Undec-10-enal

Toxicity to reproduction

Administrative data

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)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Materials and methods

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Paracetamol

EC Number:

203-157-5

EC Name:

Paracetamol

Cas Number:

103-90-2

Molecular formula:

C8H9NO2

IUPAC Name:

N-(4-hydroxyphenyl)acetamide

Constituent 2

Reference substance name:

Aldehyde C-11 Undecylenic

IUPAC Name:

Aldehyde C-11 Undecylenic

Constituent 3

Reference substance name:

Undec-10-enal

EC Number:

203-973-1

EC Name:

Undec-10-enal

Cas Number:

112-45-8

Molecular formula:

C11H20O

IUPAC Name:

undec-10-enal

Test material form:

other: Liquid

Details on test material:

- Name of test material (as cited in study report): Aldehyde C-11 Undecylenic
- 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 %

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 %

Test animals

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

Administration / exposure

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

Doses / concentrations

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

Examinations

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

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Details on results (P0)

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.

Effect levels (P0)

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

Results: F2 generation

Effect levels (F2)

Remarks on result:

not measured/tested

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

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.