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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed publication

Data source

Reference
Reference Type:
publication
Title:
Subacute and Subchronic Oral Toxicity of p-Chlorotoluene in the Rat
Author:
JAMES B. TERRILL, MERREL ROBINSON, GARY W. WOLFE. And LEONARD H. BILLUPS
Year:
1990
Bibliographic source:
Journal Of The American College Of Toxicology, Volume 9, Number 5, Pg 487-495, 1990

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
14 days repeated dose oral toxicity study was performed to evaluate the toxic nature of the test compound p-Chlorotoluene
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Liquid
Details on test material:
- Name of test material: p-Chlorotoluene- Molecular formula: C7H7Cl- Molecular weight : 126.585 g/mol- Substance type: Organic- Physical state: Clear, colorless liquid- Impurities (identity and concentrations): > 98% pure

Test animals

Species:
rat
Strain:
other: Sprague-Dawley-derived (Crl:CD@ BR)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Charles River Laboratories, Inc. (Raleigh, NC)- Age at study initiation: 46 days- Weight at study initiation: 227.3-276.1 g males, 153.2-195.8 g females- Fasting period before study: No data- Housing: The rats were housed in stainless-steel wire-bottomed suspended cages, color-coded for dosage level. The rats within any treatment level were caged vertically to minimize light, temperature, and airflow differences between exposure groups- Diet (e.g. ad libitum): Purina Rodent Chow No. 5002 (Ralston Purina Co., St. Louis, MO) ad libitum- Water (e.g. ad libitum): Tap water ad libitum- Acclimation period: 2 weeksENVIRONMENTAL CONDITIONS- Temperature (°C): 22-24°C- Humidity (%):40-60%- Air changes (per hr): No data- Photoperiod (hrs dark / hrs light): 12-h light-dark cycleIN-LIFE DATES: From: To: No data

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
other: Corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The chemical was dissolved in corn oil at dose levels of 0, 200, 600 or 1800 mg/Kg/dayDIET PREPARATION- Rate of preparation of diet (frequency): No data- Mixing appropriate amounts with (Type of food): No data- Storage temperature of food: No dataVEHICLE- Justification for use and choice of vehicle (if other than water): Corn oil- Concentration in vehicle: 0, 200, 600 or 1800 mg/Kg/day- Amount of vehicle (if gavage): No data- Lot/batch no. (if required): No data- Purity: No data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The purity was determined to be greater than 98% by gas chromatographic-mass spectral analysis (GC-MS
Duration of treatment / exposure:
14 days
Frequency of treatment:
7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:0, 200, 600 or 1800 mg/Kg/dayBasis:
No. of animals per sex per dose:
Total: 800 mg/Kg/day: 10 males and 10 females200 mg/Kg/day: 10 males and 10 females600 mg/Kg/day: 10 males and 10 females1800 mg/Kg/day: 10 males and 10 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The high-dose level was chosen as one half of the reported LD50 and was expected to produce a toxic effect. The lowest dose was selected to be a no-effect level.- Rationale for animal assignment (if not random): Yes, randomized- Rationale for selecting satellite groups: No data- Post-exposure recovery period in satellite groups: No data- Section schedule rationale (if not random): No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes- Time schedule: Twice daily for Mortality, Morbidity. All rats were observed daily by careful cageside observation. Physicalexaminations were performed weekly- Cage side observations checked in table [No.?] were included. Mortality, Morbidity, overt signs of toxicity, DETAILED CLINICAL OBSERVATIONS: Yes, any abnormalities in housing. food, water, or clinical signs involving general appearance, behavior, excretion, respiration, skin, pelage. or eyes were recorded- Time schedule: No dataBODY WEIGHT: Yes- Time schedule for examinations: Individual body weights were measured prior to randomization, at initiation of dosing, and weekly thereafteFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, Food consumption was measured weekly- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations: No dataOPHTHALMOSCOPIC EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: Yes- Time schedule for collection of blood: Prior to necropsy- Anaesthetic used for blood collection: Yes, ketamine- Animals fasted: Yes, overnight fasting- How many animals: All animals- Parameters checked in table [No.?] were examined. leukocyte, erythrocyte. hematocrit, and hemoglobin tests; leukocyte differentials and cell morphologyCLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: Prior to necropsy- Animals fasted: Yes, overnight fasting- How many animals: All animals- Parameters checked in table [No.?] were examined. sodium, potassium, total protein, albumin, calcium, total bilirubin, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH). and blood urea nitrogenURINALYSIS: Yes- Time schedule for collection of urine: Prior to necropsy- Metabolism cages used for collection of urine: No data- Animals fasted: No data- Parameters checked in table [No.?] were examined. pH, glucose, protein, bilirubin, occult blood. and urobilinogenNEUROBEHAVIOURAL EXAMINATION: Y No data- Time schedule for examinations: No data- Dose groups that were examined: No data- Battery of functions tested: sensory activity / grip strength / motor activity / other: No dataOTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, Animals were weighed. anesthetized with sodium pentobarbital, exsanguinated and necropsied. Organ weights were obtained for the following organs: liver, kidneys. spleen, adrenal glands. thymus, brain, heart, lung, testes with epididymis and ovaries. Organ-to-terminal body weight ratios were calculated.Additionally, necropsies were performed on all animals that died prior to the terminal sacrifice. A full tissue list was preserved from each animal.HISTOPATHOLOGY: Yes, The following tissues were evaluated from all animals in the 600 mgikg per day animals in the 14-day study as well as from five randomly selected animals per gender in corn oil control animals: adrenals, thyroid, esophagus, trachea, larynx, heart, spleen, liver, kidney, stomach, duodenum, jejunum, colon, pancreas, and gross lesions.
Other examinations:
No data
Statistics:
All appropriate data were subjected to Levene's test of homogeneity of variance and an analysis of variance. Non-homogeneous data were subjected to a series of transformations in order to achieve homogeneity . When the series of transformations were ineffective in achieving homogeneity, analysis of ranked data were performed. Group comparisons were evaluated using Dunnett's t-test at the 5.0% two-tailed probability Ievel.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Animals at 1800 mg/Kg bw frequently exhibited prostration, salivation, and tremors following dosing
Mortality:
mortality observed, treatment-related
Description (incidence):
At 1800 mg/Kg bw- Males- 8/10 Females- 8/10
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A statistically significant decrease in body weight was exhibited by both males and females in the high-dose group (1800 mg/kg/day) at Weeks 1 and 2. Body weight gain (Weeks 0-2) for these animals was also significantly decreased. Mid-dose males (600 mg/kp/day) exhibited a significant decrease in body weight gain (Weeks 0-2).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Total food consumption (Week 1) was significantly decreased for males in the mid- and high-dose groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment related effects were noted
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:
effects observed, treatment-related
Description (incidence and severity):
Organ weight comparisons between mid-dose animals with control animals revealed a number of differences: all were considered related to a lower terminal body weight or considered to be a general indication of stress.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment related gross pathology effects were noted
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related lesions were observed
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
600 other: mg/Kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment related effects were noted

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The No observed adverse effect level (NOAEL) for the test chemical is considered to be 600 mg/Kg/day when male and female Sprague-Dawley-derived (Crl:CD@ BR) rats were treated for 14 days.
Executive summary:

14 days repeated dose oral toxicity study was performed to evaluate the toxic nature of the test compoundp-Chlorotoluene. Male and female Sprague Dawley rats were dosed daily at dose levels of 0, 200, 600 or 1800 mg/Kg/day for 14 days. The animals were observed for cage side observations, clinical signs, body weight and food consumtion, hematology, clinical pathology parameters and usinalysis following gross and histopathology. Treatment related severe effects were noted at 1800 mg/Kg/day. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 600 mg/Kg/day when male and female Sprague-Dawley-derived (Crl:CD@ BR) rats were treated for 14 days.