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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is from study report

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
Subacute Repeated Dose Oral Toxicity Study of the test chemical in Wistar Rats
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Aldehyde C-11 Undecylenic
IUPAC Name:
Aldehyde C-11 Undecylenic
Constituent 2
Chemical structure
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
- Purity: 1.18 %

Test animals

Species:
rat
Strain:
Wistar
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 oral exposure:
PREPARATION OF DOSING SOLUTIONS: Dose solution were prepared by dissolving Aldehyde C-11 Undecylenic in corn oil to achieve desired concentration of test item. 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
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Doses were analyzed for Homogeneity and Stability by using HPLC method
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 250, 500 or 1000 mg/kg body weight/day
Basis:
actual ingested
No. of animals per sex per dose:
Total: 60
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:
- 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.
- 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
- Section schedule rationale (if not random): No data available
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked in table [No.?] were included: Morbidity and mortality was observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
General observation: once a day Detailed clinical examinations: once before the first treatment (to allow for within-subject comparisons) and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: 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 checked in table [No.?] were 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 checked in table [No.?] were 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 weighted .
Sacrifice and pathology:
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
Organ 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 amnd Vagina were examined.
Other examinations:
No data
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.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS: No apparent treatment related clinical signs were observed in treated rats as compared to control. Statistically significant variations in no. 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.

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

BODY WEIGHT AND WEIGHT GAIN: 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)
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.

Compound intake:
The mean Active Ingredient content at 25, 50 and 100 mg/ml concentration of Aldehyde C-11 Undecylenic 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

FOOD EFFICIENCY No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study) No data available

OPHTHALMOSCOPIC EXAMINATION: No Ophthalmological changes were observed at the pre-treatment and end of treatment and recovery periods in treated animals as compared to control.

HAEMATOLOGY: 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 decrease Potassium level was observed in male rats.

When treated with 500 mg/kg bw/day, Statistically significant decrease Potassium, Cholesterol and increase in Chloride level in male and Bile acids and Potassium level in female rats were observed as compared to control.

When treated with 1000 mg/kg bw/day, Statistically significant decrease Potassium and increase in Chloride level in male and Bile acids, Potassium and sodium and decrease in 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 in male and increase in 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: 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 and 1000 mg/kg body weight/day were observed. Changes observed were inconsistent/ biologically insignificant and not dose dependant, hence considered as incidental and not attributed to the effect of treatment.

ORGAN WEIGHTS: In female rats, absolute and relative weight of spleen significantly increases during treatmentas 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: No external and internal gross pathological changes were observed in treated rats as compared to control during treatment and recovery period.

HISTOPATHOLOGY: 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 body weight. Therefore, exhibited no dose relationship and occurrence of these lesions could be considered as spontaneous or incidental in nature.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No Adverse effect on survival, clinical sign, body weight, food consumption, Opthalmoscopic examination, Haematology, Clinical chemistry, Urinanalysis, Neurobehaviour , Organ weight, Gross pathology and Histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 1000 mg/kg body weight/day when Wistar male and female Rats were treated with the test chemical.
Executive summary:

In a sub-acute repeated dose oral toxicity study, male and female Wistar rats were treated with the test chemical in the concentration of 0, 250, 500 or 1000 mg/kg body weight/day by gavage. No effects were observed on survival and clinical sign of treated rats.Statistically significant variations in the number of rears were observed during pre-treatmentin maleat week 2 and female at week 3, but the observed effect were not regarded to be treatment-related. No statistically significant changes in bodyweight and weight gain, food consumption or ophthalmological changes were observed in treated rats. Hematologic results showed astatistically significant decreaseinMCV and MCH in males,and in RBC, hemoglobin, hematocrit, prothrombin time (PT) in female at 1000 mg/kg bw/day in recovery period. However, the observed changes were considered to be of no toxicological significance since changes were observed in only one sex, of a minimal in nature.Statistically significant decrease in pH and urine volume were seen at 250 mg/kg bw/day, as well as a decrease in pH and urine volume and increased inspecific gravityat 500 mg/kg bw/day. A decrease in pH at 1000 mg/kg bw/day in male rats were also observed. The altered parameters were reversed to normal level during treatment free recovery period. No gross external and internal gross pathological changes were observed in all treated rats. Focal minimal to multifocal mild mononuclear cell infiltration in lungs and trachea were observed in male and female rats, and diffuse minimal lymphophagocytosis in thymusof female rats at 1000 mg/kg bw/day. Therefore, the no observed adverse effect level (NOAEL) was considered to be 1000 mg/kg body weight/day when Wistar male and female Rats were treated with the test chemical for 28 days.