Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
03 January 2018 - 31 October 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. certificate)
Limit test:
yes
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS [please address all points below]:

- Premating exposure duration for parental (P0) animals : as per guidleines
- Basis for dose level selection :
It was considered a suitable dose level range, based on the preliminary results obtained in the previous non-GLP study HF12NR 14-day Oral (Gavage) Dose-Range Toxicity Study for OECD 422 conducted at Envigo CRS, S.A.U.:
- The high dose was selected as no toxicity was observed in the preliminary study at 1000 mg/kg/day and considering it as a limit dose to be tested.
- Intermediate and low dose levels were selected considering approximately a 3-fold interval between doses.
- New dose levels were established or Groups 5 and 6 at 5 and 25 mg/kg/day. In agreement with the Sponsor and based on regulations, it is thought that no effects would be seen at the 25 mg/kg/day level, or maybe only effects in a small number of animals; thus demonstrating a dose –effect relationship (in which case it could be considered the LOAEL). In all cases, it is thought that the 5 mg/kg/day dose level would be a NOAEL.

- Inclusion/exclusion of extension of Cohort 1B : as per guidleines
- Termination time for F2 : n/a
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B : n/a
- Inclusion/exclusion of developmental immunotoxicity Cohort 3 : n/a
- Route of administration : Oral gavage was used as the route of administration as recommended by the OECD 422 guideline, in order to deliver accurate doses. In addition, oral ingestion is a possible route for human exposure to the test item.
- Other considerations, e.g. on choice of species, strain, vehicle and number of animals [if applicable]: Species recognized by international guidelines as a recommended test system.
Specific details on test material used for the study:
Batch number: 0727/16
Storage conditions: At room temperature (20 ± 5 ºC) in the dark
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Species: Recognized by international guidelines as a recommended test system.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
Charles River Laboratories France, Domaine des Oncins, 69592 L’arbresle Cedex, France
- Females (if applicable) nulliparous and non-pregnant: no

- Age at study initiation:

Males: 9 to 13 weeks
Females: 11 to 13 weeks

- Weight at study initiation:
Males: 289-415 g
Females: 190-263 g

- Fasting period before study:
none
- Housing:

Cages with standard, granulated, S8-15 sawdust bedding (J. Rettenmaier & Söhne)
Premating period (maximum 5 animals/cage) Makrolon type IV cages
Mating period (one male and one female/cage) Makrolon type III cages
Postmating, gestation and lactation periods (individual) Makrolon type III cages

- Diet (e.g. ad libitum):
ad libitum
- Water (e.g. ad libitum):
ad libitum
- Acclimation period:
Five days after arrival and pre-treatment start. After acclimatization period, the animals were subjected to a pre-test period.

DETAILS OF FOOD AND WATER QUALITY:
Pelleted standard Teklad 2014C rat/mouse maintenance diet ad libitum (supplied by Envigo RMS, S.L.). Pelleted standard Teklad 2018C rat/mouse maintenance diet (supplied by Envigo RMS, S.L.) ad libitum, for lactating females and pups (until sacrifice).
Tap water in bottles ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
20-24 ºC
- Humidity (%):
30 and 70%
- Air changes (per hr):
15-20
- Photoperiod (hrs dark / hrs light):
12 hours fluorescent light/12 hours dark.
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulation for Group 1 (Vehicle)
The necessary volume of the vehicle was added into a suitable container (stock solution) and the formulation was aliquoted for each day of administration, when required.
Formulation for Groups 2, 3 and 4
1. The required quantity of test item was weighed in a single-use container.
2. The test item was transferred to a sufficiently large mortar and a pestle was used to pulverize it.
3. Small amounts of vehicle were added and mixed with the pestle. Any lumps were broken up at this point, resulting in a homogeneous suspension.
4. The suspension was transferred to a volumetric flask or graduated measuring cylinder that was previously moistened with vehicle. The mortar and the single-use container were rinsed completely with vehicle to ensure that there were no remnants of the test item. This vehicle was added to the volumetric container and make up to the mark.
5. If it was necessary to adjust volume, first the volume was added into volumetric vessel and after the remainder passed at final container.
6. The suspension was transferred to a suitable container and mixed until the suspension was homogenized. The necessary time to obtain a homogenized formulation was visually checked and documented in the raw data.
7. After mixing the formulation for five minutes, samples for analysis were taken, and the formulation was aliquoted for each day of administration, when required.


- DIET PREPARATION
Pelleted standard Teklad 2014C rat/mouse maintenance diet ad libitum (supplied by Envigo RMS, S.L.)

- VEHICLE
- Justification for use and choice of vehicle (if other than water):
not specified
- Concentration in vehicle:
not specified
- Amount of vehicle (if gavage):
10 mL/kg/day

- Lot/batch no. (if required):

Tween 80 - BCBG4547V
CMCNa (medium viscosity) - BCBN1690V
Water: 17382411

- Purity: not specified
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Up to 2 weeks
The following females were paired again after the first 14 consecutive days with the first male: 65, 92, 68 (at 100 mg/kg/day), 70, 72, 74, 77, 78 (at 300 mg/kg/day) and 80 (at 1000 mg/kg/day)

- Daily checks for evidence of mating: Ejected copulation plugs. Sperm within vaginal smear.

- Further matings after two unsuccessful attempts: n/a
- After successful mating each pregnant female was caged: separately on the day when mating evidence was detected
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The formulations prepared at three different concentrations were analyzed twice over the course of the study to verify its correct preparation.
Control (vehicle) formulations were analyzed to confirm the absence of test item or other substances at the retention time of the test item.
The test item was used as analytical standard.
Results were within ±20% of nominal value and the coefficient of variation (CV) was ≤10%.
Other parameters were also tested, meeting the following acceptance criteria:
• System Suitability Test (SST) --- CV ≤ 2%.
• Calibration curve --- R2 ≥ 0.99; deviation of the calibration standards ≤ 10% (75% complies).
Duration of treatment / exposure:
Males - 2 weeks before pairing up to necropsy after 5-6 weeks
Females - 2 weeks before pairing, then throughout pairing and gestation until days 13 15 of lactation (until the day before sacrifice)
Frequency of treatment:
Once daily
Details on study schedule:
- F1 parental animals not mated until 2 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 13-15 days of age.
- Age at mating of the mated animals in the study:
Males: 11 to 15 weeks
Females: 13 to 13 weeks
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)
Dose / conc.:
5 mg/kg bw/day (nominal)
Dose / conc.:
25 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: preliminary study and guidelines
- Rationale for animal assignment (if not random): Randomized
Positive control:
n/a
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Visually inspected twice daily for evidence of reaction to treatment or ill-health.

BODY WEIGHT: Yes
- Time schedule for examinations: See table 1
F1 Individual offspring body weights: Days 1, 4, 7 and 13 of age

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): See table 2
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

Thyroid Hormone Analysis (T4) - Table 3

Oestrous cyclicity (parental animals):
Estrous Cycles
Dry smears Using inoculation loops during the following phases:
• For 14 days before treatment (all females including spares); animals that fail to exhibit 4-5 day cycles were not allocated to study.
• Daily from the beginning of treatment period until evidence of mating.
• On the day of necropsy
A cotton swab impregnated in distilled water was used in order to check the evidence of mating during the mating period.
Sperm parameters (parental animals):
Parameters examined in P male parental generations: testis weight, epididymis weight
Litter observations:
Clinical observations: Observed 24 hours after the considered birth and then daily for evidence of ill-health or reaction to maternal treatment
Litter size: Daily from Day 1-13 of age
Sex ratio: Days 1, 4, 7 and 13 of age
Individual offspring body weights: Days 1, 4, 7 and 13 of age
Ano-genital distance: Day 1 - all F1 offspring
Nipple/areolae count: Day 13 of age - male offspring
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: By intraperitoneal injection of sodium pentobarbital. Each animal was subsequently exsanguinated.
- Maternal animals: By intraperitoneal injection of sodium pentobarbital. Each animal was subsequently exsanguinated.
- Offspring: Selected for thyroid hormone sampling: Cardiac puncture. Death was assured with sodium pentobarbital injection.
All other offspring: injection of sodium pentobarbital.

GROSS NECROPSY
- Gross necropsy consisted of:
F0 Males: After final investigations completed (after 5-7 weeks of treatment)
F0 Females failing to mate: Day 24-after last day of pairing
F0 Females failing to produce viable litter (not pregnant): Day 24-26 after mating
F0 Females whose litters die before Day 13: on or after day last offspring dies
Females killed at termination: Day 14-16 of lactation


HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 4 were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
SACRIFICE
- Selected for thyroid hormone sampling: Cardiac puncture. Death was assured with sodium pentobarbital injection.
All other offspring: injection of sodium pentobarbital.


GROSS NECROPSY
- Gross necropsy consisted of selected offspring for thyroid hormone analysis – Day 4 of age (two females per litter where possible)
Scheduled sacrifice - Day 13-15 of age

Statistics:
For continuous data, a parametric analysis was performed if Bartlett's test for variance homogeneity was not significant at the 1% level. Treated groups were compared to control using Williams' test, unless there was evidence against a monotonic dose-response when Dunnett's test was performed instead.
A non-parametric analysis was performed if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations. Treated groups were compared to control using Shirley's test, unless there was evidence against a monotonic dose response when Steel's test was performed instead.

- For estrous cycles an exact one-tailed (upper-tail) Linear-by-linear test was applied to all groups. If the test was statistically significant (p<0.05), the highest dose group was excluded and the test re-applied.
- For pre-coital intervals an exact one-tailed (upper-tail) Linear-by-linear test was applied to all groups. If the test was statistically significant (p<0.05), the highest dose group was excluded and the test re-applied.

For gestation length an exact two-tailed Linear-by-linear test was applied to all groups. If the test was statistically significant (p<0.05), the highest dose group was excluded and the test re-applied.

For number mating, number conceiving, number fertile, number live and terminal smear status an exact one-tailed (lower-tail) Cochran-Armitage test was applied to all groups. If the test was statistically significant (p<0.05), the highest dose group was excluded and the test re-applied.
Reproductive indices:
Estrous cycles
Pre-coital interval
Mating performance and fertility - Mating percentage, Conception rate, Fertility index
Gestation length
Gestation index
Offspring viability indices:
Litter size
Survival indices (%): Post-implantation survival index, Live birth index, Viability index, Lactation index
Sex ratio
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Adverse clinical signs were observed from day 8 of treatment and onwards at the doses of 300 and 1000 mg/kg/day (shown as thinness, piloerection, hunched posture, pallor, loss of pigmentation, low body temperature). Some of these clinical signs were also observed in females at 100 mg/kg/day during late gestation. On some occasions and at all abovementioned doses it was decided to apply the final endpoint and the animals were killed for welfare reasons (mainly females during late gestation).
At 25 mg/kg/day, hunched posture, abnormal gait, piloerection and/or pallor were observed occasionally in some males and females during the administration period.
At 5 mg/kg/day, pallor was occasionally recorded in one male on day 15 post-mating, and piloerection, hunched posture and pallor were observed in some females during late gestation/lactation.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No mortality was recorded in the males or females administered at 5 or 25 mg/kg/day.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
In males and females, groups administered at 100, 300 and 1000 mg/kg/day showed lower mean body weights than control during post-mating and gestation/lactation periods, generally in line with a dose-response relationship.
Male mean body weights at treatment start were higher compared to control. The same profile was seen at 5 mg/kg/day. At 25 mg/kg/day, however, there was no mean body weight recovery until the end of the study period.
Females showed the same trend in control and at 5 and 25 mg/kg/day; however, at 25 mg/kg/day mean body weight was always lower when compared to control (from the beginning of gestation until sacrifice).
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Test item administration at 100, 300 and 1000 mg/kg/day caused a significant decrease in food consumption with respect to control.
No relevant differences were observed between control and 5 mg/kg/day among females or between control and 5 mg/kg/day among males.
In males, significantly lower mean values with respect to control were observed in all test tem administered groups between days 1-8 post-mating, as well as between days 8-15 at 25, 100, 300 and 1000 mg/kg/day.
Significantly lower mean values were observed during gestation and lactation at 100, 300 and 1000 mg/kg/day when compared to control as well as at 25 mg/kg/day between gestation days 0-7 and during lactation.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of the administration period, males and females showed lower than control hematocrit, hemoglobin, red blood cells, reticulocytes (only in males), white blood cells and lymphocytes at 25, 100, 300 mg/kg/day and in males at 1000 mg/kg/day. Most of these mean values are outside the range commonly recorded in rats under the same conditions.
At 5 mg/kg/day, mean hematocrit and hemoglobin in males and females and white blood cells and lymphocytes in males were lower with respect to Control, although the difference was minimal and the values remained within the range of historical control values.
Statistically significant differences observed in coagulation (prothrombin time and activated partial thromboplastin time in males and females and in fibrinogen in males) were considered not relevant given their magnitude and the absence of a dose-response relationship.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of their corresponding treatment periods, lower mean triglyceride values were recorded in all test-item-administered groups with respect to control. However, mean values at 5 mg/kg/day were close to those recorded in control and within the historical control data.
Clinical biochemistry reveals higher than control mean creatinine values at 100 and 300 mg/kg/day in females and at 25, 100, 300 and 1000 mg/kg/day in males.
Blood chemistry in males after 5 weeks of treatment revealed significantly higher aspartate aminotransferase, bile acids and urea values mainly at 25, 100, 300 and 1000 mg/kg/day when compared to control. Although no dose-response relationship was observed and mean values were similar to those recorded in Control, lower than Control mean values were observed in the test item administered groups in males and at 100 mg/kg/day in females.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
Test-item-treated males showed no relevant differences with respect to control.
In females, mean values at 25 and 100 mg/kg/day were always higher than in the control group. At 100 mg/kg/day, significant differences were observed at 10 and 20 minutes and consequently in the total measurement, while at 25 mg/kg/day they were recorded at 10 minutes and in the total measurement.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Changes that were considered related to treatment with the test item were seen in the thyroids (all administered doses), sternal bone marrow (all dose levels) and thymus of both males and females (at 25, 100, 300 and 1000 mg/kg/day); testes, accessory sex organs (all administered doses), liver (100 mg/kg/day) and skin of males (at 25 and 100 mg/kg/day); and in the spleen of females (at 25 mg/kg/day).
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Reproductive function: oestrous cycle:
effects observed, non-treatment-related
Description (incidence and severity):
All females allocated to the study showed regular 4/5-day estrous cycles prior to treatment start and during treatment, with the exception of one female at 25 mg/kg/day (no. 161) and another from control (no. 50) that showed irregular cycles during treatment.
At termination, all reproductive phase females showed diestrus, with the following exceptions:
- females no. 56 at 0 mg/kg/day and no. 167 at 25 mg/kg/day showing estrus
- females no. 97 at 100 mg/kg/day and no. 87 at 1000 mg/kg/day showing metaestrus
- female no. 88 at 1000 mg/kg/day showing proestrus
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
Pre-coital interval increased at 100, 300 and 1000 mg/kg/day. All females at 5, 25 mg/kg/day and in the control group mated within four days at the first estrus.
At 100, 300 and 1000 mg/kg/day there was a dose-related decrease in the gestation index. Gestation length was also increased at 25, 100 and 300 mg/kg/day. At 5 and 25 mg/kg/day there was no test-item-related effect on gestation index.
Conception rate and fertility index were affected in males and females administered at 100, 300 and 1000 mg/kg/day. However, at 5 and 25 mg/kg/day mating performance was not affected by treatment (100%), and conception and fertility rates were 90% (9/10) for males and females at 5 mg/kg/day, and 100% (10/10) for males and females at 25 mg/kg/day, demonstrating that there was no dose-related effect.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive function (oestrous cycle)
reproductive performance
other:
Remarks on result:
other: based on the data obtained
Key result
Dose descriptor:
NOAEL
Effect level:
0 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive performance
Remarks on result:
not determinable because of methodological limitations
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
25 mg/kg bw/day (nominal)
System:
endocrine system
Organ:
parathyroid gland
thymus
thyroid gland
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Clinical signs were observed among the F1 litters that could be attributable to parental treatment with Triazolone as shown by thin pups in all test-item-administered groups. The rest of the clinical signs recorded (cold body temperature, cut tail, little or no milk present in the stomach, scars, etc.) could be related with maternal neglect due to the signs recorded in females.
However, no thinness was recorded at 5 mg/kg/day in any of the pups from day 4 of lactation, demonstrating that the thinness could be due to occasional maternal neglect (firsts days of lactation) or placenta exposure of the animals, which recovered the weight during the lactation period.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There was no effect of treatment on mean body weights of male or female offspring on day 1 of age or on subsequent body weight measurements until day 13 at 5 mg/kg/day. Body weight profile was similar to that recorded in control offspring.
Offspring mean body weights were reduced at 25, 100 and 300 mg/kg/day with respect to control, as shown by the statistically significant differences observed during the lactation period.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Analyses of samples for thyroxine (T4) obtained from main study males and F1 offspring on Day 13 of age reveal statistically significant differences at all dose levels. A dose-related decrease in T4 levels was observed at increasing dose. At the low dose administered (5 mg/kg/day), recorded values in F0 males and on day 13 offspring have been found to be within 61 and 72% with respect to Control.
Although at 5 mg/kg/day male and female offspring mean T4 values on lactation day 13 are significantly lower than control, they are within the historical control range.

See table 5.
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no macroscopic findings observed in the offspring that died prior to the scheduled termination or among those offspring killed on days 4 or 13-15 of age that were attributable to maternal treatment with Triazolone.
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Triazolone did not affect the ano-genital distance of male or female offspring.
There was no effect on male nipple observations.
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
At 5 and 25 mg/kg/day, the test item administration is related with a decrease in post-implantation survival index as the dose increased as well as the offspring mean body weight at 25 mg/kg/day. There were no offspring clinical signs other than thin pups at 25 mg/kg/day (maybe related to maternal neglect) or necropsy signs indicative of a reaction to Triazolone. Litter size was slightly reduced at 25 mg/kg/day with respect to Control and there was no effect on sex ratio, ano genital distance or nipple areolae.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
haematology
clinical biochemistry
gross pathology
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
0 mg/kg bw/day (nominal)
System:
other: no toxicity observed
Organ:
other: none observed
Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
5 mg/kg bw/day (nominal)
Treatment related:
no

Table 5. Mean serum T4 concentrations (pg/mL)

Group

 

F0

Males

Day 13 Offspring

Males

Day 13 Offspring

Females

Statistical test

 

Sh

Wi

Wi

0 mg/kg/day

Mean

SD

N

53399

9342.0

10

56027

6308.2

8

51869

5584.8

6

5 mg/kg/day

Mean

SD

N

32797***

12339.9

10

38418***

9832.8

9

37402**

5922.1

8

25 mg/kg/day

Mean

SD

N

623***

489.6

9

5896***

3716.0

9

5469***

3553.8

8

100 mg/kg/day

Mean

SD

N

893***

1177.6

4

338***

308.1

3

132***

53.7

3

300 mg/kg/day

Mean

SD

N

91***

15.5

4

-

-

-

-

-

-

1000 mg/kg/day

Mean

SD

N

128***

31.2

3

-

-

-

-

-

-

Historical Control

Data[1]

 

Mean 53632

Range 35964 to 80106

Mean 50692

Range 32755 to 68116

Mean 51793

Range 36068 to 70126


[1]Obtained in eight studies conducted between 2017 and 2018, control rats of the same strain housed in similar environmental conditions.

Conclusions:
In conclusion, the effects of oral (gavage) administration of Triazolone to Wistar rats receiving 5, 25, 100, 300 or 1000 mg/kg/day for 14 days prior to mating and until sacrifice can be summarized as follows:

Reproductive / developmental toxicity - Within the confines of this study, the No Observed Adverse Effect Level (NOAEL) for reproductive / developmental toxicity was considered to be 5 mg/kg/day, based on the reduction observed in T4 determinations.
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
5 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Good

Justification for classification or non-classification