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Key value for chemical safety assessment

Effects on fertility

Description of key information
No further data available. 
Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test guideline (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 1980-June 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, data reporting complete and accurate.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Inc., New York
- Age at study initiation: F0 ( parental): 8 weeks old
- Housing: housed indvidually in standard stainless steel suspended rat cages in an environmentally controlled animal room.
- Diet: ad libitum, Purina certified rodent chow 5002
- Water: ad libitum, tap water, analyzed quarterly
- Acclimation period: F0 animals were acclimated for 24 days prior to dosing.

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 dark, 12 light

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
During the acclimation period (24 days) rats were periodically dosed with corn oil to accomodate them to the gavaging procedure. Rats were examined for masses and observed for abnormal behavioral reactions. Based on these observations, 80 healthy males and 80 healthy females were assigned randomly
to four treatment groups by sex. An additional 5 males and 5 females were selected randomly to be utilized in establishing baseline clinical pathology values.
Rats were divided randomly into four treatment groups: Group I (control), Group II (5 mg/kg/day), Group III (15 mg/kg/day), Group IV (45 mg/kg/day). Rats were dosed in 2 ml/kg body weight volumes via gavage with test solutions of varying concentrationsfor each dosage.

F1 rats vere administered test material orally via gavage for 90 days and until sacrifice.
Details on mating procedure:
F0 rats were dosed for four weeks prior to mating and through one reproduction period until F1 litters bad been weaned. After F0 rats had been administered the test material in corn oil for four weeks, F0 females were housed on a one-to-one basis with males from the same test group for the purpose of mating. The presence of a copulatory plug was considered positive evidence of mating. When copulatory plugs were found, males were removed and returned to individual cages. If after one week, no evidence of positive mating was observed, the male was removed and a different male of the same dose group was placed with the female. Day one of gestation was defined as the first day that a copulatory plug was observed. Approximately five days prior to parturition, each female was placed in a plastic shoe box cage equipped with a stainless steel top. Bedding was changed twice weekly or more often if needed through weaning. Females were disturbed for daily dosing, bedding changes and data collection only. Except for emergencies females were not disturbed for any reason during labor, delivery, or until pups had been cleaned and nursed for the first time.
Duration of treatment / exposure:
Test was aadministered to the parental (F0) rats for 76 to 83 days. Weanling F1 rats were dosed for at least 90 days.
Frequency of treatment:
Daily
Details on study schedule:
At 21 days of age, pups were weaned and weighed. F1 pups were selected raadomly from all litters within a group for assigmnent to corresponding treatment groups. Two extra rats of each sex were salected from each group to allow for replacement of any experimental rats that died during the initial dosing period. Day 21 of age for the youngest F1 pups coincided with day 1 of dosing for the F1 rats. All rats weaned prior to day 1 were dosed daily from weaning until the youngest F1 pups had reached 21 days of age.
Remarks:
Doses / Concentrations:
5 mg/kg/day
Basis:
nominal in diet
Group II
Remarks:
Doses / Concentrations:
15 mg/kg/day
Basis:
nominal in diet
Group III
Remarks:
Doses / Concentrations:
45 mg/kg/day
Basis:
nominal in diet
Group IV
No. of animals per sex per dose:
20 males and 20 females for each dose group.
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: based on a prelimary pilot stydy of 14 days.


Parental animals: Observations and examinations:
All rats were observed twice daily five days a week and once daily on weekends. Animals were checked for general appearance, behavior, elimination, and signs of toxic or pharmacologic effects. Daily observations were recorded and unusual appearance or behavior was reported. During the mating period, femles were observed for presence of the copulatory plug as positive evidence of mating.

F0 rats were weighed weekly.
Weekly individual feed consumption was recorded weeks 1-4 of study.

Blood was obtained for hematology and clinical chemistry determinations from the following randomly selected animals:
1) 5 males an 5 females prior to the initiation of dosing
2) 5 F0 males and 5 F0 females from each group after 2 weeks of study
3) 5 F1 males and 5 F1 females from each group prior to sacrifice at termination of the study.

All rats were fasted overnight and anesthetized with ether prior to collection of blood samples. Blood was collected from the
suborbital sinus in F0 rats.
Litter observations:
F1 rats were weighed on days 1 (day of birth), 4 and 21, and weekly thereafter. Mean body weights and mean weight gains since date on test were computed and compared by sex for statistically signi£icant differences among groups. Individual body weights were used for weekly dose adjustments . Terminal body weights were recorded for all rats.

Gross pathology and histopathological examinations were performed on all F1 animals, and selected organ weights were recorded. Organ/body weight ratios were calculated.

Litter data were collected on the following: total number of pups born alive and dead; number of male and female pups on days 1, 4, 14 and 21; individual pup weights, average pup weight/litter and dam weight on days 1, 4 and 21; and the number (percent) of pups surviving on days 4, 14 and 21. Litters were culled to 10 on day 14. Therefore, survivability data was calculated for day 14 based on counts before culling and data for day 21 was based on litter counts after culling.

Weekly individual feed consumption was recorded weeks 13-25 of study. Total weekly feed consumption was recorded for each rat, and group means
were compared by sex for statistically significant differences.


Postmortem examinations (parental animals):
After a sufficient number of F1 pups had whelped, F0 males were killed and subjected to a complete gross necropsy. F0 females were killed and necropsied after all litters had-been weaned.
Postmortem examinations (offspring):
All rats were fasted overnight and anesthetized with ether prior to collection of blood samples. Blood was collected via cardiac puncture in F1 rats.
Statistics:
Statistical analyses were perfomed on all tested measurable parameters.
Whenever a probability value of less than 0.05 was found, a Tukey's HSD procedure was performed to detect statistically significant differences among groups. All data which were analyzed statistically (litter data, body weights, feed consumption, hematology, clinical chemistry, and absolute organ weights) were recorded on computer coding forms and keypunched into the computer. Statistics were generated by the Statistical Package for the Social Sciences (SPSS) program.
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Gains for study groups significantly gretaer ( p<0.05) than for controls in all male treatment groups for week 14, and for Group II males in week 15. Group IV females had decreased weight gains during weeks 15 and 16.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Gains for study groups significantly gretaer ( p<0.05) than for controls in all male treatment groups for week 14, and for Group II males in week 15. Group IV females had decreased weight gains during weeks 15 and 16.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Mean liver weight was increased, but the increase was not significant.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: No dosage-related trends were evident.
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Clinical pathology: The percent monocytes for Group II (5 mg/kg) females was significantly (p < 0.05) decreased at day 14 compared with controls. Erythrocyte counts were significantly (p < 0.05) decreased in Group II (5 mg/kg) females compared with controls. Mean corpuscular hemoglobin (MCH) values were significantly reduced in all male treatment groups but these values were within normal historical limits. No corresponding effect in MCH values was present in female treatment groups. Group IV (45 mg/kg) females had decreased mean corpuscular hemoglobin concentration (MCHC) and increased mean corpuscular volume (MCV). These values were within normal historical limits.

Individual urine analysis determinatiotns for baseline animals, F0 animala on day 14, and F1 animals at termination recorded values within normal limits.

The changes observed in the respiratory system (lung) were those commonly accompanying an oral gavage study in which occasional inhalation of the test material or control material may be anticipated. The prostate gland inflammatory lesion, recognized in both dose groups examined were attributed to spontaneous disease phenomena.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
45 other: mg/kg/day nominal in diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Reproductive effects observed:
not specified
Conclusions:
Under the conditions of the test and at the dosages given, the test item PCBTF was found to be safe at all levels. A toxic no-effect level in rats was greater than or equal to 45 mg/kg.
Executive summary:

170 Sprague-Dawley rats were used to test the subchronic toxicity of PCBTF in F1 rats following in utero exposure. Rats were divided randomly into 4 treatment groups: Group I (control), Group II (5 mg/kg/day), Group III (15 mg/kg/day), Group IV ( 45 mg/kg/day). Rats were dosed in 2 mL/kg body weight volumes via gavage with test solutions of varying concentrations for each dosage. Test material was administered to the parental (F0) rats for 76 to 83 days. F0 rats were killed and subjected to a gross necropsy. Weanling F1 rats were dosed for at least 90 days, then killed and necropsied.

Throughout the study, weekly feed consumption and body weights were recorded; new doses were calculated weekly on the basis of current body weights. Clinical pathology parameters were obtained predose on baseline animals, after 14 days treatment of F0 rats, and terminally on F1 animals, and selected organ weights were recorded. Organ/body weight ratios were calculated. Statistical aualysis were perfomed on all tested measurable parameters. Clinical observations, clinical pathology parameters, and histopathology examinations showed no treatment related abnormalities.

A trend was observed in main liver weights and mean liver/body weight ratios among treatment groups. The effects seen were a physiologic response of this organ to PCBTF. The increased metabolic response did not reflect necessarily a toxic response to the test material. No other treatment related effects were observed. Under the conditions of the test, the test item PCBTF was found to be safe at all levels. A toxic no-effect level in rats was greater than or equal to 45 mg/kg.

 

 



Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
45 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
There is only one study but it is of high quality (GLP, data reporting complete and accurate)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The oral NOEL of PCBTF for reproduction (45 mg/kg bw/day) is equal to the oral LOEL after the 90-d oral exposure

(45 mg/kg bw/day) and the main effects are in both cases reletaed to the liver weight and hystopatology.

These results supports the conclusion that PCBTF does not accumulate in the body and supports the reliability of the results of the subchronic studies.


Short description of key information:
Effects in parental animals included increased mean liver weight , but the increase was not significant even at the highest dose. No effects were observed in the offspring.

Justification for selection of Effect on fertility via oral route:
Only one study available

Justification for selection of Effect on fertility via inhalation route:
Inhalatory hazard was not found to be higher than the oral in acute and subchronic studies. Therefore a reproductive study with inhlation exposure is not deemed to be necessary as the effects on fertility are covered by the results after oral exposure.

Justification for selection of Effect on fertility via dermal route:
Dermal exposure is not likely to be the main route of exposure, especially when prolonged exposure is considered. It aslo considered to be covered by the gavage test as in this way the test item is absorbed very quickly.

Effects on developmental toxicity

Description of key information
No study is available on developmental toxicity. However, there is no basis to believe that PCBTF could have adverse developmental effects based on the whole set of subchronic and reproductive data. 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No study is available on developmental toxicity. However, there is no basis to believe that PCBTF could have adverse developmental effects based on the whole set of subchronic and reproductive data. In fact, one study on reproductive effects on one generation is available and show no effects on at the highest tested dose neither on fertility, nor on the offspring. Futhermore, in all the available sub-chronic studies, no effect on reproductive organ tissues was observed.


Justification for selection of Effect on developmental toxicity: via oral route:
One study on reproductive effects on one generation is available and show no effects on at the highest tested dose neither on fertility, nor on the offspring. Futhermore, in all the available sub-chronic studies, no effect on reproductive organ tissues was observed. Therefore, there is no basis to believe that PCBTF could have adverse developmental effects.

Justification for selection of Effect on developmental toxicity: via inhalation route:
One study on reproductive effects on one generation is available and show no effects on at the highest tested dose neither on fertility, nor on the offspring. Futhermore, in all the available sub-chronic studies, no effect on reproductive organ tissues was observed. Therefore, there is no basis to believe that PCBTF could have adverse developmental effects.

Justification for selection of Effect on developmental toxicity: via dermal route:
Dermal exposure is not likely to be the main route of exposure, especially when prolonged exposure is considered. Furthermore, One study on reproductive effects on one generation is available and show no effects on at the highest tested dose neither on fertility, nor on the offspring. Also, in all the available sub-chronic studies, no effect on reproductive organ tissues was observed. Therefore,

Justification for classification or non-classification

PCBTF is not classified for reproductive effects. In fact there is no basis to believe that PCBTF could have adverse developmental effects based on the whole set of subchronic and reproductive data. In fact, one study on reproductive effects on one generation is available and show no effects on at the highest tested dose neither on fertility, nor on the offspring. Futhermore, in all the available sub-chronic studies, no effect on reproductive organ tissues was observed.