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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May- August 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: not GLP, but in accordance with guidelines

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
For more details on test method, please refer to the executive summary.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid - liquid: suspension
Details on test material:
- Name of test material as cited in study report: PCBTF
- Impurities (identity and concentrations): two impurities were found in the test article characterization. They were identified as 3-chlorobenzo-trifluoride (0.10%), MCBT (0.59%), 2-chlorobenzotrifluoride (0.02%) and OCBT (0.84%).
- Composition of test material, percentage of components: PCBT (97.83%)
- Purity test date: 1983
- Lot/batch No.: 633F02
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan-Sprague Dawley Inc., Indianapolis, Indiana
- Age at study initiation: 5 to 6 weeks
- Weight at study initiation: males 86.8 ± 1.5 g, females 62.5 ± 0.7 g
- Housing: individually caged in ventilated units of stainless steel sheet metal with wire mesh floors. The units were suspended over disposable waste trays changed at least weekly.
- Diet (e.g. ad libitum): the rats were allowed free access to a standard mash diet (Purina Certified Rodent Chow n. 5002) contained in stainless steel feeders.
- Water (e.g. ad libitum): Greenfield city water was supplied to rats through an automatic watering system.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24.5 ± 2.5 °C
- Humidity (%): minimum 40%
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

IN-LIFE DATES: From: May 10, 1983 To: August 10, 1983

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
results of a dedicated assay indicate that PCBTF was stable at room temperature for at least 8 days when dissolved in corn oil.
Details on oral exposure:
TEST MATERIAL PREPARATION AND ADMINISTRATION

Daily doses of 0, 10, 40, 150, or 500 mg of PCBTF/kg of body weight were administered to rats. Solutions of PCBTF in corn oil were prepared weekly. A volume of 5.0 ml/kg of a 0.2, 0.8, 3.0, or 10% weight/volume solution was given to achieve the appropriate mg/kg dose. Control animals were dosed with an equivalent volume of corn oil. A log of each liquid preparation was made that included the date of preparation, the lot number of the PCBTF used, the study number, the weighed quantity of test article and volume of solution. Samples from each concentration of freshly prepared PCBTF solutions were collected from the first and final makeups for the study as well as from a makeup midway through the study and analyzed for the presence and concentration of the test article. Prior to the initiation of study R05983, a 0.2% solution of PCBTF was prepared for an evaluation of the test article stability. The solution was assayed 3, 4, 5 and 8 days after preparation for PCBTF concentration.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
3 months (90, 91 or 92 days)
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
10 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
40 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
150 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
500 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
15/sex/group ( 4 treatment groups)
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
Ophtalmic examinations: prior to initiating treatment and near the termination of the study on each rat. Approx. 10-60 minutes after the application of tropicamide the eyes of each rat were examined under reduced illumination to increase the contrast between the different ocular structures.

Survival and Signs of Toxicity: test animals were examined daily for general physical condition and beahviour. A detailed examination was performed weekly in which muscle tone, condition of pelage, colour and appearance of eyes, respiration, posture, excreta, locomotion and presence of external lesions or growths were evaluated.

Body weight and Food consumption: the test animals were weighed and food consumption was determined weekly using an electron ic balance interfaced with a magnetic atape recorder.

Hematology: at the termination of the test period the rats were fasted overnight. Just prior to necropsy, the test animals were aneshetized with ether and blood samples were obtained by cardiac puncture.

Clinical Chemistry: clinical chemistry parameters determined on all rats at the conclusion of this study included: serum concentrations of glucose, urea nitrogen, creatinine, total birilubin, and activities of the ALP and alanine transaminase.

Urinalysis: the week prior to the termination of the study urine samples were collected from 5 rats per sex per dose level. Each of these samples were analyzed for color, clarity, pH, protein, specifica gravity, glucose and blood.
Sacrifice and pathology:
PATHOLOGY: yes
Other examinations:
Enzyme induction: at the time of necropsy, determining the activity of heaptic p-nitroanisole O-demethylase

Organ weights: for adrenals, heart, kidneys, liver, ovaries, prostate, spleen, testes, thyroids, and uterus.

PATHOLOGY: yes
Statistics:
The statistical method described by Dunnet was used in the analysis of differences between control and treated group. The homogeneity of variances was tested by the method of Bartlett (Steel and Torries, 1960).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1/15 male rats in the 10 mg/kg group and 2/15 male rats in the 500 mg/kg group died during the study.
Mortality:
mortality observed, treatment-related
Description (incidence):
1/15 male rats in the 10 mg/kg group and 2/15 male rats in the 500 mg/kg group died during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
weight gain was slightly depressed for the high dose males
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mean food consumption decreased for all rats. Decreases were similar among all groups of female rats, and among the male groups receiving 10,40 and 150 mg/kg PCBTF. The most pronounced decrease occurred for the male group receiving 500 mg/kg.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
decreased early in the study but the effct was transient and by the end of the study nost treated animals had greater feed efficiency than controls.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
No altered value in the females. In high dose males total erythrocytes were reduced and there was a dose-related shift toward an increase in neutrophils and a decrease in lymphocites.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In 2 males of the two highest dose groups elevated levels of blood urea nitrogen. Total birilubin elevated in the high dose males and females. Alkaline phosphatase levels slighty elevated in all treated males.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Mild proteinuria in high dose males and in females of the 150 and 500 mg/kg dose groups.
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Slight increase in the weights of liver, kidney, relative adrenal in males and females. Thyroid weight increase only registered for second and fourth dose females.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Whole tissue alterations in kidneys in male rats of the two highest doses groups.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Dose-related pathologic changes in kidneys and livers of treated rats. Slight to moderate renal tubules degeneration found only in male rats at the two highest doses. Centrilobular hypertrophy observed in males and females at the the two highest rates.
Histopathological findings: neoplastic:
no effects observed
Details on results:
HISTOPATHOLOGY: NON-NEOPLASTIC: minimal renal tubular degenerations were observed in one male from the low dose group and in all males from the second, slight to moderate renal lesions found at third and high dose groups. Centrilobular hypertrophy was present in the liver of all third dose males and in one female of third dose and in all high dose rats.

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: organ weights (liver); histopathology (renal tubular degenerations)
Dose descriptor:
LOEL
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: organ weights (liver); histopathology (renal tubular degenerations)
Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: pathological lesions in liver and kidney
Dose descriptor:
LOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Pathological lesions in liver and kidney

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In this study the observed effects to a 90-d gavage administration of PCBTF to male and female rats were elevated levels of blood urea nitrogen, totalbirilubin and alkaline phosphatase; induction of hepatic p-nitroanisole O-demethylase activity, increased liver and kidney weights, tubular degeneration in the kidneys and centrilobular hyperthrophy in the liver. Males were more sensitive to the effects of PCBTF than females. Compound induced changes were dose-related and were more pronounced at doses of 150 and 500 mg/kg. The lowest dose employed, 10 mg/kg, was tolerated for 90 days without significant toxicity in the rat.
Executive summary:

Fischer 344 rats, 5 to 6 weeks age, were dosed orally by gavage each day for 3 months with corn oil solutions containing PCBTF. The doses, administered on an equal volume basis, were 0, 10, 40, 150 or 500 mg/kg body weight. Fifteen animals of each sex were included in each group. One low dose male and two high dose males died during the study. There were no treatment related physical or behavioral changes noted in any of the treated or control animals. Effects in this study were: elevated levels of blood urea nitrogen, total birilubin and alkaline phosphatase; induction of hepatic p-nitroanisole O-demethylase activity, increased liver and kidney weights, tubular degeneration in the kidneys and centrilobular hyperthrophy in the liver. Males were more sensitive to the effects of PCBTF than females. Compound induced changes were dose-related and were more pronounced at doses of 150 and 500 mg/kg. The lowest dose employed, 10 mg/kg, was tolerated for 90 days without significant toxicity in the rat.