Undec-10-enal

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive Toxicity Study:

A 28 days repeated dose oral toxicity study of the test chemical in Wistar rats with 14 days recovery was conducted, where in 0, 250, 500 or 1000 mg/kg body weight in corn oil, doses were tested. Animals of all dose groups were observed for Clinical signs/ symptoms daily during the experimental period. No treatment related toxic clinical signs or symptoms and reproductive effects were observed in any of the animals from all treated groups, throughout the study. Also,No statistical significant was observed in absolute (g) and relative weights (%) among all organs including the reproductive organs testes, prostate with seminal vesicle, epididymis, ovaries with oviduct and uterus in both sexes when compared to control group. The reproductive No Observed Adverse Effect Level (NOAEL) for the test chemical is found to be1000 mg/kg body weight/day when Wistar male and female Rats were treated with the test chemical in a 28 day sub-acute toxicity study.

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Guideline:

other: OECD 407 Repeated Dose 28-Day Oral Toxicity Study in Rodents

Principles of method if other than guideline:

Subacute toxicity study was conducted to detect the toxic nature of the test chemical and reproductive parameters were examined by reproductive organ weight changes.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No Data Available

Specific details on test material used for the study:

- Molecular formula (if other than submission substance): C11-H20-O
- Molecular weight (if other than submission substance): 168.278 g/mole
- Substance type: Organic
- Physical state: Clear Colourless liquid
- Impurities (identity and concentrations): 1.18 %

Species:

rat

Strain:

Wistar

Details on species / strain selection:

No Data Available

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: In-House Bred at sa-FORD, Animal Facility (CPCSEA Registration No. 1256/bc/09/CPCSEA)
- Age at study initiation: 5-8 weeks
- Weight at study initiation: Male: 149-185 g, Female: 150-198 g
- Fasting period before study: No data available
- Housing: Animals were housed in group of 2-3 rats/sex in polycarbonate cages with sterilized corn cob as bedding in a controlled environment.
- Diet (e.g. ad libitum): A conventional laboratory pelleted diet, ad libitum
- Water (e.g. ad libitum): Aqua guard filtered drinking water in bottles, ad libitum.
- Acclimatization period: 6 days (male) and 7 days (female)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.60-23.30°C
- Humidity (%): 47.20-69.30%
- Air changes (per hr): 12 times per hour and filtered adequately
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

IN-LIFE DATES: From: April 13, 2015
To: May 23, 2015

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Dose solution were prepared by dissolving the test chemical in corn oil to achieve desired concentration. Dose formulation was freshly prepared daily. At the time of dosing, dose formulation was kept on the magnetic stirrer to maintain the homogeneity of test item.

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 was used as a vehicle based on the solubility testing.
- Concentration in vehicle: 0, 250, 500 or 1000 mg/kg bw/day
- Amount of vehicle (if gavage): 1 ml/100g body weight
- Lot/batch no. (if required): MKBS6944V, MKBN5383V and MKBD7039V, Source: Sigma Aldrich
- Purity: No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Doses were analyzed for Specificity, Linearity, Homogeneity and Stability by using HPLC method.

Duration of treatment / exposure:

28 days

Frequency of treatment:

Daily

Details on study schedule:

No data available

Remarks:

Doses / Concentrations:
0, 250, 500 or 1000 mg/kg body weight/day
Basis:

No. of animals per sex per dose:

Total: 60 animals
0 mg/kg bw/day: 5 male , 5 female
250 mg/kg bw/day: 5 male , 5 female
500 mg/kg bw/day: 5 male , 5 female
1000 mg/kg bw/day: 5 male , 5 female

Recovery group:
0 mg/kg bw/day: 5 male , 5 female
1000 mg/kg bw/day: 5 male , 5 female

Control animals:

yes, concurrent vehicle

Details on study design:

Details on study design
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): Animals were assigned to test group on the basis of recent body weight. The animals were allocated to the different test groups using validated software named VSS_STATS. Individual body weights were considered within ± 20 % of the groups mean.

- Other: Rationale for selecting satellite groups: 5 male, 5 female was selected at 0 and 1000 mg/kg bw/day dose group for recovery.
- Post-exposure recovery period in satellite groups: Yes, 14 days

Positive control:

No data available

Parental animals: Observations and examinations:

Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations included: Morbidity and mortality was observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No Data Available
General observation: Once daily Detailed clinical examinations: once before the first treatment (to allow for within-subject comparisons) and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: During randomization, at start of treatment and weekly thereafter

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: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to treatment (during Acclimatization Period) and at the end of the dosing for main groups and at the end of recovery periods for recovery group
- Dose groups that were examined: All 60 animals were examined.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the treatment and recovery periods.
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: All 60 animals were examined.
- Parameters examined: RBC, HCT, MCV, Hgb, MCH, MCHC, Platelet, WBC, Neutrophil, Lymphocyte, Monocyte, Eosinophil, Basophil, Reticulocyte, PT, aPTT and Cell Morphology was examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the treatment and recovery periods.
- Animals fasted: No data available
- How many animals: All 60 animals were examined.
- Parameters examined: Glucose (Glu), Cholesterol (Chol), Triglycerides (TRIG), Alanine amino transferase (ALT), Aspartate amino transferase (AST), Gamma-Glutamyl Transpeptidase (GGT), Calcium, Creatine Kinase (CK), Albumin, Total Protein (TP), Creatinine (Crea), Total Bilirubin (T.Bil), Phosphorus, Alkaline phosphatase (ALP), Urea, Lactate Dehydrogenase (LD), Sodium (Na), Potassium (K), Chloride (Cl), Blood urea nitrogen (BUN), Globulin (Glob), A/G and Bile acids was examined.

URINALYSIS: Yes
- Time schedule for collection of urine: At the end of the treatment and recovery periods.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined: Blood / Blood Cell, Bilirubin, Urobilinogen, Ketone, Protein, Nitrite, Glucose, pH, Specific Gravity, Leucocytes, urine sediments, casts, crystals and other sediments, Colour and appearance were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: At the last week of treatment and recovery period.
- Dose groups that were examined: All 60 animals were examined.
- Battery of functions tested: sensory activity / grip strength / motor activity / other: Yes, Sensory reactivity to stimuli, assessment of grip strength, hind limb foot splay and motor activity was examined.

OTHER:
Organ Weight: Absolute and relative liver, kidneys, adrenals, testes, epdidymides, Prostate and Seminal vesicle with coagulating glands, uterus with cervix, ovary with oviduct, thymus, spleen, brain and heart weight were weighed.

GROSS PATHOLOGY: Yes
All the animals from 0 and 1000 mg/kg bw/day dose group were examined for gross abnormalities.

All collected organs / tissues were fixed and preserved in 10 % neutral buffered formalin, except eye(s) and testes; which were initially fixed in modified Davidson’s fluid for 24 hr and then transferred to 10 % neutral buffered formalin (NBF) for preservation.

HISTOPATHOLOGY: Yes
Organs examined: Adrenals, Pancreas, Aorta, Peyer's Patches, Bone (femur) with joint, Pituitary, Brain (cerebrum, cerebellum, mid brain), Prostate and Seminal vesicle with coagulating glands as a whole, Cecum, Rectum, Colon, Salivary glands, Duodenum, Sciatic Nerve, Epididymides, Skeletal muscle, Eyes with optic nerve, Skin, Heart, Spinal Cord (cervical, mid-thoracic and lumbar), Ileum, Spleen, Jejunum, Sternum with marrow , Kidneys, Stomach, Liver, Testes, Lung, Thymus, Mammary glands, Thyroid with Parathyroids, Mesenteric and Mandibular lymph node, Trachea, Oesophagus, Urinary Bladder, Ovary with oviduct, Uterus with Cervix and Vagina were examined.

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

Statistical analysis for Raw data was analysed using statistical software “Sigma Plot 11.0” (Supplied by Cranes Software International Ltd. Bangalore). The mean and standard deviation was calculated using the software. All continuous data (body weight, feed consumption, hematology, clinical chemistry, absolute and relative organ weights) were checked for their homogeneity using Bartlett’s test. All homogenous data was analysed using ANOVA and data showing significance in their variances was subjected to Dunnett’s t-test. All heterogeneous data was analysed using Kruskal-Wallis one way ANOVA, Mann- Whitney Rank Sum Test and Student’s t-test.

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

no effects observed

Description (incidence and severity):

Clinical signs:
No apparent treatment related clinical signs were observed in treated rats as compared to control. Statistically significant variations in number of rears were observed during pre-treatment in male at week 2 and female at week 3 but the observed effect were not treatment related.

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Description (incidence):

No mortality and morbidity were observed in treated rats as compared to control.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weight:
No statistically significant changes in body weight and weight gain were observed at the pre-treatment and end of treatment and recovery periods in treated animals as compared to control.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No statistically significant changes in food consumption were observed at the pre-treatment and end of treatment and recovery periods in treated animals as compared to control.

Food efficiency:

not specified

Ophthalmological findings:

no effects observed

Description (incidence and severity):

Ophthalmological examination did not reveal any test item related changes in both the eyes of any of the experimental animals, at the pre-treatment and end of treatment and recovery periods.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

ll hematological parameters in animals of different treated groups of both the sexes were comparable to their respective control groups.
When treated with 1000 mg/kg bw/day, statistically significant decrease in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) in males and RBC, hemoglobin, hematocrit, prothrombin time (PT) in female were observed during recovery as compared to control.
The observed change in MCV, MCH, RBC, hemoglobin, hematocrit and PT during recovery period were considered to be of no toxicological significance since changes were observed in only one sex, of a minimal in nature.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Clinical chemistry:
During treatment period:
When treated with 250 mg/kg bw/day, statistically significant decreased potassium level was observed in male rats.
When treated with 500 mg/kg bw/day, statistically significant decreased potassium and cholesterol, and increase in chloride level in male, were observed while bile acids and potassium level in female rats were observed as compared to control.
When treated with 1000 mg/kg bw/day, statistically significant decreased potassium and increased chloride level in male were seen, and increased bile acids, potassium and sodium and decreased creatinine level in female rats were observed as compared to control.
The observed changes were considered incidental and not treatment related as it was observed in only one sex, inconsistent and or not dose-dependent.
During recovery period:
Statistically significant increase in chloride and triglyceride level and decrease in creatinine level were seen in males, and increased bile acids and potassium in female rats were observed as compared to control.
The change in chloride and bile acid has no biological impact on the individual animals and also not evidenced by histopathological observations. Further, these alterations were observed in either in male or female rats hence it could be considered as an incidental finding and not incurred due to treatment.

Urinalysis findings:

not specified

Description (incidence and severity):

Urine parameters did not show any significant difference among all the experimental animals of both the sexes and were comparable to animals of control group.
When treated with 250 mg/kg bw/day, statistically significant decrease in pH and volume were observed in male rats.
When treated with 500 mg/kg bw/day, statistically significant decrease in pH and volume and increased in specific gravity were observed in male rats.
When treated with 1000 mg/kg bw/day, statistically significant decrease in pH was observed in male rats.
These alterations could be considered incidental, since it was observed only in male rats without clear dose response and further it is not evidenced by microscopic examination of urine and organs of urinary system. The altered parameters were reversed to normal level during treatment free recovery period.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

No changes in sensory reactivity, Foot splay and fore limb and hind limb grip strength were observed at end of treatment and recovery periods in treated animals were observed as compared to control.
Statistically significant differences observed in DT (Distance Travelled), RT (Resting Time) and AT (Ambulatory Time) in female treated with 250, 500 or 1000 mg/kg body weight/day were observed.
Changes observed were inconsistent/biologically insignificant and not dose-dependent, hence considered as incidental and not attributed to the effect of treatment.

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

No changes in sensory reactivity, Foot splay and fore limb and hind limb grip strength were observed at end of treatment and recovery periods in treated animals were observed as compared to control.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

When treated with 1000 mg/kg bw/day, focal minimal to multifocal mild mononuclear cell infiltration in lungs and trachea were observed in male and female and diffuse minimal lymphophagocytosis in thymus of female rats as compared to control.

When treated with 500 mg/kg bw/day, focal minimal to multifocal mild mononuclear cell infiltration in trachea was observed in female rats as compared to control.
When treated with 250 mg/kg bw/day, unilateral accessory adrenocortical tissue in adrenals gland of male and focal mild atrophy in thymus of female rat were observed in female rats as compared to control. Mononuclear cell infiltration in lungs and trachea in male and female rats of control and treated at 1000 mg/kg body weight. Presence of accessory adrenocortical tissue in adrenal glands was observed in male rats of control group. Atrophic changes of thymus were observed in female rats of control group and lymphophagocytosis in female rats treated with 1000 mg/kg. Therefore, exhibited no dose relationship and occurrence of these lesions could be considered as spontaneous or incidental in nature.

Histopathological findings: neoplastic:

not specified

Other effects:

effects observed, treatment-related

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Mortality:
No mortality and morbidity were observed in treated rats as compared to control.

Clinical signs:
No apparent treatment related clinical signs were observed in treated rats as compared to control.

Statistically significant variations in number of rears were observed during pre-treatment in male at week 2 and female at week 3 but the observed effect were not treatment related.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weight:
No statistically significant changes in body weight and weight gain were observed at the pre-treatment and end of treatment and recovery periods in treated animals as compared to control.

Food Consumption: No statistically significant changes in food consumption were observed at the pre-treatment and end of treatment and recovery periods in treated animals as compared to control.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS) The mean active Ingredient content at 25, 50 and 100 mg/ml concentration of the test chemical was 24.482, 48.935 and 98.611 mg/ml on Day 1 and 24.491, 48.942 and 98.626 mg/ml on Day 15.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS) No data available

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS) No data available

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS) No data available

ORGAN WEIGHTS (PARENTAL ANIMALS) No statistical significant was observed in absolute (g) and relative weights (%) among all organs like brain, adrenals, testes, prostate with seminal vesicle, epididymis, ovaries with oviduct, uterus, heart, spleen and thymus in both sexes when compared to control group. Similarly, in recovery group after 14 day of recovery period, absolute and relative weights were not statistically significant in both sex at high dose group, compared to control group.

In female rats, absolute and relative weight of spleen significantly increased during treatment as compared to control at 1000 mg/kg bw/day.

In male rat, statistically significant decrease in relative thymus weight was observed in recovery period at 1000 mg/kg bw/day.

The observed variations in weight of spleen and thymus were considered to be of no toxicological significance since; changes were observed only in one sex, of a minimal in nature and not evidenced by histopathological observations.

GROSS PATHOLOGY (PARENTAL ANIMALS) No external and internal gross pathological changes were observed in treated rats as compared to control during treatment and recovery period.

HISTOPATHOLOGY (PARENTAL ANIMALS) When treated with 1000 mg/kg bw/day, focal minimal to multifocal mild mononuclear cell infiltration in lungs and trachea were observed in male and female and diffuse minimal lymphophagocytosis in thymus of female rats as compared to control.

When treated with 500 mg/kg bw/day, focal minimal to multifocal mild mononuclear cell infiltration in trachea was observed in female rats as compared to control.

When treated with 250 mg/kg bw/day, unilateral accessory adrenocortical tissue in adrenals gland of male and focal mild atrophy in thymus of female rat were observed in female rats as compared to control.

Mononuclear cell infiltration in lungs and trachea in male and female rats of control and treated at 1000 mg/kg body weight. Presence of accessory adrenocortical tissue in adrenal glands was observed in male rats of control group. Atrophic changes of thymus were observed in female rats of control group and lymphophagocytosis in female rats treated with 1000 mg/kg. Therefore, exhibited no dose relationship and occurrence of these lesions could be considered as spontaneous or incidental in nature.

OTHER FINDINGS (PARENTAL ANIMALS)
Opthalmoscopic examination:
Ophthalmological examination did not reveal any test item related changes in both the eyes of any of the experimental animals, at the pre-treatment and end of treatment and recovery periods.

Haematology:

All hematological parameters in animals of different treated groups of both the sexes were comparable to their respective control groups.

When treated with 1000 mg/kg bw/day, statistically significant decrease in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) in males and RBC, hemoglobin, hematocrit, prothrombin time (PT) in female were observed during recovery as compared to control.

The observed change in MCV, MCH, RBC, hemoglobin, hematocrit and PT during recovery period were considered to be of no toxicological significance since changes were observed in only one sex, of a minimal in nature.

Clinical chemistry:
During treatment period:
When treated with 250 mg/kg bw/day, statistically significant decreased potassium level was observed in male rats.

When treated with 500 mg/kg bw/day, statistically significant decreased potassium and cholesterol, and increase in chloride level in male, were observed while bile acids and potassium level in female rats were observed as compared to control.

When treated with 1000 mg/kg bw/day, statistically significant decreased potassium and increased chloride level in male were seen, and increased bile acids, potassium and sodium and decreased creatinine level in female rats were observed as compared to control.

The observed changes were considered incidental and not treatment related as it was observed in only one sex, inconsistent and or not dose-dependent.

During recovery period:
Statistically significant increase in chloride and triglyceride level and decrease in creatinine level were seen in males, and increased bile acids and potassium in female rats were observed as compared to control.

The change in chloride and bile acid has no biological impact on the individual animals and also not evidenced by histopathological observations. Further, these alterations were observed in either in male or female rats hence it could be considered as an incidental finding and not incurred due to treatment.

Urinalysis:
Urine parameters did not show any significant difference among all the experimental animals of both the sexes and were comparable to animals of control group.

When treated with 250 mg/kg bw/day, statistically significant decrease in pH and volume were observed in male rats.

When treated with 500 mg/kg bw/day, statistically significant decrease in pH and volume and increased in specific gravity were observed in male rats.

When treated with 1000 mg/kg bw/day, statistically significant decrease in pH was observed in male rats.

These alterations could be considered incidental, since it was observed only in male rats without clear dose response and further it is not evidenced by microscopic examination of urine and organs of urinary system. The altered parameters were reversed to normal level during treatment free recovery period.

Neurobehaviour: No changes in sensory reactivity, Foot splay and fore limb and hind limb grip strength were observed at end of treatment and recovery periods in treated animals were observed as compared to control.

Statistically significant differences observed in DT (Distance Travelled), RT (Resting Time) and AT (Ambulatory Time) in female treated with 250, 500 or 1000 mg/kg body weight/day were observed.

Changes observed were inconsistent/biologically insignificant and not dose-dependent, hence considered as incidental and not attributed to the effect of treatment.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed on the reproductive organ weight

Remarks on result:

other: not specified

Remarks on result:

not measured/tested

Reproductive effects observed:

not specified

Conclusions:

The reproductive No Observed Adverse Effect Level (NOAEL) for the test chemical is found to be 1000 mg/kg body weight/day when Wistar male and female Rats were treated with the test compound in a 28 day subacute toxicity study.

Executive summary:

A 28 days repeated dose oral toxicity study of the test chemical in Wistar rats with 14 days recovery was conducted, where in 0, 250, 500 or 1000 mg/kg body weight in corn oil, doses were tested. Animals of all dose groups were observed for Clinical signs/ symptoms daily during the experimental period. No treatment related toxic clinical signs or symptoms and reproductive effects were observed in any of the animals from all treated groups, throughout the study. Also,No statistical significant was observed in absolute (g) and relative weights (%) among all organs including the reproductive organs testes, prostate with seminal vesicle, epididymis, ovaries with oviduct and uterus in both sexes when compared to control group. The reproductive No Observed Adverse Effect Level (NOAEL) for the test chemical is found to be1000 mg/kg body weight/day when Wistar male and female Rats were treated with the test chemical in a 28 day sub-acute toxicity study.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

K1 level testing data.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive Toxicity Study:

Following study were performed to assess reproductive toxicity of the test chemical:

Reproductive Toxicity Study 1:

A 28 days repeated dose oral toxicity study of the test chemical in Wistar rats with 14 days recovery was conducted, where in 0, 250, 500 or 1000 mg/kg body weight in corn oil, doses were tested. Animals of all dose groups were observed for Clinical signs/ symptoms daily during the experimental period. No treatment related toxic clinical signs or symptoms and reproductive effects were observed in any of the animals from all treated groups, throughout the study. Also,No statistical significant was observed in absolute (g) and relative weights (%) among all organs including the reproductive organs testes, prostate with seminal vesicle, epididymis, ovaries with oviduct and uterus in both sexes when compared to control group. The reproductive No Observed Adverse Effect Level (NOAEL) for the test chemical is found to be1000 mg/kg body weight/day when Wistar male and female Rats were treated with the test chemical in a 28 day sub-acute toxicity study.

Reproductive Toxicity Study 2:

In a one-generation reproductive toxicity study, female Sprague-Dawley rats (10/dose) were administered with the test chemical via gavage for 7 days prior to mating and 32 days thereafter at doses of 0, 300, 1500 or 3000 mg/kg/day. Body weights were decreased at 1500 mg/kg/day during pre-mating and pregnancy. At 300 mg/kg/day, food consumption and body weight were reduced only during the pre-mating period and were not considered adverse effects. Pregnancy rates and fertility were similar in control and treated dams. Pup viability and litter size was reduced at 1500 mg/kg/day. Therefore, NOAEL was considered to be 300 mg/kg while LOAEL was considered to be 1000 mg/kg for the maternal generation after exposure to the test chemical.

Reproductive Toxicity Study 3:

In a developmental/reproductive toxicity study, the toxic effect of the test chemical were evaluated in virgin female Sprague-Dawley rats. The rats were orally exposed to the test chemical at a dosage of 0, 200, 1000 or 2000 mg/kg body weight/day from one week prior to a 7-day cohabitation period through gestation, parturition and a 4-day postpartum period. Mortality was observed in the high-dose (3/10 rats) and mid-dose (1/10 rats). At 2000 mg/kg bw/day, food consumption was reduced throughout the study, average maternal body weights were decreased on days 10-16 of gestation and body weight gains were significantly reduced. Pup weights were reduced on day 4 post parturition in the high-dose group. No effects were noted on implantations, length of gestation, and a proportion of dams delivering at least one live pup or pup viability. No malformations or gross lesions were seen in pups at any dose level. Therefore, NOAEL was considered to be 1000 mg/kg for the maternal generation and the F1 generation when pregnant female Sprague-Dawley rats were orally exposed to the test chemical.

Reproductive Toxicity Study 4:

A combined repeated and reproductive/developmental toxicity screening test was performed to assess and evaluate the reproductive toxicity of the test chemical in rats. In this test, the rats were dosed with the test chemical using three dose groups of 100, 500 and 1000 mg/kg bw/day. A concurrent control group and a satellite group was also used. A total of 14 animals were used per group in this study. Male rats were exposed for 28 days prior to mating, and through mating until euthanasia for a total  of  43-47 consecutive days of dosing; while 12 females were dosed for 14  days prior to mating, during mating, gestation and lactation through euthanasia at lactation day 4 (42-51 consecutive days). The parental animals were observed for pathological changes and neurotoxicity. After the examinations, it was observed that, hepatocyte cytoplasmic vacuolation occurred in both sexes at >500 mg/kg/day (associated with an increase in liver weight), and pitted kidneys and  accumulation of hyaline droplets  in  the  proximal  convoluted  tubules of the kidneys of males at all dose levels. The kidney effects were interpreted to be a result of hydrocarbon nephropathy, which is specific to male rats. Also, the determined NOEL was 100 mg/kg/day which was determined by the effect of liver through histopathological examination in non-pregnant satellite females. In reproductive parameters of the rats, there was no effects observed on copulation and fertility, precoital intervals, gestation length, time  to delivery or unusual nesting behavior. In pup parameters, mortality/viability of the pups, litter size and body weights, male to female pup ratio and external anomalies. After all examinations, no effects were observed in any of the pup parameters. Thus, based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

Developmental Toxicity Study:

Based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.

Link to relevant study records

Reference

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 approach based on the available information from various test chemicals.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: Study 2: Combined Repeated and Reproductive Developmental Toxicity Screening Test

Qualifier:

according to guideline

Guideline:

other: Study 3: Combined Repeated and Reproductive Developmental Toxicity Screening Test

Qualifier:

according to guideline

Guideline:

other: Study 4: Reproductive and Developmental Toxicity Screening Test

Principles of method if other than guideline:

WoE report is based on three developmental toxicity studies on rats:
Study 2 and 3: Combined Repeated and Reproductive Developmental Toxicity Screening Test
Study 4: Reproductive and Development Toxicity Screning Test
All the above experiments were performed to assess and evaluate the reproducive and developmental toxicity of the test chemical in the test animals (rats).

GLP compliance:

not specified

Specific details on test material used for the study:

- Molecular formula (if other than submission substance): C11-H20-O
- Molecular weight (if other than submission substance): 168.278 g/mole
- Substance type: Organic

Species:

rat

Strain:

other: Study 2 and 3: Sprague Dawley; Study 3: Not Specified

Details on test animals or test system and environmental conditions:

Study 2, Study 3 and 4: No Data Available

Route of administration:

other: Study 2, 3 and 4: Oral

Vehicle:

other: Study 2 and 4: Corn Oil and Study 3: Not Specified

Details on exposure:

Study 2: 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): No data available
- Concentration in vehicle: 0, 200, 1000 or 2000 mg/kg-bw/day
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Study 3: Male rats were exposed for 28 days prior to mating, and through mating until euthanasia for a total of 43-47 consecutive days of dosing; while 12 females were dosed for 14 days prior to mating, during mating, gestation and lactation through euthanasia at lactation day 4 (42-51 consecutive days).

Study 4: 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 best miscible in corn oil.
- Concentration in vehicle: 0, 100, 500 and 1000 mg/kg
- 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:

Study 2, 3 and 4: No Data Available

Details on mating procedure:

Study 2: - M/F ratio per cage: No Data Available
- Length of cohabitation: No data available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: No data available
- Verification of same strain and source of both sexes: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy No data available
- Any other deviations from standard protocol: No data available

Study 3 and 4: No Data Available

Duration of treatment / exposure:

Study 2: For one week prior to a 7-day cohabitation period through gestation, parturition and a 4-day postpartum period.
Study 3: Males: 43-47 consecutive days
Females: 42-51 consecutive days
Study 4: Male rats were treated for 28 days prior to mating and for an additional 16 days (44 total days).
Females were dosed for 14 days prior to mating and during mating, gestation and lactation (41-55 days).

Frequency of treatment:

Study 2, 3 and 4: No Data Available

Duration of test:

Study 2, 3 and 4: No Data Available

Remarks:

Study 2: 0, 200, 1000 and 2000 mg/kg bw/day
Study 3 and 4: 0, 100, 500 or 1000 mg/kg bw/day

No. of animals per sex per dose:

Study 2 and 4: No Data Available
Study 3: 24 animals were used per group.

Control animals:

other: Study 2,3 and 4: Yes, Concurrent Vehicle

Details on study design:

Study 2 and 4: No Data Available
Study 3: Further details on study design:
- Dose selection rationale: No Data Available
- Rationale for animal assignment (if not random): No Data Available
- Other: No Data Available

Maternal examinations:

Study 2: Maternal animals were observed for Mortality, clinical signs, food consumption, body weights, mating and fertility,
Study 3: The parental animals were observed for neurotoxic and pathological analyses.
Study 4: Maternal animals were examined for precoital intervals, gestation length, pregnancy rats, copulation, fertility indices

Ovaries and uterine content:

Study 2: Number of implantation and losses were investigated.
Study 3 and 4: No Data Available

Fetal examinations:

Study 2: Fetal examinations included implantations, length of gestation, proportion of dams delivering live pup or pup viability, Pup weights, malformations and gross lesions.
Study 3: Pup viability, pup weights and malformations or gross lesions were observed.
Study 4: Number of litters, pup survival, pup viability, pup weight, and sex ratio.

Statistics:

Study 2, 3 and 4: No Data Available

Indices:

Study 3: Copulation and fertility index, gestational index and pup viability indices
Study 2 and 4: No Data Available

Historical control data:

No Data Available

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Study 2: In the 1000 and 2000 mg/kg-bw/day dose groups, significant increases in the incidence of rales (p < 0.01) and excess salivation (p < 0.01) were reported during pre-mating and gestation. High-dose females also exhibited lethargy, unkempt coats and labored breathing.

Study 3 and 4: No Data Available

Dermal irritation (if dermal study):

not specified

Description (incidence and severity):

Study 2, 3 and 4: No Data Available

Mortality:

mortality observed, treatment-related

Description (incidence):

Study 2: Mortality occurred in the high-dose group (3 of 10 rats) and mid-dose group (1 of 10 rats).
Study 3 and 4: No Data Available

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 2: Average maternal body weights were decreased on days 10 – 16 of gestation and body weight gains were significantly (p < 0.05) reduced.
Study 3 and 4: No Data Available

Food consumption and compound intake (if feeding study):

not specified

Description (incidence and severity):

Study 2: In the high-dose group, food consumption was reduced throughout the study.
Study 3 and 4: No Data Available

Food efficiency:

not specified

Description (incidence and severity):

Study 2, 3 and 4: No Data Available

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):

Study 4: No effects were observed in any of the dose levels.
Study 2 and 3: No Data Available

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Study 3: It was observed that hepatocyte cytoplasmic vacuolation occurred in both sexes at >500 mg/kg/day (associated with an increase in liver weight), and pitted kidneys and accumulation of hyaline droplets in the proximal convoluted tubules of the kidneys of males at all dose levels. The kidney effects were interpreted to be a result of hydrocarbon nephropathy, which is specific to male rats.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Study 3: The adverse effect observed was liver effect in non-pregnant satellite females histologically examined.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No Data Available

Number of abortions:

no effects observed

Description (incidence and severity):

Study 2, 3 and 4: No effects were observed on abortion of fetus at any dose levels.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Study 2 and 4: No effects were observed at any dose levels on pre-- and post-implantation losses.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Study 2 and 4: No effects were observed on the litter losses at given dose levels.

Early or late resorptions:

no effects observed

Description (incidence and severity):

Study 2 and 4: No early or late resorptions were observed at any dose levels.

Dead fetuses:

not specified

Description (incidence and severity):

Study 2, 3 and 4: No fetuses were found dead at any dose levels.

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

Study 2, 3 and 4: No changes were observed in pregnancy duration of the female rats.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): Study 2, 3 and 4: No effects were observed on the pregnancy duration at any given dose levels.

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Study 4: No changes were observed in the number of pregnant females at any dose levels.

Other effects:

not specified

Details on maternal toxic effects:

No Data Available

Dose descriptor:

NOAEL

Effect level:

200 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

dead fetuses

early or late resorptions

effects on pregnancy duration

food consumption and compound intake

mortality

number of abortions

pre and post implantation loss

total litter losses by resorption

Abnormalities:

not specified

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 2: Pup weights were reduced on day 4 post parturition in the high-dose group.
Study 3 and 4: No effects were observed
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): effects observed, treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Study 2: Pup weights were reduced on day 4 post parturition in the high-dose group.
Study 3 and 4: No effects were observed

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

Study 2, 3 and 4: No effects were observed in reduction in number of live offsprings.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

Study 3 and 4: No changes in sex ratio were observed at given dose levels.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Study 2, 3 and 4: No changes were observed in liiter size and their weights at any dose levels.

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

Study 4: No changes were observed in post natal survival at any dose levels.

External malformations:

no effects observed

Description (incidence and severity):

Study 3: No external malformations were obsrved at any dose levels.

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

No Data Available

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

changes in litter size and weights

changes in postnatal survival

external malformations

Abnormalities:

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

Study 2: Based on all the observation it was concluded that, NOAEL was considered to be 200 and 2000 mg/kg body weight/day for the maternal generation and the F1 generation respectively.

Study 3: Based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.

Study 4: Based on all the above observations, it was concluded that, the NOAEL for both maternal and fetal parameters based on the test chemical was found to be 1000 mg/kg bw/day.

Executive summary:

Developmental Toxicity Study Summaries:

Study 2:

In a reproductive/developmental toxicity study, female Sprague-Dawley rats (10/group) were administered with the test chemical via gavage (in corn oil) at doses of 0, 200, 1000 or 2000 mg/kg-bw/day for one week prior to a 7-day cohabitation period through gestation, parturition and a 4-day postpartum period. The parental animals were observed for Mortality, clinical signs, food consumption, body weights, mating and fertility, while Fetal examinations included implantations, length of gestation, proportion of dams delivering live pup or pup viability, Pup weights, malformations and gross lesions. After all the examinations it was observed that in maternal animals, mortality occured in high dose group. In clinical signs, in the 1000 and 2000 mg/kg-bw/day dose groups, significant increases in the incidence of rales (p < 0.01) and excess salivation (p < 0.01) were reported during pre-mating and gestation. High-dose females also exhibited lethargy, unkempt coats and labored breathing. Also, average maternal body weights were decreased on days 10 – 16 of gestation and body weight gains were significantly (p < 0.05) reduced. In the high-dose group, food consumption was reduced throughout the study. Although, no effects were observed in pre and post implantation loss, resorptions, viability of the pups and pregnancy duration in maternal animals. In pup parameters, no effects were observed in change in number of offsprings and litter size, and no external anomalies were observed at any dose levels. Thus, based on all the observation it was concluded that, NOAEL was considered to be 200 and 2000 mg/kg body weight/day for the maternal generation and the F1 generation respectively.

Study 3:

A combined repeated and reproductive/developmental toxicity screening test was performed to assess and evaluate the reproductive toxicity of the test chemical in rats. In this test, the rats were dosed with the test chemical using three dose groups of 100, 500 and 1000 mg/kg bw/day. A concurrent control group and a satellite group was also used. A total of 14 animals were used per group in this study. Male rats were exposed for 28 days prior to mating, and through mating until euthanasia for a total  of  43-47 consecutive days of dosing; while 12 females were dosed for 14  days prior to mating, during mating, gestation and lactation through euthanasia at lactation day 4 (42-51 consecutive days). The parental animals were observed for pathological changes and neurotoxicity. After the examinations, it was observed that, hepatocyte cytoplasmic vacuolation occurred in both sexes at >500 mg/kg/day (associated with an increase in liver weight), and pitted kidneys and  accumulation of hyaline droplets  in  the  proximal  convoluted  tubules of the kidneys of males at all dose levels. The kidney effects were interpreted to be a result of hydrocarbon nephropathy, which is specific to male rats. Also, the determined NOEL was 100 mg/kg/day which was determined by the effect of liver through histopathological examination in non-pregnant satellite females. In reproductive parameters of the rats, there was no effects observed on copulation and fertility, precoital intervals, gestation length, time  to delivery or unusual nesting behavior. In pup parameters, mortality/viability of the pups, litter size and body weights, male to female pup ratio and external anomalies. After all examinations, no effects were observed in any of the pup parameters. Thus, based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.

A combined repeated and reproductive/developmental toxicity screening test was performed to assess and evaluate the reproductive toxicity of the test chemical in rats. In this test, the rats were dosed with the test chemical using three dose groups of 100, 500 and 1000 mg/kg bw/day. A concurrent control group and a satellite group was also used. A total of 14 animals were used per group in this study. Male rats were exposed for 28 days prior to mating, and through mating until euthanasia for a total  of  43-47 consecutive days of dosing; while 12 females were dosed for 14  days prior to mating, during mating, gestation and lactation through euthanasia at lactation day 4 (42-51 consecutive days). The parental animals were observed for pathological changes and neurotoxicity. After the examinations, it was observed that, hepatocyte cytoplasmic vacuolation occurred in both sexes at >500 mg/kg/day (associated with an increase in liver weight), and pitted kidneys and  accumulation of hyaline droplets  in  the  proximal  convoluted  tubules of the kidneys of males at all dose levels. The kidney effects were interpreted to be a result of hydrocarbon nephropathy, which is specific to male rats. Also, the determined NOEL was 100 mg/kg/day which was determined by the effect of liver through histopathological examination in non-pregnant satellite females. In reproductive parameters of the rats, there was no effects observed on copulation and fertility, precoital intervals, gestation length, time  to delivery or unusual nesting behavior. In pup parameters, mortality/viability of the pups, litter size and body weights, male to female pup ratio and external anomalies. After all examinations, no effects were observed in any of the pup parameters. Thus, based on all the above observations it was concluded that the NOEL for parental animals was found to be 100 mg/kg bw/day and the NOAEL for F1 generation was found to be 1000 mg/kg bw/day.

Study 4:

An experiment was conducted to assess the reproductive and developmental toxicity potential of the test chemical in rats. In this experiment, the test chemical was mixed with the corn oil and administered orally to the animals in the dose groups of 0, 100, 500 and 1000 mg/kg bw/day. Male rats were treated for 28 days prior to mating and for an additional 16 days (44 total days). Females were dosed for 14 days prior to mating and during mating, gestation and lactation (41-55 days). During and after the dosing the animals were observed for any adverse effects of the test chemicals. After dosing, it was observed that there were no adverse effects observed in maternal animals at any given dose levels. However, in male rats, absolute epididymal weights for males were statistically lower in all treated groups compared to controls and the epididymal/brain relative weights were also lower in all treated groups compared to controls, although only the low dose group was statistically significant. The biological significance of the decreased epididymal weights was found to be uncertain because of no apparent histopathological effects in the epididymis and no evidence of impared fertility in the treated males and there was a lack of a dose response between treated groups. In maternal parameters, there were no effects on the following reproductive parameters: precoital intervals, gestation length, pregnancy rats, copulation and fertility indices. Also, in developmental parameters, it was observed that, there were no effects on the number of litters, pup survival, pup viability, pup weight, and sex ratio. Thus, based on all the above observations, it was concluded that, the NOAEL for both maternal and fetal parameters based on the test chemical was found to be 1000 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The data is from Klimisch 2 data source.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental Toxicity Study Summaries:

Following study were performed to assess developmental toxicity of the test chemical:

Developmental Toxicity Study 2:

In a reproductive/developmental toxicity study, female Sprague-Dawley rats (10/group) were administered with the test chemical via gavage (in corn oil) at doses of 0, 200, 1000 or 2000 mg/kg-bw/day for one week prior to a 7-day cohabitation period through gestation, parturition and a 4-day postpartum period. The parental animals were observed for Mortality, clinical signs, food consumption, body weights, mating and fertility, while Fetal examinations included implantations, length of gestation, proportion of dams delivering live pup or pup viability, Pup weights, malformations and gross lesions. After all the examinations it was observed that in maternal animals, mortality occured in high dose group. In clinical signs, in the 1000 and 2000 mg/kg-bw/day dose groups, significant increases in the incidence of rales (p < 0.01) and excess salivation (p < 0.01) were reported during pre-mating and gestation. High-dose females also exhibited lethargy, unkempt coats and labored breathing. Also, average maternal body weights were decreased on days 10 – 16 of gestation and body weight gains were significantly (p < 0.05) reduced. In the high-dose group, food consumption was reduced throughout the study. Although, no effects were observed in pre and post implantation loss, resorptions, viability of the pups and pregnancy duration in maternal animals. In pup parameters, no effects were observed in change in number of offsprings and litter size, and no external anomalies were observed at any dose levels. Thus, based on all the observation it was concluded that, NOAEL was considered to be 200 and 2000 mg/kg body weight/day for the maternal generation and the F1 generation respectively.

Developmental Toxicity Study 3:

In a reproductive/developmental toxicity study, female Sprague-Dawley rats (10/group) were administered with the test chemical via gavage (in corn oil) at doses of 0, 200, 1000 or 2000 mg/kg-bw/day for one week prior to a 7-day cohabitation period through gestation, parturition and a 4-day postpartum period. The parental animals were observed for Mortality, clinical signs, food consumption, body weights, mating and fertility, while Fetal examinations included implantations, length of gestation, proportion of dams delivering live pup or pup viability, Pup weights, malformations and gross lesions. After all the examinations it was observed that in maternal animals, mortality occured in high dose group. In clinical signs, in the 1000 and 2000 mg/kg-bw/day dose groups, significant increases in the incidence of rales (p < 0.01) and excess salivation (p < 0.01) were reported during pre-mating and gestation. High-dose females also exhibited lethargy, unkempt coats and labored breathing. Also, average maternal body weights were decreased on days 10 – 16 of gestation and body weight gains were significantly (p < 0.05) reduced. In the high-dose group, food consumption was reduced throughout the study. Although, no effects were observed in pre and post implantation loss, resorptions, viability of the pups and pregnancy duration in maternal animals. In pup parameters, no effects were observed in change in number of offsprings and litter size, and no external anomalies were observed at any dose levels. Thus, based on all the observation it was concluded that, NOAEL was considered to be 200 and 2000 mg/kg body weight/day for the maternal generation and the F1 generation respectively.

Developmental Toxicity Study 4:

An experiment was conducted to assess the reproductive and developmental toxicity potential of the test chemical in rats. In this experiment, the test chemical was mixed with the corn oil and administered orally to the animals in the dose groups of 0, 100, 500 and 1000 mg/kg bw/day. Male rats were treated for 28 days prior to mating and for an additional 16 days (44 total days). Females were dosed for 14 days prior to mating and during mating, gestation and lactation (41-55 days). During and after the dosing the animals were observed for any adverse effects of the test chemicals. After dosing, it was observed that there were no adverse effects observed in maternal animals at any given dose levels. However, in male rats, absolute epididymal weights for males were statistically lower in all treated groups compared to controls and the epididymal/brain relative weights were also lower in all treated groups compared to controls, although only the low dose group was statistically significant. The biological significance of the decreased epididymal weights was found to be uncertain because of no apparent histopathological effects in the epididymis and no evidence of impared fertility in the treated males and there was a lack of a dose response between treated groups. In maternal parameters, there were no effects on the following reproductive parameters: precoital intervals, gestation length, pregnancy rats, copulation and fertility indices. Also, in developmental parameters, it was observed that, there were no effects on the number of litters, pup survival, pup viability, pup weight, and sex ratio. Thus, based on all the above observations, it was concluded that, the NOAEL for both maternal and fetal parameters based on the test chemical was found to be 1000 mg/kg bw/day.

Justification for classification or non-classification

Based upon the available information, the test chemical may not be classified according to CLP classification since it does not exhibit any toxicity to the reproductive and developmental parameters of the test animals.