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Description of key information

NOEL and NOEC values are available from animal studies after repeated oral and inhalatory exposure.  The lowest available oral NOEL is a 90-d value of 10 mg/kg bw/day and the lowest available inhalation 90-d NOEC is 51 mg/m³. No information on dermal effects of subchronic exposure is available. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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
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
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
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
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
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).
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.

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
Critical effects observed:
not specified
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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The key study is no GLP compliant, but is of high quality and well documented (Klimisch score = 2); the supporting studies are public papers therefore their quality is not as high as that of the key study. However, comparable results were obtained among the studies.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: published study; non GLP, no guideline followed but OECD 413-like
Principles of method if other than guideline:
10 animals/sex/group were exposed via whole-body inhalation exposure for 13 weeks to different levels of PCBTF. Additional animals were included for evaluation after a 13 weeks-recovery, neuropathology and toxicokinetic analyses. Hematological and clinical chemistry parameters were assessed and mortality, body weight change, organ weight were observed, as well as effects on the nervous system. Macro- and microscopic examinations were performed. A NOAEL was determined.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Remarks:
Doses / Concentrations:
10 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
51 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
252 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
10 males and 10 females
additionally, 5/sex/group for recovery evaluation, 5/sex/group/interval for neuropathology
Control animals:
yes
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: 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

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weekly
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weekly
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: no data
- Parameters checked in table [No.?] were examined. no data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weekly
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: no data
- Dose groups that were examined: all
- Battery of functions tested: motor activity

OTHER: organ weight, microscopic examination of liver
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
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 examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
FOOD CONSUMPTION: possible but minimal and reversible decrease in food consumption (6%) at the highest test dose
ORGAN WEIGHTS: in the 252 ppm group, an 11% increase in relative liver weights was observed in both males and females.
HISTOPATHOLOGY: NON-NEOPLASTIC: centrilobular hypertrophy in 3 males and 3 females at 252 ppm

Dose descriptor:
NOEL
Effect level:
51 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: organ weights; histopathology (hepatocyte hypertrophy)
Dose descriptor:
LOAEC
Effect level:
252 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: organ weights; histopathology (hepatocyte hypertrophy)
Critical effects observed:
not specified
Conclusions:
The NOEL for repeated inhalatory exposure in a 90-days study was found to be 51 ppm based on increase in relative liver weights in both sexes at highest dose tested (252 ppm) correlated with centrilobular hypertrophy.
Executive summary:

In a literature study the effects of repeated exposure of rats to PCBTF via inhalation for 13 weeks were assessed. 10 Sprague Dawley rats/sex/dose were exposed to 10, 51, or 252 ppm of the test item for 6 hours/day, 5 days/week for 13 weeks. No PCTB-related effects were observed either during exposures or weekly clinical evaluations; no changes observed in body weight gain or measured hematological and clinical chemistry parameters; increase (11%) in relative liver weights in both sexes at highest dose tested correlated with centrilobular hypertrophy. NOEL (hepatocyte hypertrophy) = 51 ppm

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
51 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
The key study is not GLP, but it is OECD 413-like. The supporting study is of poor quality. However, taken together, the resulting NOAEC are considered consistent given that the NOAEC from the 4-months study, also having a 24 h daily exposure, was lower than that of the 3-months study where theexposure was 6 h/day, 5 days/week.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The oral NOEL after 90-d exposure of 10 mg/kg bw/day has the same value of the oral NOEL after 14 and 28 days that was found in two literature studies that are here provided as supporting data. These results supports the conclusion that PCBTF does not accumulate in the body. The selected inhalation NOEC was obtained after 3 months and had a value of 51 mg/m³ for

6 h/day, 5days/week; this fits quite well with the supporting study NOEC of 5.5 mg/m³ obtained in a 4 months study where the exposure was 24 hours daily. No local effect was observed after the prolonged inhalation exposure.

Despite the low quality of the single data, the overall data base is considered relevant and reliable given the coherence of the results.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the longest duration (90 days vs 14 and 28 days) was chosen (key study); the lowest NOEL was the same in all the available studies.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The OECD 413-like study was selected even if it was not the lowest NOEC. The selected study was also the best documented among the two available.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

The substance is not classified for subchronic toxicity based on the results of repeated dose oral and inhalation studies showing that the threshold for classification was not reached.