1,1,1"((methylsilanetriyl)tris)(oxy))tris(2-methylpropan-2-amine)

Endpoint summary

Description of key information

Based on all the observations and results from read across studies and applying weight of evidence, it was concluded that the No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 1000 mg / kg body weight when Wistar male and female rats were orally treated with test chemical.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

experimental data of read across substances

Justification for type of information:

The information is from handbook or collection of data

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: as given below

Principles of method if other than guideline:

To estimate repeated oral exposure toxicity of the test chemical.

GLP compliance:

not specified

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

From WoE 2 and WoE 3:
Source: In-House Bred at sa-FORD, Animal Facility (CPCSEA Registration No. 1256/bc/09/CPCSEA)
Health Status: Healthy young adult animals were used for the study. Females were nulliparous and non-pregnant.
Body weight of animals:
Male: Minimum: 240 g; Maximum: 315 g
Female: Minimum: 210 g; Maximum: 260 g (Individual body weights were within ± 20% of mean body weight, prior to treatment)
Age: 12 - 13 weeks at the start of Oestrous Cycle evaluation.
Acclimatisation: Animals were acclimatised to the test conditions for 20 days prior to test item administration
Housing: Before the animals are brought in, the study room and cages were cleaned and disinfected. During the study, the floor of the experimental room and work tops were swept and mopped with disinfectant solution every day or as on requirement. Cages were cleaned at regular intervals.
A total 2-3 rats/sex were housed in Polycarbonate cages (size 37 [cm] x 21 [cm], height 20 [cm]). Cage rotation was carried out weekly during study period except during mating for males and females both and during gestation and lactation for females. Sterilized corn cob produced from pure corn, dried and free from dust, procured from approved supplier, was used as bedding material. It was renewed as often as necessary to keep the animals dry and clean.
Bedding material of batch No. SPAR-30/2015 (Sparconn Life Sciences Bangalore) was used in this study and a copy of report of microbial and chemical contaminants analysed periodically by manufacturer of bedding material are incorporated in the raw data.

Environmental conditions:
The room temperature was maintained at 18.30 to 22.70 °C and the relative humidity was kept between 43.90 to 67.60%. Artificial light was set to give a cycle of 12 hours light and 12 hours dark. Air changes were about minimum 12 times per hour and filtered adequately.

Diet :A conventional laboratory pelleted diet of batch no. 004915, 041215 and 041015 from approved supplier (Nutrivet Life Sciences, Pune) was offered ad libitum. The copy of composition, microbial and chemical contaminant reports analysed periodically by manufacturer are incorporated in the raw data.

Water : Aqua guard filtered drinking water in bottles was offered ad libitum. Samples of the drinking water was subjected periodically to bacteriological tests and to chemical contaminant analysis. The latest test results are included in the raw data.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

From WoE 2 and WoE 3:
PREPARATION OF DOSING SOLUTIONS: The test item was weighed and dissolved in a vehicle (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. The details of dose formulation preparation is maintained in raw data.

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

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, 308, 556 and 1000 mg/kg bw
- Amount of vehicle (if gavage): 0.5 ml/kg
- Lot/batch no. (if required): MR301015, MR161215
- Purity:

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

From WoE 2 and WoE 3:
Homogeneity and Stability of dose formulation by analysing the sample at different time points (Stability was determined by sampling and analyzing the aliquots from the sample stored at 25 ± 2°C at the time points of 0, 2 and 6 hours).Two replications was analyzed at each time point.The dose formulation analysis were carried out at the start (on the day 1) of treatment, on day 21 and day 40 during the study period.

Duration of treatment / exposure:

WoE 2
Male: 47 days
Female : 63 days

WoE 3:
≤ 90 days

Frequency of treatment:

Daily

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

308 mg/kg bw/day (actual dose received)

Dose / conc.:

556 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Total: 124
0 mg/kg bw: 13 male, 13 female
308 mg/kg bwm: 13 male, 13 female
556 mg/kg bwm: 13 male, 13 female
1000 mg/kg bwm: 13 male, 13 female
Control recovery: 5 male, 5 female
1000 mg/kg bw recovery: 5 male, 5 female

Control animals:

yes

Details on study design:

- Dose selection rationale:
- Rationale for animal assignment (if not random): Vaginal smear of all females was evaluated for regular cyclicity before treatment (14 days). At the time of randomization females not showing regular cycle were euthanised and discarded
- Other:

Positive control:

No Data Available

Observations and examinations performed and frequency:

From WoE 2 and WoE 3:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (morning and evening)
- Cage side observations checked in table [No.?] were included. : morbidity and mortality were examined.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a day, preferably at the same time each day considering the peak period of anticipated effects after dosing.
Detailed clinical examinations were carried out once before the first treatment (to allow for within-subject comparisons) and weekly thereafter.
The detailed clinical examinations were made outside the home cage, at approximately the same time, on each occasion.

BODY WEIGHT: Yes
- Time schedule for examinations: on the first day of dosing, at least weekly thereafter, and at termination. During pregnancy, females were weighed on days 0, 7, 14 and 20 and within 24 hours of parturition (day 0 or 1 post-partum), day 4 post-partum and before terminal sacrifice.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

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

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: just prior to necropsy.
- Anaesthetic used for blood collection: No
- Animals fasted: Yes, overnight (approximately 16-18 hr) prior to blood collection
- How many animals: five males and five females, randomly selected from each group
- Parameters checked in table [No.?] were examined.: Total Erythrocyte Count (RBC), Hematocrit (HCT), Mean Corpuscular Volume (MCV), Hemoglobin (HGB), Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), Platelet Count (PLT), Total Leukocyte count (WBC), Prothombin Time (PT) and Activated Partial Thromboplastin time (aPTT) were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: just prior to necropsy.
- Animals fasted: Yes, overnight (approximately 16-18 hr) prior to blood collection
- How many animals:five males and five females, randomly selected from each group
- Parameters checked in table [No.?] were examined: Glucose (Glu), Cholesterol (Chol), Triglycerides (TRIG), Alanine amino transferase (ALT), Aspartate amino transferase (AST), Calcium, Albumin (Alb), Total Protein (TP), Creatinine (Crea), Phosphorus, Urea, Sodium (Na), Potassium (K), Blood urea nitrogen (BUN) – Calculated, Globulin (Glob) - Calculated, Alb/ Glb (A:G) – Calculated and Bile acidswere examined.

URINALYSIS: Not specified
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Yes / No / Not specified
- Parameters checked in table [No.?] were examined.

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

IMMUNOLOGY:Not specified
- Time schedule for examinations:
- How many animals:
- Dose groups that were examined:
- Parameters checked in table [No.?] were examined.

OTHER:
Organ weight were examined.
Weighing of brain, adrenals, ovaries with oviduct, testes, epididymides, heart, liver, kidneys, thymus and spleen was performed for randomly selected 5 male and 5 female rats. Testes and epididymides of all male rats were weighed.

Sacrifice and pathology:

From WoE 2 and WoE 3:
GROSS PATHOLOGY: Yes, At scheduled sacrifice date, all rats of main and recovery groups were euthanized by over dose of carbon dioxide followed by exsanguination. The animals were examined externally in unopened condition.

HISTOPATHOLOGY: Yes, All the preserved organs (Testes, epididymides, prostate and seminal vesicle with coagulating glands, ovaries, uterus and cervix with vagina) of all the rats, all the preserved tissues of randomly selected five male and five female rats of groups G1 and G4 and preserved thyroid of one male and one female pup of each litter were subjected to histopathological examination. All the tissues were trimmed, processed, embedded in paraffin wax. Sections were cut at a thickness of 3-5 micron and stained with hematoxylin and eosin stain.
Processed tissues were subjected to histopathological examination. The prepared slides were examined under microscope by the Pathologist to note histopathological lesions, if any in different organs. Special attention was paid to observe effect of test item on reproductive system and spermatogenesis.

Other examinations:

From WoE 2 and WoE 3:
Number and sex of pups, stillbirths, live births, runts (pups that are significantly smaller than corresponding control pups), body weight and the presence of gross abnormalities.

Statistics:

From WoE 2 and WoE 3:
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 and all data was summarized in tabular form. All continuous data (body weight, feed consumption, Functional Observational Battery parameters, hematology, clinical chemistry, absolute and relative organ weights, maternal and pup parameters etc.) were checked for normality using Shapiro Wilk 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 F test and Student’s t-test, Dunn’s Test, Kruskal-Wallis, ANOVA on ranks,

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

from WoE 1 and WoE 2:
No apparent treatment related clinical signs were observed in any of the animals throughout the treatment and recovery period.
Detailed clinical examinations like Home cage observation, Handling observation and Open field observation of all animals were observed to be normal during study period. Statistically significant decrease was observed in number of rears of G3 (556 mg/kg body weight) and G4 (1000 mg/kg body weight) male on pre-treatment as compared to control G1 (0 mg/kg body weight). The statistically significant increase was observed in number of urine pools of G3 (556 mg/kg body weight) and G4 (1000 mg/kg body weight) male at pre-treatment as compared to control G1 (0 mg/kg body weight). Statistically significant increase was observed in number of fecal bolus of G3 (556 mg/kg body weight) male at pre-treatment as compared to control G1 (0 mg/kg body weight). Statistically significant increase was observed in number of rears of G4 (1000 mg/kg body weight) male at week 4 as compared to control G1 (0 mg/kg body weight). Statistically significant increase was observed in number of urine pools of G3 (556 mg/kg body weight) male at week 6 as compared to control G1 (0 mg/kg body weight). Statistically significant increase was observed in number of rears of G2 (308 mg/kg body weight), G3 (556 mg/kg body weight) and G4 (1000 mg/kg body weight) female at pre-treatment as compared to control G1 (0 mg/kg body weight). Statistically significant increase was observed in number of fecal bolus of G4 (1000 mg/kg body weight) female at week 5 as compared to control G1 (0 mg/kg body weight).
The above changes observed were inconsistent/ biologically insignificant and not dose dependant, hence considered as incidental and not attributed to the effect of test item administration.

Mortality:

no mortality observed

Description (incidence):

from WoE 1 and WoE 2:
No mortality or morbidity was observed in any animal of the control and treatment groups throughout the study period.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

From WoE 1 and WoE 2:
A statistically significant decrease was observed in body weight of G4 (1000 mg/kg body weight) male on day 30 as compared to control G1 (0 mg/kg body weight). Statistically significant decrease was observed in body weight of G4 (1000 mg/kg body weight) female on day 20 of gestation as compared to control G1 (0 mg/kg body weight). Statistically significant decrease was observed in body weight of G4-R (1000 mg/kg body weight) male on day 29, 36, 41 as compared to control G1-R (0 mg/kg body weight). Statistically significant decrease was observed in percent body weight change of G3 (556 mg/kg body weight) and G4 (1000 mg/kg body weight) male on day 1-8, 1-14 whereas statistically significant decrease was observed in percent body weight change of G4 (1000 mg/kg body weight) male on day 1-21, 1-28, 1-30, 1-37, 1-44, 1-46 as compared to control G1-R (0 mg/kg body weight). Statistically significant decrease was observed in percent body weight change during gestation period of G4 (1000 mg/kg body weight) female on day 0-14, 0-20 as compared to control G1 (0 mg/kg body weight). Statistically significant decrease was observed in percent body weight change of G4-R (1000 mg/kg body weight) male on day 1-8, 1-15, 1-22, 1-29 as compared to control G1-R (0 mg/kg body weight).
Body weight and Percent body weight changes in animals of the all other test groups of both the sexes was comparable and did not show any significant difference as compared to the respective control group.
These changes observed were inconsistent, hence not considered as effect of the test item administration.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

From WoE 1 and WoE 2:
Statistically significant decrease in feed consumption was observed in G4 (1000 mg/kg body weight) female on gestation day 14-20 as compared to the control group G1. Feed consumption in animals of the all other test groups of both the sexes was comparable and did not show any significant difference as compared to the respective control group. Changes observed in feed consumption were inconsistent, hence not considered as effect of the test item administration.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

From WoE 1 and WoE 2:
All hematological parameters in animals of different treated groups of both the sexes were comparable to their respective control groups, except statistically significant decrease observed for MCHC, WBC in males of G4 (1000 mg/kg body weight) as compared to G1, statistically significant increase observed for aPTT in males of G4 (1000 mg/kg body weight) and G3 (556 mg/kg body weight) as compared to G1. Statistically significant decrease observed for RBC, HCT, HGB, WBC in males of G4-R (1000 mg/kg body weight) as compared to G1-R. Statistically significant decrease observed for PT in females of G3 (556 mg/kg body weight) as compared to G1. Statistically significant decrease observed for MCHC and statistically significant increase observed for RBC, HCT, HGB in females of G4-R (1000 mg/kg body weight) as compared to G1-R.
The above changes were inconsistent, not related to the test item and may be due to the preanalytical and analytical variables (J. Robinson and G.O.Evans, 2005).

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

from WoE 1 and WoE 2:
All clinical chemistry parameters in animals of different treated groups of both the sexes were comparable to their respective control groups, except statistically significant increase observed for ALT and statistically significant decrease observed for Sodium (Na) in males of G4 (1000 mg/kg Body weight) as compared to G1. Statistically significant increase observed for Creatinine in males of G2 (308 mg/kg Body weight) as compared to G1. Statistically significant decrease observed for Total Protein and statistically significant increase observed for A/G ratio in females of G3 (556 mg/kg Body weight) as compared to G1. The above changes were inconsistent, not dose dependent hence considered as incidental in nature.

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):

At the end of treatment and recovery period, absolute and relative weight of organs of treated rats of either sex did not differ significantly except a significant increase in relative wieght of Adrenal of G4-R male group when compared to the respective control group rats.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

External examination of all male and female rats of control and all treated groups including recovery groups did not reveal any abnormality of pathological significance

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

from WoE 1 and WoE 2:
Visceral examination of the rats of control and other treated groups did not reveal any pathological abnormality.
Microscopic examination of control group and rats treated at 308, 556 and 1000 mg/kg revealed varying degree of pathological changes in different organs. This includes Liver: focal to multifocal minimal lymphocytic infiltration (Male: G1:1/5, G4:2/5; Female: G1: 1/5; G4: 2/5); focal minimal necrosis (Male: G1:1/5; Female: G1: 1/5); Kidneys: focal minimal lymphocytic infiltration (Male: G1:2/5; Female: G4:1/5); focal mild mineralization (Female: G1:1/5); Lungs: multifocal minimal lymphocytic infiltration (Male:G1:1/5, G4:1/5; Female: G1: 2/5, G4: 3/5); focal minimal histiocyte infiltration (Female: G1: 1/5, G4: 1/5); Heart: focal minimal lymphocytic infiltration (Male: G1:1/5, G4:1/5); Aorta: focal minimal aneurysm (Male:G1:1/5, G4:1/5); Mandibular Lymph Node: focal moderate cystic dilation of cortex (Female: G4:1/5); Stomach: focal mild squamous epithelium hyperplasia (Female: G1: 1/5); Mesenteric lymph node: focal moderate cystic dilation of cortex (Female:G1:1/5); Spleen: focal to diffuse minimal to mild extramedullary hematopoesis (Female: G1: 2/5, G4: 3/5); Thymus: mild to moderate atrophy (Female: G1:3/5, G4:4/5); focal mild cystic epithelial dilation (Male: G4:1/5; Female: G1: 1/5, G4:1/5); Trachea: focal to multifocal minimal to moderate Neutrophilic/lymphocytic infiltration (Male: G1:3/5, G4:3/5; Female: G1: 2/5, G4:1/5); Adrenals: unilateral accessory adrenocortical tissue (Male: G1:1/5, G4:1/5); Testes: focal to multifocal minimal to mild retention of mature sperm (Male: G1:4/13, G2:8/13, G3:8/13, G4:8/13); focal minimal to mild degeneration of seminiferous tubules (Male: G1:2/13, G2:1/13, G3:1/13, G4:1/13); focal to multifocal minimal sloughing of Pachytene Spermatocyte (Male: G1:2/13, G2:2/13, G3:2/13, G4:2/13); focal minimal sloughing of round spermatid (Male: G1:1/13, G2:1/13, G3:1/13, G4:1/13); focal mild infiltration of multinucleated giant cells (Male: G1:1/13); Seminal Vesicles: multifocal mild neutrophilic/lymphocytic infiltration (Male: G1:1/13); Prostate: focal moderate necrotic debris in lumen (Male: G2:1/13); Uterus: multifocal to diffuse mild reduction of stromal cells (Female: G1:1/13; G4:2/13); focal moderate necrosis (Female: G3:1/13); multifocal mild to moderate nodular hyperplasia (Female: G1:1/13; G2:1/13; G4:1/13); Cervix: focal minimal lymphocytic infiltration (Female: G2:1/13).

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Description (incidence and severity):

No effect were observed on Number and sex of pups, stillbirths, live births, runts (pups that are significantly smaller than corresponding control pups), body weight and gross abnormalities of treated pups as compared to control.

Details on results:

Body weight and weight gain: No data

Food consumption and compound intake: No data

Food efficiency: No data

Water consumption and compound intake: No data

Opthalmoscopic examination: No data

Haematology: No data

Clinical chemistry: Serum levels of GOT, GPT, lactate dehydrogenase, and alkaline phosphatase were not altered in the treated animals

Urinanalysis: No data

Neurobehaviour: No data

Organ weights: No changes in organ weight were noted in the treated animals

Gross pathology: No gross organ lesions were observed

Histopathology: No data

Key result

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

other: No effects observed

Remarks on result:

other: No toxic potential was observed

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: No significant alteration noted in growth rate, clinical signs, organ weight, clinical chemistry and gross pathology

Critical effects observed:

no

Conclusions:

Based on all the observations and results from read across studies and applying weight of evidence, it was concluded that the No Observed Adverse Effect Level (NOAEL) is considered to be 1000 mg / kg body weight when Wistar male and female rats were orally treated with test chemical.

Executive summary:

Data available of the read across chemicals has been reviewed to determine the toxic effect of the test chemical on repeated oral exposure to rats. The studies are as mentioned below:

Combined repeated dose -reproductive / developmental toxicity screening test was performed to determine the toxic nature of the test chemical. The study was performed using male and female Crj:CD(SD)IGS rats. The test chemical was mixed with water and used at dose levels of 0(control), 8, 40, 200 mg/kg/day. The doses were selected on the basis of the prelimiary dose range finding study. Males animals were treated doe 42 days and females were treated from 14 days before mating to day 4 of lactation. During the study period, the treated animals were observed for clinical signs, mortality, changes in body weight, food consumptoin, hematology, urinanalysis, clinical chemistry, organ weight changes and the animals were subjected to gross and histopathology.Two males and one female died in the 200 mg/kg group. Stridor and temporary salivation were observed in males and females of the 200 mg/kg group. Body weight tended to decrease and food consumption to decrease in males of the 200 mg/kg group. On biochemical analysis, plasma

levels of total protein and albumin concentrations were decreased in males of the 200 mg/kg group. Pathological examination revealed inflammation, ulceration and hyperplasia of squamous epithelium and edema of submucosa in the gastrointestinal tract in males and females of the 200 mg/kg group. There were no adverse effects on other organs including reproductive organs. No alteration was observed for body weight or food consumption in females, organ weights, urinalysis values or hematological parameters in males and females with administration of trimethylamine. Based on the observations made, the No observed Adverse Effect level (NOAEL) for the test chemical using male and female rats is considered to be 40 mg/Kg/day.

Subchronic repeated dose toxicity study was performed to determine the toxic nature of the test chemical. The test chemical was dosed orally at 1000 mg/Kg/day for ≤90 days in rats. The animals were observed for changes in growth rate and clinical signs. Organ weight and gross pathological lesions were also observed. The clinical chemistry serum levels of GOT, GPT, lactate dehydrogenase, and alkaline phosphatase were observed in the treated animals. The treated animals did not show any clinical signs of toxicity and Serum levels of GOT, GPT, lactate dehydrogenase, and alkaline phosphatase were not altered in the treated animals. The animals did not show any alterations in organ weight and no gross organ lesions were noted. On the basis of results observed, No Observed Adverse Effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Data available of the read across chemicals has been reviewed to determine the toxic effect of the test chemical on repeated oral exposure to rats. The studies are as mentioned below:

Combined repeated dose -reproductive / developmental toxicity screening test was performed to determine the toxic nature of the test chemical. The study was performed using male and female Crj:CD(SD)IGS rats. The test chemical was mixed with water and used at dose levels of 0(control), 8, 40, 200 mg/kg/day. The doses were selected on the basis of the prelimiary dose range finding study. Males animals were treated doe 42 days and females were treated from 14 days before mating to day 4 of lactation. During the study period, the treated animals were observed for clinical signs, mortality, changes in body weight, food consumptoin, hematology, urinanalysis, clinical chemistry, organ weight changes and the animals were subjected to gross and histopathology.Two males and one female died in the 200 mg/kg group. Stridor and temporary salivation were observed in males and females of the 200 mg/kg group. Body weight tended to decrease and food consumption to decrease in males of the 200 mg/kg group. On biochemical analysis, plasma

levels of total protein and albumin concentrations were decreased in males of the 200 mg/kg group. Pathological examination revealed inflammation, ulceration and hyperplasia of squamous epithelium and edema of submucosa in the gastrointestinal tract in males and females of the 200 mg/kg group. There were no adverse effects on other organs including reproductive organs. No alteration was observed for body weight or food consumption in females, organ weights, urinalysis values or hematological parameters in males and females with administration of trimethylamine. Based on the observations made, the No observed Adverse Effect level (NOAEL) for the test chemical using male and female rats is considered to be 40 mg/Kg/day.

Subchronic repeated dose toxicity study was performed to determine the toxic nature of the test chemical. The test chemical was dosed orally at 1000 mg/Kg/day for ≤90 days in rats. The animals were observed for changes in growth rate and clinical signs. Organ weight and gross pathological lesions were also observed. The clinical chemistry serum levels of GOT, GPT, lactate dehydrogenase, and alkaline phosphatase were observed in the treated animals. The treated animals did not show any clinical signs of toxicity and Serum levels of GOT, GPT, lactate dehydrogenase, and alkaline phosphatase were not altered in the treated animals. The animals did not show any alterations in organ weight and no gross organ lesions were noted. On the basis of results observed, No Observed Adverse Effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day.

Justification for classification or non-classification

Based on all the observations and results from read across studies and applying weight of evidence, the No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 1000 mg / kg body weight when Wistar male and female rats were orally treated with test chemical and as per CLP classification criteria, the test substance is not classified.