IGS, (SPF)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan
- Age at study initiation: 10 week old
- Weight at study initiation: 332-383 g for male, 206-238 g for female.
- Fasting period before study: Not available
- Housing: Stainless steel cages were used to keep up to 5 groups per cage, and after grouping they were individually raised using a stainless steel cage.
- Diet (e.g. ad libitum): The feed was made free from solid feed (CRF-1, Oriental Yeast Industry Co., Ltd.)
- Water (e.g. ad libitum): The drinking water was freely taken in all of the tap water
- Acclimation period: Not available
ENVIRONMENTAL CONDITIONS .
- Temperature (°C): 20 to 26 ° C.
- Humidity (%): 40 to 70%
- Air changes (per hr): 12 times / hour.
- Photoperiod (hrs dark / hrs light): Light and dark each for 12 hours (lighting: 6 am to 6 pm) - Route of administration:
- oral: gavage
- Vehicle:
- other: 5% gum arabic solution.
- Details on exposure:
- Details on exposure
PREPARATION OF DOSING SOLUTIONS: The test substance was prepared by suspending it in a 5% gum arabic solution. The test substance was converted to purity, and the dose was expressed in terms of the original weight. Since it was confirmed that the prepared solution had no problem of stability even after storage for 7 days under refrigeration / light-shielding conditions and further at room temperature under light-shielding conditions for 4 hours, the preparation solution of each concentration was prepared , Stored under refrigerated / light-proof conditions, and used within 7 days after preparation. Also, as a result of confirming the concentration of the test substance in the administration solution at each concentration used at the administration start date and the end date of the male administration period, there was no problem with the concentration of the test substance.
DIET PREPARATION
- Rate of preparation of diet (frequency): No Data Available
- Mixing appropriate amounts with (Type of food): No Data Available
- Storage temperature of food: No Data Available
VEHICLE
- Justification for use and choice of vehicle (if other than water): No Data Available
- Concentration in vehicle: Concentration of 5, 20 and 80 mg/mL of test item for low, mid and high dose groups respectively.
- Amount of vehicle (if gavage): No Data Available
- Lot/batch no. (if required): No Data Available
- Purity: No Data Available - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No Data Available
- Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: 14 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy vaginal plug
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility. Not available
- Further matings after two unsuccessful attempts: [no / yes (explain)] Not available
- After successful mating each pregnant female was caged (how):Not available
- Any other deviations from standard protocol:Not available - Duration of treatment / exposure:
- Male: 50-52 days
Female: 40 to 48 days. - Frequency of treatment:
- Daily
- Duration of test:
- Approximately 68 days
- Remarks:
- Doses / Concentrations:
12.5, 50, 200, 800 mg/kg/day (in 5% gum arabic)
Basis:
no data - No. of animals per sex per dose:
- Control-12 female and 12 male
12.5 mg/kg/day- 12 female and 12 male
50 mg/kg/day-12 female and 12 male
200 mg/kg/day-12 female and 12 male
800 mg/kg/day-12 female and 12 male - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No Data Available
- Maternal examinations:
- (1) General condition: The general condition and the presence or absence of death were observed twice a day before and after administration.
(2) Sex cycle: The sex cycle was observed once a day from the administration start date to the mating confirmation date. In addition, when the estrus period was observed over 2 consecutive days, it was counted as 1 time.
(3) Weight measurement: Body weights were measured twice a week during the 14 days before the mating and during the mating period, at 0, 7, 14 and 21 gestation during gestation, on 0 and 4 days of feeding during the feeding period, respectively .
(4) Food consumption measurement: Food consumption was measured twice a week until 14 days before the start of the mating. Also, during pregnancy, gestation was measured on 2, 9, 16 and 21 gestation, and 4 days after nursing during gestation period.
(5) Observation of delivery status: Mating females were allowed to spontaneously deliver, and the presence or absence of abnormality in labor condition and confirmation of end of delivery were confirmed once a day from day 21 of pregnancy until 25th day of pregnancy. If delivery was completed at 10:00 am, that day was taken as nursing day 0.
(6) Animals not delivered by 25th day gestation: Females who did not deliver until 25th day of pregnancy were necropsied after lethality from the abdominal aorta under ether anesthesia.
(7) Observation of nursing condition and autopsy: Maternal animals were observed for nursing condition once a day until 4th day of nursing and autopsied after death from the abdominal aorta under ether anesthesia on the day when all newborn cases died or on nursing 4th day, necropsied, and the number of implantation traces and corpus luteum were conted. The ovaries were weighed and fixed in 20% neutral buffered formalin. The relative weight was also calculated by dividing the ovarian weight by the final body weight.
(8) Histopathology examination: For the ovary, a paraffin-embedded specimen was prepared according to an ordinary method. HE stained tissue specimens were prepared for the control group and the ovaries of the 800 mg / kg group and histopathological examination was performed.
3) Effects of parent animals on reproductive development: Male and female rats administered for 14 days were mated together in a 1: 1 combination within the same group. The mating period was limited to 14 days, but all cases mated in 8 days. In addition, we continued cross-living until we confirmed copulation.
Mating was confirmed approximately every morning at a fixed time and a female who confirmed sperm or vaginal plug in vaginal plaque was a mating animal and the day was counted as the 0th day of pregnancy. - Ovaries and uterine content:
- In uterine content, the number of implantation traces and corpus luteum were conted. The ovaries were weighed and fixed in 20% neutral buffered formalin. The relative weight was also calculated by dividing the ovarian weight by the final body weight.
- Fetal examinations:
- (1) Observation at birth: At birth the number of total births and sex, the number of stillborn babies, the number of neonates and the presence or absence of outer table abnormalities were observed.
(2) Observation of newborns: Neonates were observed for general condition and the presence or absence of death once a day.
(3) Body weight: Body weight was measured on day 0 of nursing (birthday) and 4th day.
(4) Autopsy: The surviving child was sacrificed by abdominal aorta from the abdominal aorta under necropsy under ether anesthesia on 4th day of nursing and then necropsied. - Statistics:
- For statistical analysis, homodispersity was tested by the Bartlett method. In the case of equi-variance, variance analysis was performed by one-way method, and if significant, it was performed by the Dunnett method. On the other hand, when it was not recognized as equal variance, we performed analysis by the one-way method using rank order (Kruskal-Wallis test), and if significant, we used Dunnett type test method using ranking. Mating rate, conception rate and birth rate were determined by χ ^ 2 test. In histopathological examination, the toxicological effects were suggested in the 800 mg / kg group, and findings of organs and tissues examined for other groups were ranked using comparison between groups with the control group Dunnett type test method was used. Therefore, when a significant difference was observed with the control group, the dose reactivity test was conducted using Cochran · Armitage trend test.
- Indices:
- Resorption and Implantation Index, Pup Viability index, Gestation Index
- Historical control data:
- No Data Available
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Transient salivation was observed in the 200 and 800 mg / kg group in general condition observation. In addition, loose stools were observed in each group including the control group, but no relation with the dose was observed.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- Death and moribund cases were not observed in either group.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Before the mating, there was no significant difference in body weight at any measurement day in each administration group compared with the control group.
During the gestation period, there was no significant difference in body weight at any measurement day in the 12.5, 50 and 200 mg / kg group compared with the control group. In the 800 mg / kg group, there was a significant lower value of body weight on 0 to 21 days of pregnancy than in the control group.
period, there was no significant difference in body weight at any measurement day in the 12.5 and 50 mg / kg group compared to the control group. In the 200 and 800 mg / kg group, a significant lower value of body weight was seen on 4th day of nursing compared with the control group. - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Before the mating, there was no significant difference in food consumption on any measurement day in the 12.5 and 50 mg / kg group compared with the control group. In the 200 mg / kg group, a significant lower value of food intake was observed on days 3 and 6 compared to the control group. In the 800 mg / kg group, a significant low value of food intake was seen on the 3rd day of administration compared with the control group. During the gestation period, there was no significant difference in food intake on any measurement day in the 12.5 and 50 mg / kg group compared with the control group. In the 200 and 800 mg / kg group, a significant lower value of food intake was seen on the 2nd day of pregnancy than in the control group. There was no significant difference in food intake in the 12.5 and 50 mg / kg group during the nursing period compared with the control group. In the 200 and 800 mg / kg group, a significant low value of food intake was seen on the 4th day of nursing compared with the control group.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There was no significant difference in body weight at day of necropsy compared with control group in 12.5 and 50 mg / kg group. In the 200 and 800 mg / kg group, there was a significant lower value of body weight on the necropsy day compared to the control group. There was no significant difference in the absolute and relative weights of ovaries in each treatment group compared to the control group.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- In the control group, renal pelvic dilation was found in one case. No abnormality was found in any of the administration groups.
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- In the 12.5 and 50 mg / kg groups, there was no significant difference in number of corpus luteum, number of implantation traces and landing rate compared to the control group. In the 200 mg / kg group, although there was no significant difference compared with the control group, there was a tendency for the number of corpus luteum and the number of implantation traces to be low. In the 800 mg / kg group, the number of corpus luteum and the number of implantation traces were significantly lower than in the control group.
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- effects observed, treatment-related
- Description (incidence and severity):
- In the 12.5 and 50 mg / kg groups, there was no significant difference in the number of surviving children and survival rate on 4th day of nursing compared to the control group. In the 200 mg / kg group, there was a significant low value of the number of surviving children on 4th day of nursing compared to the control group. In the 800 mg / kg group, although there was no significant difference compared with the control group, a low value trend of the number of surviving children on nursing 4th day was observed. There was no abnormality in each group in the observation of the external table of the newborn. There was no abnormality in each group in the general condition of the newborn.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
- Dose descriptor:
- NOAEL
- Remarks:
- Maternal developmental
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- changes in number of pregnant
- dead fetuses
- other: The number of pups borm, number of live pups born was significantly decreased at 200 and 800 mg/kg.Delivery index was signifcantly decrease at 200 mg/kg and above.
- Abnormalities:
- not specified
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the 12.5 and 50 mg / kg group, there was no significant difference in body weights of sexes on 0 and 4 days of nursing compared with the control group. In the 200 mg / kg group, there was a significant high value of sex and body weight on 0th day of nursing compared to the control group, but because there was no significant difference in the 800 mg / kg group, it was not due to administration It is judged. In the 800 mg / kg group, there was no significant difference in male body weight on 4th day of nursing compared to the control group, but there was no significant difference in female body weight on 4th day of nursing though there was no significant difference.
- Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- In the 12.5 and 50 mg / kg groups, there was no significant difference in the number of surviving children and survival rate on 4th day of nursing compared to the control group. In the 200 mg / kg group, there was a significant low value of the number of surviving children on 4th day of nursing compared to the control group. In the 800 mg / kg group, although there was no significant difference compared with the control group, a low value trend of the number of surviving children on nursing 4th day was observed.
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- No Data Available
- Dose descriptor:
- NOAEL
- Remarks:
- Developmental
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- fetal/pup body weight changes
- changes in postnatal survival
- Remarks on result:
- other: Not Specified
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- Based on the findings of necropsy, organ weight measurements, sperm test findings and histopathology of male sexual organs, the reproductive NOAEL (No Observed Adverse Effect Level) for male SD rats was 12,5 mg/kg/day. The test chemical had no effect on female gonad function, fertility, mating behaviour and conception as it was evidenced by the unchanged fertility and copulation index and by the lack of histopathological findings. The reproductive NOAEL for female rats was 800 mg/kg/day. The developmental NOAEL was estimated to be 50 mg/kg/day for both maternal and F1 generations based on the reduced delivery index and viability of the pups.
- Executive summary:
A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was carried out to evaluate the toxic potential ofthe test chemicalon reproductive performance and the development of offspring in male and female Sprague-Dawley rats. The test chemical was administered by gavage daily at the concentrations of 12.5, 50, 200 and 800 mg/kg/ bw/day. Males were dosed for the total of 50-52 days (14 days before mating and 36 to 38 days after mating), while for females, the total administration period was 40 to 48 days (14 days before mating, 14 days of mating, 21 days pregnancy and 3 days of lactation). The test chemical was solved in 5% aqueous gum Arabic solution and employed as a vehicle in controls. The purity and the stability of the test chemical were confirmed, and it was stored in refrigerator under light-proof conditions.During the administration period, ratswere observed for general condition, body weight alteration and food consumption. After the last administration day, a complete necropsy of reproductive organs was carried out. The sperm parameters including sperm motion, morphology, viability and survivability were recorded in males. Detailed histopathological examination of testis and epididymis were performed, as well. In females the weight of ovaries, and uterus parameters including number of corpora lutea, implantation, gestation length and number of live pups born were recorded. Newborn pups were observed for general conditions, neonatal survival and body weights. In male rats, no difference in body weights and food intake values were observed during the experiment. However, in the 200 and 800 mg/kg groups the relative and absolute weights of testis and epididymis were significantly decreased.The results of sperm analysesshowedsignificantlyreduced ofsperm motility, viability, survivability and the number of sperms in the left epididymis in the group treated with 50 mg/kg or more of the test chemical compared with controls. The percentage of sperms with abnormal morphology significantly increased in 50, 200 and 800 mg/kg groups in comparison to control. The histopathological examination of the gonads revealed atrophy of seminiferous tubule of testis and the epididymis in the two highest dose groups (200 and 800 mg/kg). Giant cell formation in the testis, which is usually accompanies germinal celldegeneration/atrophy was observed at the dose of 50 mg/kg and above. No death and alterations in general conditions were observed among the female rats during the test chemical administration. However, the body weight gain was significantly decreased in the high-dose group between 0-21 day of pregnancy and during the lactation period in 200 and 800 mg/kg treated group compared to controls. Similarly, the food consumption in female rats is dropped significantly on day 3-6 of pre-mating period, on day 2 of pregnancy and day 4 of lactation in the two highest dose groups. No abnormalities were seen by necropsy and the weights of ovaries showed no significant alterations between any treated and control groups. The histopathological analyses showed no alterations of uterus parameters. Similarly, no changes in fertility and mating performance between any of the treated and control groups were observed. However, the number of pups born showed a significant and dose-dependent decrease in the 200 and 800 mg/kg group compared with controls. The number of live pups born and the number of live pups on lactation day 4 significantly dropped in the two high-dose groups. The necropsy of newborns revealed no abnormalities in any of the treated-group, although the body weight of pups dropped significantly in the two highest-dose group. In summary, the present study provides clear evidence that the repeated oral exposure ofthe test chemical exertedstrong adverse effect of testicular spermatogenesis and promotes the atrophy of male gonads in male Sprague-Dawley rats. The reproductive NOAEL (No Observed Adverse Effect Level) for male SD rats was 12,5 mg/kg/day based on findings of necropsy, organ weight measurement,sperm testfindingsand histopathology. The repeated exposure of the test chemical during pre-mating and mating period had no effect on female gonad function, fertility, mating behaviour and conception as it was evidenced by the unchanged fertility and copulation index and by the lack of histopathological findings. The reproductive NOAEL for maternal generation was 800 mg/kg/day. The number of pups born, number of live pups born and the number of live pups on lactation day 4, as well as the delivery index were significantly decreased at 200 mg/kg and remained reduced, but not significantly at 800 mg/kg, which was still considered important from toxicological point of view, when female SD rats were administeredthe test chemicalduring the period of pre-mating mating, pregnancy and early lactation. Hence, the developmental NOAEL was estimated to be 50 mg/kg/day for both maternal and F1 generations. The NOAEL for systemic maternal toxicity was considered as 50 mg/kg/day based on reduced body weight and feed consumption at the two highest dose. The NOAEL for general toxicity for males was 800 mg/kg/day as no alteration of bodyweight and food consumption was seen.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- The data is from a j-check report
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 422 (Combined Repeated Dose Toxicity Study with the Reproductive/Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- Combined Repeated Dose Toxicity Study With the Reproductive/Developmental Toxicity Screening Test of the test chemical.
- GLP compliance:
- not specified
- Specific details on test material used for the study:
- - Molecular weight (if other than submission substance): 136.19 g/mole
- Substance type:organic
- Physical state: White powder
- Impurities (identity and concentrations):12.3 %(identity and conc.not available) - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available
IN-LIFE DATES: From: To: - Route of administration:
- oral: gavage
- Vehicle:
- other: 0.1w/v%Tween 80 + 0.5w/v% CMC-Na solution
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: No data available
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.1w/v%Tween 80 + 0.5w/v% CMC-Na solution
- Concentration in vehicle: 0, 10, 30, 300 mg/kg/day Recovery: 0, 300 mg/kg/day (R300)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No Data Available
- Details on mating procedure:
- No data available
- Duration of treatment / exposure:
- F0 Males = 42 days (2 weeks pre-breeding, 2 weeks mating, 2 weeks post-mating)
Females = 42-54 days (from 14 days before mating to day 4 of lactation)
F1 offspring = PDN 4 - Frequency of treatment:
- Daily
- Duration of test:
- F1 generation PND 4
- Remarks:
- Doses / Concentrations:
0, 10, 30 and 300 mg/kg/day
Recovery group: 0, 300 mg/kg/day
Basis:
no data - No. of animals per sex per dose:
- Treated animals
Control: no data
10 mg/kg/day: no data
100 mg/kg/day: no data
200 mg/kg/day: no data
Treated recovery animals
Control: no data
300 mg/kg/day: no data - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Doses were selected for this study based on the results of a 14-day dose range-finding (DRF) study. In the DRF study, TMP was dosed by gavage to male and female rats for 14 consecutive days at 0, 100, 300, 600 or 1000 mg/kg/day. Results are the follows:
1000 mg/kg/day: Prone position (M, F), Decrease in locomotor activity (M, F), Abnormal gait(M, F), Body weight decreased (M, F), Food consumption decreased (M, F), Thickening in the forestomach wall (M, F), Thickening in the limiting ridge of stomach (M, F), Yellow coloured forestomach mucosa or limiting ridge of the stomach (M, F), Irregular respiration (M, F), ALT increase (M, F), Liver A increase (M, F), Distention of the cecum (M, F), Small thymus (M), ALP decrease (F), T-cho increase (F), TG increase (F), Erosion/ulcer in the forestomach or glandular stomach (F)
600 mg/kg/day: Prone position (M, F), Decrease in locomotor activity (M, F), Abnormal gait (M,F), Body weight decreased (M, F), Food consumption decreased (M, F), Thickening in the forestomach wall (M, F), Thickening in the limiting ridge of stomach (M, F), Yellow coloured forestomach mucosa or limiting ridge of the stomach (M, F), ALT increased (M), Erosion/ulcer in the forestomach or glandular stomach (M), Distention of the cecum (M)
300 mg/kg/day: Thickening in the limiting ridge of stomach (M)
Therefore, 300 mg/kg/day was considered as the highest dose for the OECD 422 study design.
- Rationale for animal assignment (if not random): No data available
- Other: No other details available - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
Time schedule: No data available.
CLINICAL OBSERVATIONS: Yes
Time schedule: Daily
BODY WEIGHT: Yes
Time schedule for examinations: No data available
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- 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: No data available
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At necropsy
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters examined: Hematocrit, hemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, RBC indices and prothrombin time (PT).
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At necropsy
- Animals fasted: No data available
- How many animals: No data available
- Parameters examined: Sodium, potassium, chloride, glucose, total cholesterol, blood urea nitrogen (BUN), creatinine, total protein and albumin, and 2 enzymes indicative of hepatocellular effects (alanine aminotransferase and aspartate aminotransferase).
URINALYSIS: Yes
- Time schedule for collection of urine: At necropsy
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters examined: No data available
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: No data available
Performed on F0 males prior to dosing during quarantine and weekly to termination at sd 28.
Performed on F0 females prior to dosing and weekly during pre-breed, mating, gestation, and lactation and on recovery animals (male and female) prior to dosing, weekly during dosing, and once during the recovery period.
- Dose groups that were examined: 0, 10, 30 and 300 mg/kg/day
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Yes, no data available
POST-MORTEM EXAMINATIONS: Yes
Histopathology: Yes
Organs examined: No data available - Ovaries and uterine content:
- The uterine examined after termination: Yes
Examinations included:
Organ weight: Yes
Number of live fetuses: No data available
Number of dead fetuses: No data available
Number of corpora lutea: No data available
Number of implantations: No data available
Number of resorptions: No data available - Fetal examinations:
- Fetal weight: Yes
Litter size: Yes
Sex: Yes
Survival index: Yes
External anomalies: Yes
Soft tissue anomalies: Yes
Skeletal anomalies: Yes
Postnatal mortality: Yes - Statistics:
- For all statistical tests, p<0.05 (one- or two-tailed) was used as the criterion for significance.
- Indices:
- No data available
- Historical control data:
- No data available
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Salvation and abnormal gait was seet at 300 mg/kg.
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects on body weight or food consumption for the adult animals in the study.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No treatment-related effects on body weight or food consumption for the adult animals in the study.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Functional observational battery, including home-cage observations, handling observations, sensory and neuromuscular observations or open field observations. There were no differences among groups for any parameters evaluated for auditory startle, motor activity or grip strength.
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no changes in histopathology related to treatment.
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- Live birth and stillbirth indices were unaffected, as were the survival indices for PND 0-4, 4-7, 7-14 and 14-21 as well as the lactational index for PND 4 (postcull) through 21.
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY
No mortality or clinical signs of toxicity observed in F0 males, Recovery males or Recovery females, and F0 females.
Clinical signs of rooting post-dosing were observed in a dose-related manner throughout the study. These signs are considered to be a response to taste aversion to the dosing solution and not an indication of toxicity, per se.
BODY WEIGHT AND FOOD CONSUMPTION
No treatment-related effects on body weight or food consumption for the adult animals in the study.
CLINICAL CHEMISTRY AND HEMATOLOGY
No clinical chemistry or hematology parameters exhibited treatment or dose-related changes.
URINALYSIS
There were no treatment or dose-related changes for urinary specific gravity, pH or other urinary parameters in F0 males and 28-day females.
ORGAN WEIGHTS
There were no treatment-related effects on organ weights.
HISTOPATHOLOGY
There were no changes in histopathology related to treatment.
OTHERS
There were no significant differences for any parameters included in the Functional observational battery, including home-cage observations, handling observations, sensory and neuromuscular observations or open field observations. There were no differences among groups for any parameters evaluated for auditory startle, motor activity or grip strength. - Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: No maternal developmental toxicity, attributable to the test chemical administartion was seen.
- Abnormalities:
- not specified
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no effects on F1 pups.
- Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
VIABILITY
Live birth and stillbirth indices were unaffected, as were the survival indices for PND 0-4, 4-7, 7-14 and 14-21 as well as the lactational index for PND 4 (postcull) through 21.
BODY WEIGHT (OFFSPRING)
- Mean F1 pup body weights per litter (sexes combined or separately) were unaffected by treatment for all time points across all dose groups.
- There were no effects on F1 male or female body weights at sacrifice on PND 21 at any dose.
FOOD CONSUMPTION
There were no differences in food consumption, expressed as g/day or g/kg/day, for any post-wean interval in any group.
OTHER
No effects observed on hematology, urinalysis, sexual maturation, organ weights or histopathology in F1 males or females. - Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related developmental effects were seen.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- The test chemical produced no adverse effect on offspring development; therefore the developmental NOAEL was considered to be 300 mg/kg/day in both the F0 and the F1 generation when SD rats were administered with the test chemical during the periods of pre-mating, mating, gestation and early lactation.
- Executive summary:
A combined repeated dose toxicity study with reproduction/developmental toxicity screening test (OECD TG 422) was carried out to evaluate the toxic potential of the test chemicalon male and female reproductive performance and offspring development in Sprague-Dawley rats. The test chemical was administered by gavage once daily at the doses of 0 (vehicle control), 10, 30 or 300 mg/kg/day. In the recovery groups rats were administered with 0 (vehicle control) and 300 mg/kg of test chemical to monitor delayed effects and the reversibility of effects occurred. The administration periodfor male rats was 42 days (periods of 14-days premating, 14-days mating and 14-days post-mating), while females were treated for 42-55 days (from 2 weeks before mating till 4thof lactation). Salvation and abnormal gait were observed as clinical signs of systemic toxicity in both males and females at 300 mg/kg.No treatment-related effects on body weight gain and on food consumption values were observed at any dose level in treated and recovery groups. Neurobehavioral assessment (FOB) revealed no difference between treated and control animals at any dose level in treated and recovery groups. Hematology, blood clinical biochemistry and urinalysis showed no treatment-related effects in dosed animals. Organ weights including male and female reproductive organs were comparable with control rats. Similarly, the histopathological examination of males and female reproductive organs showed no adverse effects attributable to test chemical administration. The male and female reproductive performance and fertility were not affected be the oral administration ofthe test substance.Similarly, no developmental effects were recorded among pups. Hence, the reproductive and developmental NOAEL was considered as 300 mg/kg/day for both P0 and F1 generations when Sprague-Dawley rats were administeredtest chemicalby gavage during the periods of pre-mating, mating, gestation and early lactation.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- data from handbook or collection of data
- Justification for type of information:
- Data is from a publication.
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- The following study was performed to evaluate the fetal resorptions due to the administration of the test chemical in rats.
- GLP compliance:
- not specified
- Limit test:
- no
- Specific details on test material used for the study:
- - Molecular formula (if other than submission substance):C23H32O2
- Molecular weight (if other than submission substance):340.51 g/mol
- Substance type:organic
- Physical state:White powder
- Impurities (identity and concentrations):Not available - Species:
- rat
- Strain:
- other: Walter Reed Carworth Farms
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation:200 g
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%): No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available
IN-LIFE DATES: From: To: - Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: No data available
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test chemical was mixed with the diet before administration in animals.
- Concentration in vehicle: 0 or 0.25 g
- Amount of vehicle (if gavage): Not available
- Lot/batch no. (if required): Not available
- Purity: Not available - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No data Available
- Details on mating procedure:
- The females were mated with male rats and positively mated animals were used in the study.
- Duration of treatment / exposure:
- Females were treated for 22 days.
- Frequency of treatment:
- Daily
- Duration of test:
- No data available
- Remarks:
- Doses / Concentrations:
0 or 0.25 g/day (250 mg/day)
Basis:
nominal in diet - No. of animals per sex per dose:
- No Data Available
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: No data available
- Rationale for animal assignment (if not random): No data available
- Other: Walter Reed-Carworth Farms strain rats in their first gestation were used. After positive mating the females were randomly distributed into experimental and control groups and the former were given per os or directly into diet the test compound. Twenty-two days after positive mating the pregnant rat was sacrificed in 100% nitrogen and after 21 minutes the young delivered by caesarian section. Both horns of the uterus were completely incised and a careful macroscopic survey made for resorption sites. - Maternal examinations:
- The number and distribution of resorption, the number of implantations, litters, normal fetuses and litters with resorptions were observed.
- Ovaries and uterine content:
- Horns of the uterus were completely incised and a careful macroscopic survey made for resorption sites.
- Fetal examinations:
- No data available
- Statistics:
- No data available
- Indices:
- Resorption Index, Implantation Index
- Historical control data:
- No data available
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Total litter losses by resorption:
- effects observed, treatment-related
- Description (incidence and severity):
- Litters with resorptions were found to be 37.5%.
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- Litters with resorptions were found to be 37.5%.
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Effects were reported as follows-
No. of litters-8
Implantations-101
Normal fetuses-90
Litters with reorptions-37.5%
Reorption %-10.9% - Dose descriptor:
- LOAEL
- Remarks:
- Maternal developmental
- Effect level:
- 250 other: mg
- Based on:
- test mat.
- Basis for effect level:
- other: Increased percenatge of resorption at 250 mg/kg.
- Remarks on result:
- other: Not Specified
- Abnormalities:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no data
- Remarks on result:
- not measured/tested
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- The developmental maternal LOAEL was considered to be 250 mg/day in pregnant female mice when exposed to the test chemical
- Executive summary:
The possible adverse effect ofthe test chemicaltested on prenatal development and fetal resorption, Walter Reed-Carworth Farms strain female rats were fed with diet containing 250 mg per day for 21 days of gestation. On day 22 female rats were sacrificed, and the pups were delivered by caesarian sections. Both horns of the uterus were completely incised, and a careful macroscopic survey were made for resorption sites. As seen by the result the dietary administration ofthe test chemicalproduced an increased percentage of resorption in comparison to controls, animals held on normal diet. Pups from 9 litters were examined and 66.6 % of the litters had one or more resorption and 17,1 % of recognizable implantation had terminated in resorption. No maternal toxicity was observed at the given dose. In conclusion, the dietary administration ofthe test chemicalincreased the resorption of embryos during prenatal development at 250 mg/kg/day in pregnant Walter Reed-Carworth Farms strain rats. Hence, the developmental LOAEL formaternalwas estimated to be 250 mg/day under the described experimental conditions.
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
- Reference Type:
- other: study report
- Title:
- Modified Combined Repeated Dose Toxicity Study With the Reproductive/Developmental Toxicity Screening Test Of 2,4,6-Trimethyl Phenol (TMP; CAS RN 527-60-6) Administered Via Oral Gavage to CD® (Sprague-Dawley) Rats (OECD 422)”
- Author:
- Tyl, R.W., Myers, C.B., and Marr, M.C.
- Year:
- 2 005
- Bibliographic source:
- General Electric Company,Bedford, NH, USA
- Reference Type:
- publication
- Title:
- Fetal Resorption in the Rat as Influenced by Certain Antioxidants.
- Author:
- IRA R. TELFORD, CAROLINE S. WOODRUFF AND RAY H. LINFORD
- Year:
- 1 962
- Bibliographic source:
- An. J. Anat. 110, 29-36,
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD 421 (Reproductive and Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- The above test substance is referred to as the test chemical in the study.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- 4,4'-methylenedi-2,6-xylenol
- EC Number:
- 226-378-9
- EC Name:
- 4,4'-methylenedi-2,6-xylenol
- Cas Number:
- 5384-21-4
- Molecular formula:
- C17H20O2
- IUPAC Name:
- 4-[(4-hydroxy-3,5-dimethylphenyl)methyl]-2,6-dimethylphenol
- Details on test material:
- Details on test material
- Name of test material (as cited in study report): 4,4'-Methylenedi-2,6-xylenol
- Molecular formula (if other than submission substance): C17-H20-O2
- Molecular weight (if other than submission substance): 256.343 g/mol
- Substance type: Organic
- Physical state: White Powder
- Impurities (identity and concentrations): No Data Available
Constituent 1
- Specific details on test material used for the study:
- - Molecular weight (if other than submission substance): 256.343 g/mol
- Substance type: Organic
- Physical state: White Powder
- Impurities (identity and concentrations): No Data Available
Test animals
- Species:
- other: Study 2, 3 and 4: Rat
- Strain:
- other: Study 2: Crj: CD (SD) IGS, (SPF); Study 3: Sprague-Dawley; Study 4: Walter Reed Carworth Farms
- Details on test animals or test system and environmental conditions:
- Study 2: TEST ANIMALS
- Source: Charles River Japan
- Age at study initiation: 10 week old
- Weight at study initiation: 332-383 g for male, 206-238 g for female.
- Fasting period before study: Not available
- Housing: Stainless steel cages were used to keep up to 5 groups per cage, and after grouping they were individually raised using a stainless steel cage.
- Diet (e.g. ad libitum): The feed was made free from solid feed (CRF-1, Oriental Yeast Industry Co., Ltd.)
- Water (e.g. ad libitum): The drinking water was freely taken in all of the tap water
- Acclimation period: Not available
ENVIRONMENTAL CONDITIONS .
- Temperature (°C): 20 to 26 ° C.TEST ANIMALS
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available
IN-LIFE DATES: From: To:
Study 4: TEST ANIMALS
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation:200 g
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): No data available
- Water (e.g. ad libitum): No data available
- Acclimation period: No data available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%): No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available
IN-LIFE DATES: From: To:
Administration / exposure
- Route of administration:
- other: Study 2, 3: oral: gavage; Study 4: Oral: Feed
- Vehicle:
- other: Study 2: 5% gum arabic solution; Study 3: Mazola corn oil; Study 4: Diet
- Details on exposure:
- Study 2: Details on exposure
PREPARATION OF DOSING SOLUTIONS: The test substance was prepared by suspending it in a 5% gum arabic solution. The test substance was converted to purity, and the dose was expressed in terms of the original weight. Since it was confirmed that the prepared solution had no problem of stability even after storage for 7 days under refrigeration / light-shielding conditions and further at room temperature under light-shielding conditions for 4 hours, the preparation solution of each concentration was prepared , Stored under refrigerated / light-proof conditions, and used within 7 days after preparation. Also, as a result of confirming the concentration of the test substance in the administration solution at each concentration used at the administration start date and the end date of the male administration period, there was no problem with the concentration of the test substance.
DIET PREPARATION
- Rate of preparation of diet (frequency): No Data Available
- Mixing appropriate amounts with (Type of food): No Data Available
- Storage temperature of food: No Data Available
VEHICLE
- Justification for use and choice of vehicle (if other than water): No Data Available
- Concentration in vehicle: Concentration of 5, 20 and 80 mg/mL of test item for low, mid and high dose groups respectively.
- Amount of vehicle (if gavage): No Data Available
- Lot/batch no. (if required): No Data Available
- Purity: No Data Available
Study 3: PREPARATION OF DOSING SOLUTIONS: Prior to the start of the study, homogeneity of TMP in corn oil, storage stability, and stability under conditions simulating the dosing procedures were conducted at concentrations of 2 and 40 mg/ml TMP in corn oil. TMP was shown to be stable in vehicle for at least 35 days under ambient and refrigerated conditions.
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 10, 100 or 200 mg/kg/day
- Amount of vehicle (if gavage): 5 ml/kg/day
- Lot/batch no. (if required): No data available
- Purity: No data available
Study 4: PREPARATION OF DOSING SOLUTIONS: No data available
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): The test chemical was mixed with the diet before administration in animals.
- Concentration in vehicle: 0 or 0.25 g
- Amount of vehicle (if gavage): Not available
- Lot/batch no. (if required): Not available
- Purity: Not available - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No Data Available
- Details on mating procedure:
- Study 2: - M/F ratio per cage: 1/1
- Length of cohabitation: 14 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy vaginal plug
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility. Not available
- Further matings after two unsuccessful attempts: [no / yes (explain)] Not available
- After successful mating each pregnant female was caged (how):Not available
- Any other deviations from standard protocol:Not available
Study 3: F0 Males = 4 weeks (2 weeks pre-breeding, 2 weeks mating)
Females = 10 weeks (2 weeks pre-breeding, 2, weeks mating, 3 weeks gestation and 3 weeks lactation)
F1Offspring = 7 weeks post-weaning
Study 4: The females were mated with male rats and positively mated animals were used in the study. - Duration of treatment / exposure:
- Study 2: Male: 50-52 days
Female: 40 to 48 days.
Study 3: No Data Available
Study 4: Females were treated for 22 days. - Frequency of treatment:
- Study 2, 3 and 4: Daily
- Duration of test:
- Study 2: Approximately 68 days
Study 3: F1 Generation dosed until ~ PND 80
Study 4: No data available
Doses / concentrations
- Remarks:
- Study 2: Doses / Concentrations:
12.5, 50, 200, 800 mg/kg/day (in 5% gum arabic)
Basis:
no data
Study 3: Doses / Concentrations:
0, 10, 100, and 200 mg/kg/day
Basis:
no data
Study 4: Doses / Concentrations:
0 or 0.25 g/day (250 mg/day)
Basis:
nominal in diet
- No. of animals per sex per dose:
- Study 2: Control-12 female and 12 male
12.5 mg/kg/day- 12 female and 12 male
50 mg/kg/day-12 female and 12 male
200 mg/kg/day-12 female and 12 male
800 mg/kg/day-12 female and 12 male
Study 3: Treated animals
Control: 10 males, 10 females
10 mg/kg/day: 10 males, 10 females
100 mg/kg/day: 10 males, 10 females
200 mg/kg/day: 10 males, 10 females
Treated recovery animals
Control: 5 males, 5 females
200 mg/kg/day: 5 males, 5 females
Non-pregnated animals (“28-days females”)
Control: 5 females
200 mg/kg/day: 5 females
Study 4: No Data Available - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Study 2: No Data Available
Study 3: - Dose selection rationale: Doses were selected for this study based on the results of a 10-day dose range-finding (RF) study. In this study, TMP was dosed by gavage to male and female rats for 10 consecutive days at 0, 100, 300 or 1000 mg/kg/day. Body weight loss over the 10-day period was observed for males at 1000 mg/kg/day and females at 300 and 1000 mg/kg/day. In addition, weight gain in males at 300 mg/kg/day was reduced by 43% compared to the controls. Therefore, 300 mg/kg/day was considered to toxic for the OECD 422 study design.
- Rationale for animal assignment (if not random):No data available
- Other: No other details available
Study 4: - Dose selection rationale: No data available
- Rationale for animal assignment (if not random): No data available
- Other: Walter Reed-Carworth Farms strain rats in their first gestation were used. After positive mating the females were randomly distributed into experimental and control groups and the former were given per os or directly into diet the test compound. Twenty-two days after positive mating the pregnant rat was sacrificed in 100% nitrogen and after 21 minutes the young delivered by caesarian section. Both horns of the uterus were completely incised and a careful macroscopic survey made for resorption sites.
Examinations
- Maternal examinations:
- Study 2: (1) General condition: The general condition and the presence or absence of death were observed twice a day before and after administration.
(2) Sex cycle: The sex cycle was observed once a day from the administration start date to the mating confirmation date. In addition, when the estrus period was observed over 2 consecutive days, it was counted as 1 time.
(3) Weight measurement: Body weights were measured twice a week during the 14 days before the mating and during the mating period, at 0, 7, 14 and 21 gestation during gestation, on 0 and 4 days of feeding during the feeding period, respectively .
(4) Food consumption measurement: Food consumption was measured twice a week until 14 days before the start of the mating. Also, during pregnancy, gestation was measured on 2, 9, 16 and 21 gestation, and 4 days after nursing during gestation period.
(5) Observation of delivery status: Mating females were allowed to spontaneously deliver, and the presence or absence of abnormality in labor condition and confirmation of end of delivery were confirmed once a day from day 21 of pregnancy until 25th day of pregnancy. If delivery was completed at 10:00 am, that day was taken as nursing day 0.
(6) Animals not delivered by 25th day gestation: Females who did not deliver until 25th day of pregnancy were necropsied after lethality from the abdominal aorta under ether anesthesia.
(7) Observation of nursing condition and autopsy: Maternal animals were observed for nursing condition once a day until 4th day of nursing and autopsied after death from the abdominal aorta under ether anesthesia on the day when all newborn cases died or on nursing 4th day, necropsied, and the number of implantation traces and corpus luteum were conted. The ovaries were weighed and fixed in 20% neutral buffered formalin. The relative weight was also calculated by dividing the ovarian weight by the final body weight.
(8) Histopathology examination: For the ovary, a paraffin-embedded specimen was prepared according to an ordinary method. HE stained tissue specimens were prepared for the control group and the ovaries of the 800 mg / kg group and histopathological examination was performed.
3) Effects of parent animals on reproductive development: Male and female rats administered for 14 days were mated together in a 1: 1 combination within the same group. The mating period was limited to 14 days, but all cases mated in 8 days. In addition, we continued cross-living until we confirmed copulation.
Mating was confirmed approximately every morning at a fixed time and a female who confirmed sperm or vaginal plug in vaginal plaque was a mating animal and the day was counted as the 0th day of pregnancy.
Study 3: CAGE SIDE OBSERVATIONS: Yes
Time schedule: Performed on all initial animals once during quarantine and at least once per week for F0 animals during pre-breed, mating, gestation and lactation treatment periods, and on 5 F1 females and 5 F1 males once midway during the post-wean exposure period.
CLINICAL OBSERVATIONS: Yes
Time schedule: At least once daily for F0 females and F1 offspring.
BODY WEIGHT: Yes
Time schedule for examinations:
- Body weights for F0 male and female rats were recorded weekly during the pre-breed period.
- F0 females were weighed weekly during gestation and lactation.
- Selected F1 offspring were weighed weekly weaning through scheduled sacrifice.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- 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: No data available
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At necropsy
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: All 28-day females, for 5 randomly selected parental F0 males and females per dose group, and for 5 F1 adult males and females per dose group.
- Parameters examined: Hematocrit, hemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, RBC indices and prothrombin time (PT).
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At necropsy
- Animals fasted: No data available
- How many animals: All 28-day females, for 5 randomly selected parental F0 males and females per dose group, and for 5 F1 adult males and females per dose group.
- Parameters examined: Sodium, potassium, chloride, glucose, total cholesterol, blood urea nitrogen (BUN), creatinine, total protein and albumin, and 2 enzymes indicative of hepatocellular effects (alanine aminotransferase and aspartate aminotransferase).
URINALYSIS: Yes
- Time schedule for collection of urine: At necropsy
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters examined: Specific gravity and pH
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
Performed on F0 males prior to dosing during quarantine and weekly to termination at sd 28.
Performed on F0 females prior to dosing and weekly during pre-breed, mating, gestation, and lactation and on recovery animals (male and female) prior to dosing, weekly during dosing, and once during the recovery period.
- Dose groups that were examined: 0, 10, 100 and 200 mg/kg/day
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Five F0 males and 5 F0 females per dose group were evaluated for auditory function, motor activity, and assessment of grip strength prior to necropsy.
POST-MORTEM EXAMINATIONS: Yes
All F0 parental animals, non-selected F1 weanlings, and retained F1 adults were necropsied with complete histologic evaluation of the 28-day females and for 5 selected F0 and F1 males and females in the 0 and 200 mg/kg/day groups.
Histopathology was performed on control and high-dose animals only.
Organs examined: Brain, thymus, heart, liver, spleen, kidneys, adrenal glands, testes, epididymides, prostate, uterus with vagina and cervix and paired Ovaries.
Study 4: The number and distribution of resorption, the number of implantations, litters, normal fetuses and litters with resorptions were observed. - Ovaries and uterine content:
- Study 2: In uterine content, the number of implantation traces and corpus luteum were conted. The ovaries were weighed and fixed in 20% neutral buffered formalin. The relative weight was also calculated by dividing the ovarian weight by the final body weight.
Study 3: The uterine examined after termination: Yes
Examinations included:
Organ weight: Yes
Number of live fetuses: Yes
Number of dead fetuses: Yes
Number of corpora lutea: No
Number of implantations : Yes
Number of resorptions: No
Study 4: Horns of the uterus were completely incised and a careful macroscopic survey made for resorption sites - Fetal examinations:
- Study 2: (1) Observation at birth: At birth the number of total births and sex, the number of stillborn babies, the number of neonates and the presence or absence of outer table abnormalities were observed.
(2) Observation of newborns: Neonates were observed for general condition and the presence or absence of death once a day.
(3) Body weight: Body weight was measured on day 0 of nursing (birthday) and 4th day.
(4) Autopsy: The surviving child was sacrificed by abdominal aorta from the abdominal aorta under necropsy under ether anesthesia on 4th day of nursing and then necropsied.
Study 3: Fetal weight: Yes
Litter size: Yes
Sex: Yes
Survival index: Yes
External anomalies: Yes
Soft tissue anomalies: Yes
Skeletal anomalies: Yes
Postnatal mortality: Yes
Study 4: No Data Available - Statistics:
- Study 2: For statistical analysis, homodispersity was tested by the Bartlett method. In the case of equi-variance, variance analysis was performed by one-way method, and if significant, it was performed by the Dunnett method. On the other hand, when it was not recognized as equal variance, we performed analysis by the one-way method using rank order (Kruskal-Wallis test), and if significant, we used Dunnett type test method using ranking. Mating rate, conception rate and birth rate were determined by χ ^ 2 test. In histopathological examination, the toxicological effects were suggested in the 800 mg / kg group, and findings of organs and tissues examined for other groups were ranked using comparison between groups with the control group Dunnett type test method was used. Therefore, when a significant difference was observed with the control group, the dose reactivity test was conducted using Cochran · Armitage trend test.
Study 3: For all statistical tests, p<0.05 (one- or two-tailed) was used as the criterion for significance. - Indices:
- Study 2: Resorption and Implantation Index, Pup Viability index, Gestation Index
Study 3: F0
- Females: Mating, fertility, gestational, percentage postimplantation loss per litter
- Males: Mating, fertility and pregnancy.
F1
Stillbirth index, live birth index, survival index, lactation index and sex ratio.
Study 4: No data available - Historical control data:
- Study 2: No Data Available
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Transient salivation was observed in the 200 and 800 mg / kg group in general condition observation. In addition, loose stools were observed in each group including the control group, but no relation with the dose was observed.
Study 3: Clinical signs of rooting post-dosing were obseClinical signs of rooting post-dosing were observed in a dose-related manner throughout the study. These signs are considered to be a response to taste aversion to the dosing solution and not an indication of toxicity, per se.rved in a dose-related manner throughout the study. These signs are considered to be a response to taste aversion to the dosing solution and not an indication of toxicity, per se.
Study 4: no effects observed - Dermal irritation (if dermal study):
- not specified
- Mortality:
- no mortality observed
- Description (incidence):
- Study 2: Death and moribund cases were not observed in either group.
Study 3: No Data Available
Study 4: no mortality observed - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Before the mating, there was no significant difference in body weight at any measurement day in each administration group compared with the control group.
During the gestation period, there was no significant difference in body weight at any measurement day in the 12.5, 50 and 200 mg / kg group compared with the control group. In the 800 mg / kg group, there was a significant lower value of body weight on 0 to 21 days of pregnancy than in the control group.
period, there was no significant difference in body weight at any measurement day in the 12.5 and 50 mg / kg group compared to the control group. In the 200 and 800 mg / kg group, a significant lower value of body weight was seen on 4th day of nursing compared with the control group.
Study 3:No treatment-related effects on body weight or food consumption for the adult animals in the study.
Study 4: no effects observed - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Before the mating, there was no significant difference in food consumption on any measurement day in the 12.5 and 50 mg / kg group compared with the control group. In the 200 mg / kg group, a significant lower value of food intake was observed on days 3 and 6 compared to the control group. In the 800 mg / kg group, a significant low value of food intake was seen on the 3rd day of administration compared with the control group. During the gestation period, there was no significant difference in food intake on any measurement day in the 12.5 and 50 mg / kg group compared with the control group. In the 200 and 800 mg / kg group, a significant lower value of food intake was seen on the 2nd day of pregnancy than in the control group. There was no significant difference in food intake in the 12.5 and 50 mg / kg group during the nursing period compared with the control group. In the 200 and 800 mg / kg group, a significant low value of food intake was seen on the 4th day of nursing compared with the control group.
Study 3:No treatment-related effects on body weight or food consumption for the adult animals in the study. - Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- Study 3: no effects observed
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- Study 3: no effects observed
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- Study 3: no effects observed
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Study 3: There were no significant differences for any parameters included in the Functional observational battery, including home-cage observations, handling observations, sensory and neuromuscular observations or open field observations. There were no differences among groups for any parameters evaluated for auditory startle, motor activity or grip strength.
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Study 2: There was no significant difference in body weight at day of necropsy compared with control group in 12.5 and 50 mg / kg group. In the 200 and 800 mg / kg group, there was a significant lower value of body weight on the necropsy day compared to the control group. There was no significant difference in the absolute and relative weights of ovaries in each treatment group compared to the control group.
Study 3: no effects observed - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Study 2: In the control group, renal pelvic dilation was found in one case. No abnormality was found in any of the administration groups.
Study 3: No Data Available - Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- Study 3: There were no changes in histopathology related to treatment.
- Other effects:
- not specified
- Details on results:
- No Data Available
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: In the 12.5 and 50 mg / kg groups, there was no significant difference in number of corpus luteum, number of implantation traces and landing rate compared to the control group. In the 200 mg / kg group, although there was no significant difference compared with the control group, there was a tendency for the number of corpus luteum and the number of implantation traces to be low. In the 800 mg / kg group, the number of corpus luteum and the number of implantation traces were significantly lower than in the control group.
Study 3:No Data Available - Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- Study 3: no effects observed
Study 4: Litters with resorptions were found to be 37.5%. - Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- Study 3: no effects observed
Study 4: Litters with resorptions were found to be 37.5%. - Dead fetuses:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: In the 12.5 and 50 mg / kg groups, there was no significant difference in the number of surviving children and survival rate on 4th day of nursing compared to the control group. In the 200 mg / kg group, there was a significant low value of the number of surviving children on 4th day of nursing compared to the control group. In the 800 mg / kg group, although there was no significant difference compared with the control group, a low value trend of the number of surviving children on nursing 4th day was observed. There was no abnormality in each group in the observation of the external table of the newborn. There was no abnormality in each group in the general condition of the newborn.
Study 3: Live birth and stillbirth indices were unaffected, as were the survival indices for PND 0-4, 4-7, 7-14 and 14-21 as well as the lactational index for PND 4 (postcull) through 21. - Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- changes in number of pregnant
- changes in pregnancy duration
- clinical biochemistry
- clinical signs
- dead fetuses
- effects on pregnancy duration
- food consumption and compound intake
- gross pathology
- haematology
- mortality
- organ weights and organ / body weight ratios
- pre and post implantation loss
- total litter losses by resorption
- urinalysis
- Remarks on result:
- other:
- Remarks:
- Not Specified
Maternal abnormalities
- Abnormalities:
- not specified
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: In the 12.5 and 50 mg / kg group, there was no significant difference in body weights of sexes on 0 and 4 days of nursing compared with the control group. In the 200 mg / kg group, there was a significant high value of sex and body weight on 0th day of nursing compared to the control group, but because there was no significant difference in the 800 mg / kg group, it was not due to administration It is judged. In the 800 mg / kg group, there was no significant difference in male body weight on 4th day of nursing compared to the control group, but there was no significant difference in female body weight on 4th day of nursing though there was no significant difference.
Study 3: There were no effects on F1 male or female body weights at sacrifice on PND 21 at any dose. - Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: In the 12.5 and 50 mg / kg groups, there was no significant difference in the number of surviving children and survival rate on 4th day of nursing compared to the control group. In the 200 mg / kg group, there was a significant low value of the number of surviving children on 4th day of nursing compared to the control group. In the 800 mg / kg group, although there was no significant difference compared with the control group, a low value trend of the number of surviving children on nursing 4th day was observed.
Study 3: No Data Available - Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- no effects observed
- Description (incidence and severity):
- Study 2 and 3: no effects observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Study 3: no effects observed
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Study 2 and 3: no effects observed
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- No data Available
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- reduction in number of live offspring
- fetal/pup body weight changes
- external malformations
- skeletal malformations
- visceral malformations
- Remarks on result:
- other: Not Specified
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
- Treatment related:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Study 2: In the 12.5 and 50 mg / kg groups, there was no significant difference in the number of surviving children and survival rate on 4th day of nursing compared to the control group. In the 200 mg / kg group, there was a significant low value of the number of surviving children on 4th day of nursing compared to the control group. In the 800 mg / kg group, although there was no significant difference compared with the control group, a low value trend of the number of surviving children on nursing 4th day was observed.
Study 3: NOAEL was considered to be ≥200 mg/kg/day in both the F0 and the F1 generation in CD (Sprague-Dawley) rats exposed to the test chemical.
Study 4: The LOAEL was considered to be 250 mg/day in pregnant female mice when exposed to the test chemical. - Executive summary:
Developmental Toxicity Study:
The Data from developmental toxicity studies are as follows:
Developmental Toxicity Study 2:
A combined repeated and reproductive/developmental toxicity test by oral administration to rats of the test chemical was conducted to investigate the effects on the reproductive ability of the male and foster parents and development and development of the next generation .The dose was 800 mg / kg as the highest dose, and 200, 50 and 12.5 mg / kg as below.As a control, a vehicle (5% aqueous gum arabic solution) administration group was provided. The test substance was prepared by suspending it in a 5% gum arabic solution.The test substance was converted to purity, and the dose was expressed in terms of the original weight.Since it was confirmed that the prepared solution had no problem of stability even after storage for 7 days under refrigeration / light-shielding conditions and further at room temperature under light-shielding conditions for 4 hours, the preparation solution of each concentration was prepared , Stored under refrigerated / light-proof conditions, and used within 7 days after preparation.Also, as a result of confirming the concentration of the test substance in the administration solution at each concentration used at the administration start date and the end date of the male administration period, there was no problem with the concentration of the test substance. 8-week-old Sprague-Dawley male and female rats [Crj: CD (SD) IGS, (SPF)] were purchased from Charles River Japan.The obtained animals were subjected to a quarantine period of 5 days and a subsequent acclimatization period of 7 days, and animals that were not abnormal in general state and body weight transition and had no abnormality by sexual cycle observation were grouped.Grouping was carried out on the administration start date so that the average body weight and variance of each group were almost equal by random sampling method after dividing body weight by stratification using a computer.The number of animals in one group was 12 male and female. The animals were kept in a room kept at room temperature 20 to 26 ° C., humidity 40 to 70%, light and dark each for 12 hours (lighting: 6 am to 6 pm), ventilation frequency 12 times / hour.During the quarantine / acclimatization period, stainless steel cages were used to keep up to 5 groups per cage, and after grouping they were individually raised using a stainless steel cage.The mother animals were individually transferred to a plastic cage containing autoclaved bedding (Sunflake, Japan Charles River Co., Ltd.) on the 18th day of pregnancy to allow natural delivery and nursing.The feed was made free from solid feed (CRF-1, Oriental Yeast Industry Co., Ltd.), and the drinking water was freely taken in all of the tap water. The administration route was selected for oral administration.Upon administration, it was forcibly orally administered using a polypropylene disposable syringe fitted with a metal oral gastric tube.In the males, the volume of the liquid to be administered was calculated as 10 mL / kg based on the administration day or the weight on the measurement day closest to the administration day.In females, the body weight of the measurement day closest to the administration day or the administration day before the mating and during the mating period, the body weights of 0, 7, 14, and 21 days of pregnancy during gestation, the body weight of day 0 nursing during the nursing period As a standard, calculated at 10 mL / kg.The number of administrations was once a day. The age at the start of administration was 10 weeks for both males and females, the body weight ranged from 332 to 383 g for males and from 206 to 238 g for females. In males, no death or moribund cases were observed in any group.In general condition and body weight, no change due to administration was observed.Feeding amount was transient low in the 800 mg / kg group.Autopsy showed atrophy of testis and epididymis in 200 mg / kg group, atrophy of testis, epididymis and seminal vesicle in 800 mg / kg group.In the organ weight, low absolute and relative weights of testis and epididymis were observed in groups of 200 mg / kg or more.Sperm examination showed an increase in spermatozoa rate, survival sperm ratio, survival sperm ratio, sperm count, sperm count per gram of epididymal tail, and malformed sperm ratio in the 50 and 200 mg / kg group .In the 800 mg / kg group, no active spermatozoa was observed, and the increase tendency of malformed sperm, the number of sperm and the low number of sperm per 1 g of epididymal body tail were observed.Histopathological examination showed giant cell formation in the testes in the 50 mg / kg group, atrophy of the seminiferous tubules in the testis in the 200 mg / kg group, degeneration of the seminiferous tubules, spermic depletion and giant cell formation, spermatozoa in the epididymis In the 800 mg / kg group, atrophy of seminiferous tubules and spermatozoa in the epididymis were observed in the testes. No deaths or moribund cases were observed in females in either group.In general condition, no change due to administration was observed.Weight gain was suppressed in the nursing stage in the 200 mg / kg group, and increased in the pregnancy and nursing period in the 800 mg / kg group.Feeding levels were low in the 200 and 800 mg / kg groups before mating, during pregnancy and nursing.Necropsy, organ weight and histopathological examination showed no change due to administration. In sperm examination and histopathological examination, as described above, changes were observed in the group of 50 mg / kg or more. There was no change due to the administration in the number of estruses, copulation rate, number of days required for copulation, conception rate, gestation period, delivery status, and nursing condition.In the 800 mg / kg group, one female who was unable to deliver a newborn baby and one mother who died all the newborn at the nursing stage were observed.In addition, in the 800 mg / kg group, the low or low tendency of sex and body weight in sex and body weight was observed in the number of corpus luteum, number of implantation traces, number of total births, number of neonates on 0 and 4 nursing, fertility rate, There was a tendency for the number of births to be high.In the 200 mg / kg group, the number of corpus luteums, the number of implantation traces, the total number of babies born, and the low or low tendency of the number of newborns on 0 and 4 nursing were observed.There was no change due to the administration in the external table, general condition and necropsy of the newborn. As described above, the general toxicological ineffective amount of thed test chemical is 50 mg / kg in males and the sperm test results and testicular histopathological examination It was considered to be 50 mg/kg / day because it was found that 12.5 mg / kg / day was affected by the results and 200 mg / kg in females suppressed body weight gain and low food intake .In addition, reproductive developmental toxicological ineffective dose was 12.5 mg / kg / day in females because it affected sperm examination results and testicular histopathological examination results by 50 mg / kg administration in males, 200 A low tendency of the number of corpus luteum and the number of implantation traces was observed by mg / kg administration, so 50 mg / kg / day was administered at a dose of 50 mg / kg / day, and in children, 200 mg / kg administration resulted in a low number of newborns on day 0 and day 4 It was considered to be 50 mg / kg / day.
Developmental Toxicity Study 3:
In a reproductive toxicity study, the toxic effect of the test chemical was evaluated in male and female CD (Sprague-Dawley) rats. The test chemical was administered by gavage once daily at 0, 10, 100 or 200 mg/kg/day to parental rats through pre-breed, mating, gestation and lactation, and by direct dosing to F1 offspring from weaning to scheduled sacrifice. Treatment resulted in no adult F0 parental toxicity (for pregnant females or non-pregnant females) and there was no evidence of toxicity (systemic, reproductive, or developmental) in F1 offspring animals. In addition, there were no treatment or dose-related findings in any of the systemic, reproductive, developmental, or neurobehavioral endpoints evaluated in-life, at necropsy, in gross or microscopic pathology, male andrology, clinical chemistry, hematology or urinalysis. Therefore, NOAEL was considered to be ≥200 mg/kg/day in male and female of the parental generation as well as for the F1 generation when CD (Sprague-Dawley) rats were exposed to the test chemical on a daily basis.
Developmental Toxicity Study 4:
In present study, the Walter Reed Carworth Farms strain rat was studied after being orally treated with 250 mg of the test chemical. The test chemical was administered through the diet. The weight of rats were 200 g at initiation. Fetal resorptions for the rats were studied. No clinical signs, mortality, body weights and effects on feed consumptions were observed. Marginal differences was noted in resorption of treated rats compared to control. The percentage of resorption was reported to be 37.5%. Therefore. LOAEL was considered to be 250 mg/day when pregnant female Walter Reed Carworth Farms strain rat were treated with the test chemical by oral route for 22 days.
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