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Developmental toxicity / teratogenicity

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Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
from July 28,2006 to October 29, 2007
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Reproductive/developmental screening, not a full embryofetal developmental/teratogenicity study
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from July 28,2006 to October 29, 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
The animal room accountability sheets from August 28 - September 2006, could not be located at the time the report was prepared. But this deviation does not impact the validity or interpretation of the study.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Crl CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc Raleigh, North Carolina Crl: CD(SD) rat
- Age at study initiation: Approximately 60 days
- Weight at study initiation: Males: 199.1-230.6 g Females: 170.6-207.5 g
- Fasting period before study:
- Housing:
Pretest/Premating: Individually (except during cohabitation of mating pairs) in stainless steel, wire-mesh cages suspended above cage boards; sexes on separate racks.
Cohabitation: Mating pairs (females placed in males’ cages) on a 1:1 basis in stainless steel, wire-mesh cages suspended above cage boards.
Days 0–19 of gestation: Individually in stainless steel, wire-mesh cages suspended above cage boards; sexes on separate racks.
Day 19 of gestation -
Day 4 of lactation: Females assumed pregnant were housed individually in polycarbonate pans with bedding material. Females presumed nonpregnant were housed in the same manner as pregnant females 7 days after the mating pairs were separated.
- Diet (e.g. ad libitum):PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002 (pelleted) ad libitum except during exposure and when fasted.
- Water (e.g. ad libitum):Tap water from United Water Delaware ad libitum provided by an automatic watering system except during exposure.
- Acclimation period: 18days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):18-26°C
- Humidity (%):30-70%
- Air changes (per hr):at least 10 air changes
- Photoperiod (hrs dark / hrs light):12-hour light/dark cycle
Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Vehicle:
clean air
Details on exposure:
During exposure, animals were individually placed in stainless steel wire-mesh modules (one/module) and exposed, whole-body,inside the exposure chamber, except during the mating period when animals were housed as mating pairs in stainless steel wire-mesh modules and exposed in the same manner.
Chamber atmospheres were generated by dilution of PMVE in air. The test substance was metered into the test chamber inlets using a Brooks model 0154E or 0154 mass flow controller and mixed with filtered and conditioned air. Chamber concentrations of test substance were controlled by varying the test substance feed rate and the air flow to the chamber. All exposure chambers were constructed of stainless steel and glass (NYU style) with a nominal internal volume of 350 L. A tangential feed at the chamber inlet promoted uniform chamber distribution of the test atmosphere.
Chamber temperature was targeted at 19-25°C and recorded at least 3 times during each exposure. Chamber relative humidity was targeted at 30-70% and recorded at least 3 times during each exposure. Temperature and humidity were measured with a VWR dial-type thermometer/hygrometer. Chamber airflow was set at the beginning of each exposure to achieve at least 10 air changes per hour. The airflow was monitored continually with thermoanemometers and recorded at least 2 times during each exposure. Chamber oxygen concentration was targeted to be at least 19%. The oxygen concentration was measured with a Biosystems model 3100R oxygen analyzer and recorded once during each exposure.
Details on mating procedure:
Each female was continually housed on a 1:1 basis with a randomly selected, nonsibling male of the same concentration level until evidence of copulation was observed or the cohabitation period ended (Day 14 of cohabitation), at which time the mating pairs were separated. Evidence of copulation was confirmed by daily examination of each female for an intravaginal copulation plug or sperm in the vaginal lavage sample. The day copulation was confirmed was considered to be day 0 of gestation.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During each exposure, the atmospheric concentration of the test substance in the test chambers was determined by gas chromatography (GC) at approximately 30-minute intervals. The control chamber was sampled once per exposure. Known volumes of chamber atmosphere were continually drawn from the breathing zone of the animals and were directly injected into a Hewlett Packard model 6890 gas chromatograph equipped with an automated gas sample valve and a flame ionization detector. All samples were chromatographed isothermally at 35°C on a J&W Scientific, DB-5, 30 M capillary column. The atmospheric concentration of the test substance was determined from a standard curve derived from gas standards. Standards were prepared prior to each exposure by injecting known volumes of the gaseous test substance into Tedlar® bags containing known volumes of air.
Duration of treatment / exposure:
Animals/Study Phase Duration
Premating 14 Days (Approximate)
Cohabitation Up to 14 days
Postcohabitation
Males Until sacrifice
Females with no evidence of copulation 19 Days (Approximate)
Gestation Day 0-19G
Frequency of treatment:
Exposures for males and females were conducted for 6 hours per day, 5 days per week from the initiation of the study through the 14-day premating period. Subsequently, males and non-pregnant females were exposed 7 days a week through the terminal sacrifice on test days 29 – 30. Exposures for females with evidence of mating were conducted for 6 hours per day, 7 days per week during the cohabitation period and during gestation days 0 – 19. Gestating P1 females were not exposed after gestation day 19. Offspring were not exposed in the inhalation chambers.
Details on study schedule:
Each female was continually housed on a 1:1 basis with a randomly selected, nonsibling male of the same concentration level until evidence of copulation was observed or the cohabitation period ended (Day 14 of cohabitation), at which time the mating pairs were separated.
Dose / conc.:
0 ppm (analytical)
Dose / conc.:
60 ppm (analytical)
Dose / conc.:
300 ppm (analytical)
Dose / conc.:
1 500 ppm (analytical)
No. of animals per sex per dose:
12/sex/dose
Control animals:
yes, concurrent vehicle
Positive control:
trimethyltin, acrylamide, carbaryl, and d-amphetamine
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
Frequency: All animals – At least once daily during quarantine and pretest, and once daily thereafter. On exposure days, the observations were conducted at the time animals are placed in the exposure modules.

DETAILED CLINICAL OBSERVATIONS: Yes
Frequency: All animals - Once during pretest (baseline), and weekly thereafter

BODY WEIGHT: Yes
Quarantine: at least twice/weekly
Premating: Weekly
Cohabitation: Weekly
Post-cohabitation: Weekly for males and females without evidence of copulation
Gestation: Days 0, 7, 14, 21G
Lactation: Days 0, 4L
Neurobehavioral Evaluations: All animals evaluated were weighed on the day of the FOB assessment. These weights were not necessary for the interpretation of the neurobehavioral data, and are not presented in the report.

FOOD CONSUMPTION :
Premating: Weekly
coabitation: None
coabitation: None for males and females without evidence of copulation
Gestation: Days 0, 7, 14, 21G
Lactation: Days 0, 4L
calculation of Food: Feeders were weighed at the beginning and end of the interval.
consumption: The final weight and amount of spillage (greater than 5 g) were subtracted from initial feeder weight.
Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
Evidence of copulation was confirmed by daily examination of each female for an intravaginal copulation plug or sperm in the vaginal lavage sample. The day copulation was confirmed was considered to be day 0 of gestation.
Litter observations:
On lactation days 0 and 4, offspring were individually handled and examined for abnormal behavior and appearance; any dead or abnormal pups were recorded.
Day 0
Live and dead pups in each litter were counted by sex and live pups were individually weighed as soon as possible after delivery is completed.
Postmortem examinations (parental animals):
SACRIFICE
All P1 adult rats (48 males, 48 females) survived until the scheduled sacrifice and were euthanized by carbon dioxide anesthesia and exsanguination on days 29-30 (males) or 42-49 (females). The order of sacrifice for scheduled deaths was random among all treatment groups within a sex.

GROSS NECROPSY
Gross observations (recorded at necropsy) were examined microscopically for all animals. Tissues identified as having potential test substance-related changes, in a given sex, based on the microscopic examination of selected control and high-dose rats (5/sex/dose), were processed and examined microscopically for all rats at each dose level (12/sex/dose). In this study, the kidney was identified as having test substance-related microscopic findings in both sexes. Therefore, the kidneys from all adult rats were processed to slides and examined microscopically.

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were weighed wet from all adult rats: liver, kidneys, lungs, adrenal glands, thymus, brain, spleen, heart, testes, epididymides, ovaries (with oviducts), and uterus (with cervix). Paired organs were weighed together. Organ weight ratios (% final body weight, % brain weight) and group mean values were calculated.
Postmortem examinations (offspring):
On lactation days 0 and 4, offspring were individually handled and examined for abnormal behavior and appearance; any dead or abnormal pups were recorded. Pups in each litter were counted by sex and live pups were individually weighed and a gross external examination was performed.
F1 pup pathology data was limited to an external evaluation for abnormalities. The pups were not necropsied, organ weight data were not collected, and there was no microscopic evaluation.
Statistics:
Male and female data were evaluated separately. For litter parameters, the proportion of affected pups per litter or the litter mean were used as the experimental unit for statistical evaluation.The level of significance selected is p < 0.05.
Reproductive indices:
Mating Index(%), Fertility Index(%)
Offspring viability indices:
Post Implantation Loss(%), Live Born Index(%), Viability Index(%)
Clinical signs:
no effects observed
Description (incidence and severity):
There were no test substance-related clinical signs of toxicity observed during the daily exposures to perfluoromethylvinyl ether.
Mortality:
no mortality observed
Description (incidence):
Mortality did not occur at any exposure concentration.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1. P1 Males Overall body weight gain over test days 0 – 28 was reduced 14% in 1500 ppm males compared to the control value. While not statistically significant (p < 0.05), a similar trend was observed in the range-finding study, and this reduction was considered to be test substance related; although, not biologically adverse. Body weight and overall body weight gain for males exposed to 60 and 300 ppm were within 90% of the control value.

2. P1 Females – Premating Test substance-related, statistically significant reduction (p < 0.05) in body weight gain occurred in during test days 0 – 7 of the premating period for 1500 ppm females. However, since this reduction was transient, and overall weight gain was similar to control values, it was not considered to be biologically adverse. Body weight and overall weight gain for 60 and 300 ppm females were similar to control values.

3. P1 Females – Gestation Test substance-related, statistically significant reduction in body weight gain occurred in during test days 0 – 7 of gestation for 1500 ppm females. However, since this reduction was transient, and overall weight gain was similar to control values, it was not considered to be biologically adverse. Body weight and overall weight gain for 60 and 300 ppm females were similar to control values.

4. P1 Females – Lactation There were no test substance-related or statistically significant differences in body weight or weight gain exposed to any concentration of the test substance.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
1. Male Rats There were no test substance-related or statistically significant differences in food consumption or food efficiency for P1 males exposed to any concentration of the test substance.
2. P1 Females – Premating
Test substance-related, statistically significant reductions (p<0.05) in food consumption and food efficiency occurred in 1500 ppm females. During test days 0 – 7, food consumption and food efficiency were decreased 11% and 90%, respectively, compared to the control values. However, these reductions were transient, and recovery occurred during test days 7 – 14 such that food consumption and food efficiency values over the entire premating period (test days 0 - 14) were similar to the control values. There were no test substance-related effects or statistically significant differences on food consumption or food efficiency in females exposed to 60 or 300 ppm.
3. P1 Females – Gestation Test substance-related reductions (p<0.05) in food consumption and food efficiency occurred in 1500 ppm females. During test days 0 – 7, food consumption and food efficiency were decreased 8% and 25%, respectively, compared to the control values. However, these reductions were transient, and recovery occurred during gestation days (GD) 7 – 14 such that food consumption and food efficiency values over the entire gestation period (GD 0 – 21) were similar to the control values. There were no test substance-related effects or statistically significant differences on food consumption or food efficiency in females exposed to 60 or 300 ppm.
4. P1 Females – Lactation There were no test substance-related or statistically significant differences (p<0.05) on food consumption or food efficiency in females for any exposure concentration.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Daily inhalation exposure of P1 adult rats to 1500 ppm of the test substance, for approximately 28 days (males) or 42 days (females), resulted in minimal regeneration of renal tubular epithelium.
Regeneration of the renal tubular epithelium was observed in 10/12 males and 9/12 females exposed to 1500 ppm of the test substance. It was not observed at lower exposures. The regeneration was characterized by an increase in the number of cells in the lining epithelium of the tubules and a decrease in the average cell size. An increase in mitotic figures or associated epithelial degeneration was not observed. The change was confined to the outer medulla, was usually diffuse, and was graded as minimal (grade 1 of 4) in all instances. A slight increase in kidney weight parameters was observed at the same dose in females only. There were no test substance-related microscopic or organ weight effects at exposures ≤ 300 ppm in either sex.
There were no test substance-related effects on causes of death, gross pathology, or reproductive failures at any exposure (≤ 1500 ppm).
Under the conditions of this study, the no-observed-effect concentration (NOEC) for pathology for male and female P1 adult rats was 300 ppm.
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no test substance-related or statistically significant differences in mean number of pregnant animals, number of animals delivering, mating index, fertility index, precoital interval, gestation length, number of corpora lutea, number of implantation sites, or percent of post-implantation loss for any exposure concentration.
Key result
Dose descriptor:
NOAEC
Remarks:
for systemic toxicity
Effect level:
300 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
histopathology: non-neoplastic
other: see 'Remark'
Key result
Dose descriptor:
NOAEC
Remarks:
for reproduction
Effect level:
>= 1 500 ppm
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 500 ppm
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
One male pup was found dead on PND0 in the control group.
Postnatal losses were observed during the period PND0 to 4 but were not found treatment-dependent (Table 2). Overall, there was no difference between groups in the mean number of pups alive on PND0 and on PND4.
The mean live born index was 99.5, 100, 100 and 100% at 0, 60, 300 and 1500 ppm, respectively.
The mean viability index was 98.9, 94.6, 99.4, 98.8% at 0, 60, 300 and 1500 ppm, respectively.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean pup weights as measured on PND0 and PND4 were not affected (Table 2).
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not examined
There were no test substance-related or statistically significant differences in number of litters born, number of pups born or born alive, live born index, viability index, sex ratio, incidence of clinical observations, or mean offspring body weight on postnatal days 0 or 4 for any exposure concentration.

Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
>= 1 500 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
Under the conditions of the study, the No-Observed-Adverse-Effect Concentration (NOAEC) for reproduction and offspring was 1500 ppm, the highest concentration tested.
Executive summary:

A combined repeated exposure toxicity study with reproduction/developmental toxicity screening test was conducted with the test material. Crl:CD(SD) rats (12/sex/concentration) were exposed whole body to 0, 60, 300, or 1500 ppm of perfluoromethylvinyl ether. Exposures for males and females were conducted for 6 hours per day, 5 days per week from the initiation of the study through the 14-day premating period. Exposure to the test substance did not result in adverse clinical signs or mortality. Test substance-related reductions in weight gain, food consumption, and/or food efficiency occurred in 1500 ppm males and females; however, they were transient and did not adversely affect the health or reproductive function of the animals. There were no adverse or test substance-related effects on reproductive function, clinical pathology parameters, and no effects on offspring body weight, clinical observations, or survival. Test substance related effects were a minimal and fully reversible regeneration of renal tubular epithelium that was observed at 150 ppm in males and females and was accompanied by increased absolute and relative kidney weights in 1500 ppm females (in P1 adult females, mean absolute and relative (% body weight) kidneys weight were increased 9% and 15%, respectively, in the 1500 ppm exposure group, as compared to the control values) which showed that the test substance shall not be classified according to CLP (Regulation EC No. 1272/2008).

Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
The animal room accountability sheets from August 28 - September 2006, could not be located at the time the report was prepared. But this deviation does not impact the validity or interpretation of the study.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Crl: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc Raleigh, North Carolina Crl: CD(SD) rat
- Age at study initiation: Approximately 60 days
- Weight at study initiation: Males: 199.1-230.6 g Females: 170.6-207.5 g
- Fasting period before study: Animals subjected to clinical pathology evaluation were fasted after 3 p.m. for at least 15 hours.
- Housing:
Pretest/Premating: Individually (except during cohabitation of mating pairs) in stainless steel, wire-mesh cages suspended above cage boards; sexes on separate racks.
Cohabitation: Mating pairs (females placed in males’ cages) on a 1:1 basis in stainless steel, wire-mesh cages suspended above cage boards.
Days 0–19 of gestation: Individually in stainless steel, wire-mesh cages suspended above cage boards; sexes on separate racks.
Day 19 of gestation -
Day 4 of lactation: Females assumed pregnant were housed individually in polycarbonate pans with bedding material. Females presumed nonpregnant were housed in the same manner as pregnant females 7 days after the mating pairs were separated.
- Diet (e.g. ad libitum):PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002 (pelleted) ad libitum except during exposure and when fasted.
- Water (e.g. ad libitum):Tap water from United Water Delaware ad libitum provided by an automatic watering system except during exposure.
- Acclimation period: 18days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):18-26°C
- Humidity (%):30-70%
- Air changes (per hr):at least 10 air changes
- Photoperiod (hrs dark / hrs light):12-hour light/dark cycle, with an artificial fluorescent light.
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
clean air
Remarks on MMAD:
MMAD / GSD: 0, 60, 300, and 1500 ppm.
Details on inhalation exposure:
During exposure, animals were individually placed in stainless steel wire-mesh modules (one/module) and exposed,, whole-body,inside the exposure chamber, except during the mating period when animals were housed as mating pairs in stainless steel wire-mesh modules and exposed in the same manner.
Chamber atmospheres were generated by dilution of H-27649 gas in air. The test substance was metered into the test chamber inlets using a Brooks model 0154E or 0154 mass flow controller and mixed with filtered and conditioned air. Chamber concentrations of test substance were controlled by varying the test substance feed rate and the air flow to the chamber. All exposure chambers were constructed of stainless steel and glass (NYU style) with a nominal internal volume of 350 L. A tangential feed at the chamber inlet promoted uniform chamber distribution of the test atmosphere.
Chamber temperature was targeted at 19-25°C and recorded at least 3 times during each exposure. Chamber relative humidity was targeted at 30-70% and recorded at least 3 times during each exposure. Temperature and humidity were measured with a VWR dial-type thermometer/hygrometer. Chamber airflow was set at the beginning of each exposure to achieve at least 10 air changes per hour. The airflow was monitored continually with thermoanemometers and recorded at least 2 times during each exposure. Chamber oxygen concentration was targeted to be at least 19%. The oxygen concentration was measured with a Biosystems model 3100R oxygen analyzer and recorded once during each exposure.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During each exposure, the atmospheric concentration of the test substance in the test chambers was determined by gas chromatography (GC) at approximately 30-minute intervals. The control chamber was sampled once per exposure. Known volumes of chamber atmosphere were continually drawn from the breathing zone of the animals and were directly injected into a Hewlett Packard model 6890 gas chromatograph equipped with an automated gas sample valve and a flame ionization detector. All samples were chromatographed isothermally at 35°C on a J&W Scientific, DB-5, 30 M capillary column. The atmospheric concentration of the test substance was determined from a standard curve derived from gas standards. Standards were
prepared prior to each exposure by injecting known volumes of the gaseous test substance into Tedlar® bags containing known volumes of air.
Duration of treatment / exposure:
Animals/Study Phase Duration
Premating 14 Days (Approximate)
Cohabitation Up to 14 days
Postcohabitation
Males Until sacrifice
Females with no evidence of copulation 19 Days (Approximate)
Gestation Day 0-19G
Frequency of treatment:
All exposures were conducted for 6 hours/day, 5 days/week during the premating phase.
Beginning at the start of cohabitation, exposures were conducted for 6 hours/day, 7 days/week.
Lactating dams and offspring were not exposed.
Dose / conc.:
0 ppm (analytical)
Dose / conc.:
60 ppm (analytical)
Dose / conc.:
300 ppm (analytical)
Dose / conc.:
1 500 ppm (analytical)
No. of animals per sex per dose:
12/sex/concentration
Control animals:
yes, concurrent no treatment
Details on study design:
Assignment to Groups:
Selection Criteria: Animals without adequate body weight gain and/or with clinical signs of disease or injury were eliminated from consideration for use in the study; weight variation of individual rats did not exceed ± 20% of the mean weight for each sex on test day 0.
Randomization: Computerized, stratified randomization procedure designed to produce a homogeneous distribution of body weights across groups.
Disposition of Remaining Animals: Sacrificed by carbon dioxide asphyxiation.
Positive control:
Procedures and data describing the effects of trimethyltin, acrylamide, carbaryl, and d-amphetamine are presented in 5 separate reports. These positive control studies are the basis of training certification for the people making judgments in the neurobehavioral tests. The data also documents that the equipment and procedures are capable of detecting effects that may be seen in studies of this type.
Observations and examinations performed and frequency:
Careful clinical observations were recorded once daily after the initiation of exposures. Detailed clinical observations were recorded once during pretest and weekly thereafter. Body weights and food consumption were recorded weekly for P1 males and females (premating), on days 0, 7, 14, and 21 of gestation; and on days 0 and 4 of lactation. Food consumption was not measured during cohabitation or thereafter for males, or for females with no evidence of copulation. An abbreviated neurobehavioral evaluation consisting of a functional observational battery and motor activity was conducted in P1 rats (12/sex/group) once during pretest and prior to cohabitation. F1 litter examinations (pup viability, individual pup weights, clinical observations) were performed at birth and on lactation day 4.
Sacrifice and pathology:
Clinical pathology parameters were measured in P1 rats (5/sex/group) at the end of the premating period (hematology, clinical chemistry) and at terminal sacrifice (coagulation).
Sacrifice Schedule
Males Test days 29-30
Dams with Litters Day 4L
Females without evidence of mating Test day 54
Gross Pathology All adult animals
Histopathology Control and high-dose groups (kidneys)
Other examinations:
no data
Statistics:
Male and female data were evaluated separately. For litter parameters, the proportion of affected pups per litter or the litter mean were used as the experimental unit for statistical evaluation.The level of significance selected is p < 0.05. Additional statistical tests were used, and other parameters analyzed, if deemed necessary.
The adopted statistical methods are reported in the field "Attached backgroud materials".




Clinical signs:
no effects observed
Description (incidence and severity):
There were no test substance-related clinical signs of toxicity observed during the daily exposures to PMVE.
Mortality:
no mortality observed
Description (incidence):
Mortality did not occur at any exposure concentration.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1. P1 Males Overall body weight gain over test days 0 – 28 was reduced 14% in 1500 ppm males compared to the control value. While not statistically significant (p < 0.05) a similar trend was observed in the range-finding study, and this reduction was considered to be test substance related; although, not biologically adverse. Body weight and overall body weight gain for males exposed to 60 and 300 ppm were within 90% of the control value.

2. P1 Females – Premating Test substance-related, statistically significant (p < 0.05) reduction in body weight gain occurred in during test days 0 – 7 of the premating period for 1500 ppm females. However, since this reduction was transient, and overall weight gain was similar to control values, it was not considered to be biologically adverse. Body weight and overall weight gain for 60 and 300 ppm females were similar to control values.

3. P1 Females – Gestation Test substance-related, statistically significant (p < 0.05) reduction in body weight gain occurred in during test days 0 – 7 of gestation for 1500 ppm females. However, since this reduction was transient, and overall weight gain was similar to control values, it was not considered to be biologically adverse. Body weight and overall weight gain for 60 and 300 ppm females were similar to control values.

4. P1 Females – Lactation There were no test substance-related or statistically significant differences in body weight or weight gain exposed to any concentration of the test substance.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
1. Male Rats There were no test substance-related or statistically significant differences in food consumption or food efficiency for P1 males exposed to any concentration of the test substance.

2. P1 Females – Premating
Test substance-related, statistically significant reductions in food consumption and food efficiency occurred in 1500 ppm females. During test days 0 – 7, food consumption and food efficiency were decreased 11% and 90%, respectively, compared to the control values. However, these reductions were transient, and recovery occurred during test days 7 – 14 such that food consumption and food efficiency values over the entire premating period (test days 0 - 14) were similar to the control values. There were no test substance-related effects or statistically significant differences on food consumption or food efficiency in females exposed to 60 or 300 ppm.

3. P1 Females – Gestation Test substance-related reductions in food consumption and food efficiency occurred in 1500 ppm females. During test days 0 – 7, food consumption and food efficiency were decreased 8% and 25%, respectively, compared to the control values. However, these reductions were transient, and recovery occurred during gestation days (GD) 7 – 14 such that food consumption and food efficiency values over the entire gestation period (GD 0 – 21) were similar to the control values. There were no test substance-related effects or statistically significant differences on food consumption or food efficiency in females exposed to 60 or 300 ppm.

4. P1 Females – Lactation There were no test substance-related or statistically significant differences on food consumption or food efficiency in females for any exposure concentration.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
1. Male Rats There were no test substance-related or statistically significant differences in food consumption or food efficiency for P1 males exposed to any concentration of the test substance.

2. P1 Females – Premating
Test substance-related, statistically significant reductions in food consumption and food efficiency occurred in 1500 ppm females. During test days 0 – 7, food consumption and food efficiency were decreased 11% and 90%, respectively, compared to the control values. However, these reductions were transient, and recovery occurred during test days 7 – 14 such that food consumption and food efficiency values over the entire premating period (test days 0 - 14) were similar to the control values. There were no test substance-related effects or statistically significant differences on food consumption or food efficiency in females exposed to 60 or 300 ppm.

3. P1 Females – Gestation Test substance-related reductions in food consumption and food efficiency occurred in 1500 ppm females. During test days 0 – 7, food consumption and food efficiency were decreased 8% and 25%, respectively, compared to the control values. However, these reductions were transient, and recovery occurred during gestation days (GD) 7 – 14 such that food consumption and food efficiency values over the entire gestation period (GD 0 – 21) were similar to the control values. There were no test substance-related effects or statistically significant differences on food consumption or food efficiency in females exposed to 60 or 300 ppm.

4. P1 Females – Lactation There were no test substance-related or statistically significant differences on food consumption or food efficiency in females for any exposure concentration.
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):
There were no adverse changes in hematology parameters in male or female rats.

The following statistically significant change in a mean hematology parameter was not considered to be adverse:
White blood cell count was minimally decreased at test day 14 in female rats exposed to 1500 ppm (mean was 80% of the control group mean). The decrease in white blood cell count was due primarily to a minimal decrease in lymphocyte counts (not statistically significant). Similar findings were not observed in male rats at any dose. Decreased white cell count may have been related to treatment because the consistency in the white counts of the 5 females in this group. However, this change was considered to be non-adverse because of the minimal nature of the change.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no adverse changes in clinical chemistry parameters in male or female rats.

The following statistically significant changes in mean clinical chemistry parameters were not adverse or not related to exposure to the test substance:
- Bilirubin was minimally increased at test day 14 in male rats exposed to 1500 ppm (mean was 122% of control group mean). This change was due to minimally increased bilirubin in one male (animal #403) and was considered to be unrelated to treatment and thus non-adverse.
- Albumin was minimally increased at test day 14 in female rats exposed to 1500 ppm (mean was 111% of the control group mean). This change may have been related to treatment because of the consistency in the albumin concentrations of the 5 females in this group. However, increased albumin was considered to be non-adverse because of the minimal degree of change.
- Alkaline phosphatase was mildly increased at test day 14 in females exposed to 60 ppm (mean was 153% of the control group mean). This change was considered to be unrelated to treatment because it did not occur in a concentration-related pattern.
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Under the conditions of the study, there were no test substance-related effects or any neurobehavioral parameter evaluated (forelimb grip strength, hindlimb grip strenght and open field observations) in either males or females exposed to inhalation concentrations of 1500 ppm and below.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
A test substance-related increase (in P 1 adult females, mean absolute and relative (% body weight) kidney weights were increased 9% and 15%, respectively in the 1500 ppm exposure group, as compared to control values) was observed in female rats exposed to 1500 ppm.
There was no test substance-related organ weight effect in male rats.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test substance-related gross observations in any of the P1 adults.`All gross observations, recorded at necropsy, were consistent with normal background lesions that occur in rats of this age and strain.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Daily inhalation exposure of P1 adult rats to 1500 ppm of the test substance, for approximately 28 days (males) or 42 days (females), resulted in minimal regeneration of renal tubular epithelium. Regeneration of the renal tubular epithelium was observed in 10/12 males and 9/12 females exposed to 1500 ppm of the test substance. It was not observed at lower exposures. The regeneration was characterized by an increase in the number of cells in the lining epithelium of the tubules and a decrease in the average cell size. An increase in mitotic figures or associated epithelial degeneration was not observed. The change was confined to the outer medulla, was usually diffuse, and was graded as minimal (grade 1 of 4) in all instances.
A slight increase in kidney weight parameters was observed at the same dose in females only.
There were no test substance-related microscopic or organ weight effects at exposures ≤ 300 ppm in either sex.
There were no test substance-related effects on causes of death, gross pathology, or reproductive failures at any exposure (≤ 1500 ppm).
Under the conditions of this study, the no-observed-effect level (NOEC) for pathology for male and female P1 adult rats was 300 ppm.
Histopathological findings: neoplastic:
not specified
Key result
Dose descriptor:
NOAEC
Remarks:
systemic toxicity
Effect level:
300 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
histopathology: non-neoplastic
organ weights and organ / body weight ratios
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 500 ppm (analytical)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes

Incidence of renal tubular regeneration in P1 male and female rats

 sex   Males           Females        
 concentration (ppm)  0  60  300  1500  0  60  300  1500
 number of rats  12  12  12  12  12  12  12  12

 Kidneys:

Regeneration, tubular epithelium

 0  0  0  10  0  0  0  9
Conclusions:
Under the conditions of the study, the No-Observed-Adverse-Effect Concentration (NOAEC) for systemic toxicity was 300 ppm in males and females based on the histopathological effects observed at 1500 ppm.
Executive summary:

A combined repeated exposure toxicity study with reproduction/developmental toxicity screening test was conducted with Perfluoromethylvinyl Ether. Crl:CD(SD) rats (12/sex/concentration) were exposed whole body to 0, 60, 300, or 1500 ppm of perfluoromethylvinyl ether. Exposures for males and females were conducted for 6 hours per day, 5 days per week from the initiation of the study through the 14-day premating period. Exposure to the test substance did not result in adverse clinical signs or mortality. Test substance-related reductions in weight gain, food consumption, and/or food efficiency occurred in 1500 ppm males and females; however, they were transient and did not adversely affect the health of the animals. There were no adverse or test substance-related effects on neurobehavioral parameters, clinical pathology parameters, and no effects on clinical observations, or survival. Test substance-related, minimal regeneration of renal tubular epithelium was observed in 1500 ppm males and females, and was accompanied by increased absolute and relative kidney weights in 1500 ppm females. Based on the results above, the NOEC for systemic toxicity was 300 ppm ( 2037,08 mg/m3).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
The animal room accountability sheets from August 28 - September 2006, could not be located at the time the report was prepared. But this deviation does not impact the validity or interpretation of the study.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Trifluoro(trifluoromethoxy)ethylene
EC Number:
214-703-7
EC Name:
Trifluoro(trifluoromethoxy)ethylene
Cas Number:
1187-93-5
Molecular formula:
C3F6O
IUPAC Name:
1,1,2-trifluoro-2-(trifluoromethoxy)ethene
Test material form:
other: gas
Details on test material:
Substance Tested: Perfluoromethylvinyl Ether, Ethene trifluoro(trifluoromethoxy)-, 1187-93-5(CAS Number)
Haskell Number: 27649
- Analytical purity: 99.32%
- Composition of test material, percentage of components:
0.18% Hydro-PMVE
0.292% HFP+C3
0.200% O2+N2+CO
0.02% Others

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc Raleigh, North Carolina Crl: CD(SD) rat
- Age at study initiation: Approximately 60 days
- Weight at study initiation: Males: 199.1-230.6 g Females: 170.6-207.5 g
- Fasting period before study:
- Housing:
Pretest/Premating: Individually (except during cohabitation of mating pairs) in stainless steel, wire-mesh cages suspended above cage boards; sexes on separate racks.
Cohabitation: Mating pairs (females placed in males’ cages) on a 1:1 basis in stainless steel, wiremesh cages suspended above cage boards.
Days 0–19 of gestation: Individually in stainless steel, wire-mesh cages suspended above cage boards; sexes on separate racks.
Day 19 of gestation - Day 4 of lactation: Females assumed pregnant were housed individually in polycarbonate pans with bedding material. Females presumed nonpregnant were housed in the same manner as pregnant females 7 days after the mating pairs were separated.
- Diet (e.g. ad libitum):PMI® Nutrition International, LLC Certified Rodent LabDiet® 5002 (pelleted) ad libitum except during exposure and when fasted.
- Water (e.g. ad libitum):Tap water from United Water Delaware ad libitum provided by an automatic watering system except during exposure.
- Acclimation period: 18days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):18-26°C
- Humidity (%):30-70%
- Air changes (per hr):at least 10 air changes
- Photoperiod (hrs dark / hrs light):12-hour light/dark cycle

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Vehicle:
clean air
Details on exposure:
During exposure, animals were individually placed in stainless steel wire-mesh modules (one/module) and exposed, whole-body,inside the exposure chamber, except during the mating period when animals were housed as mating pairs in stainless steel wire-mesh modules and exposed in the same manner.
Chamber atmospheres were generated by dilution of PMVE in air. The test substance was metered into the test chamber inlets using a Brooks model 0154E or 0154 mass flow controller and mixed with filtered and conditioned air. Chamber concentrations of test substance were controlled by varying the test substance feed rate and the air flow to the chamber. All exposure chambers were constructed of stainless steel and glass (NYU style) with a nominal internal volume of 350 L. A tangential feed at the chamber inlet promoted uniform chamber distribution of the test atmosphere.
Chamber temperature was targeted at 19-25°C and recorded at least 3 times during each exposure.
Chamber relative humidity was targeted at 30-70% and recorded at least 3 times during each exposure. Temperature and humidity were measured with a VWR dial-type thermometer/hygrometer.
Chamber airflow was set at the beginning of each exposure to achieve at least 10 air changes per hour. The airflow was monitored continually with thermoanemometers and recorded at least 2 times during each exposure. Chamber oxygen concentration was targeted to be at least 19%. The oxygen concentration was measured with a Biosystems model 3100R oxygen analyzer and recorded once during each exposure.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
During each exposure, the atmospheric concentration of the test substance in the test chambers was determined by gas chromatography (GC) at approximately 30-minute intervals. The control chamber was sampled once per exposure. Known volumes of chamber atmosphere were continually drawn from the breathing zone of the animals and were directly injected into a Hewlett Packard model 6890 gas chromatograph equipped with an automated gas sample valve and a flame ionization detector.
All samples were chromatographed isothermally at 35°C on a J&W Scientific, DB-5, 30 M capillary
column. The atmospheric concentration of the test substance was determined from a standard curve derived from gas standards. Standards were prepared prior to each exposure by injecting known volumes of the gaseous test substance into Tedlar® bags containing known volumes of air.
Details on mating procedure:
Each female was continually housed on a 1:1 basis with a randomly selected, nonsibling male of the same concentration level until evidence of copulation was observed or the cohabitation period ended (Day 14 of cohabitation), at which time the mating pairs were separated. Evidence of copulation was confirmed by daily examination of each female for an intravaginal copulation plug or sperm in the vaginal lavage sample. The day copulation was confirmed was considered to be day 0 of gestation.
Duration of treatment / exposure:
Animals/Study Phase Duration
Premating 14 Days (Approximate)
Cohabitation Up to 14 days
Postcohabitation
Males Until sacrifice
Females with no evidence of copulation 19 Days (Approximate)
Gestation Day 0-19G
Frequency of treatment:
Exposures for males and females were conducted for 6 hours per day, 5 days per week from the initiation of the study through the 14-day premating period. Subsequently, males and non-pregnant
females were exposed 7 days a week through the terminal sacrifice on test days 29 – 30. Exposures
for females with evidence of mating were conducted for 6 hours per day, 7 days per week during the
cohabitation period and during gestation days 0 – 19. Gestating P1 females were not exposed after gestation day 19. Offspring were not exposed in the inhalation chambers.
Duration of test:
In-life period: 26-JUL-2006 to 26-OCT-2006 (anatomic pathology report)
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm (analytical)
Dose / conc.:
60 ppm (analytical)
Dose / conc.:
300 ppm (analytical)
Dose / conc.:
1 500 ppm (analytical)
No. of animals per sex per dose:
12/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Detailed under section 7.8.1

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
Frequency: All animals – At least once daily during quarantine and pretest, and once daily thereafter.
On exposure days, the observations were conducted at the time animals are placed in the exposure modules.

DETAILED CLINICAL OBSERVATIONS: Yes
Frequency: All animals - Once during pretest (baseline), and weekly thereafter

BODY WEIGHT: Yes
Quarantine: at least twice/weekly
Premating: Weekly
Cohabitation: Weekly
Post-cohabitation: Weekly for males and females without evidence of copulation
Gestation: Days 0, 7, 14, 21G
Lactation: Days 0, 4L
Neurobehavioral Evaluations: All animals evaluated were weighed on the day of the FOB assessment. These weights were not necessary for the interpretation of the neurobehavioral data, and are not presented in the report.

FOOD CONSUMPTION :
Premating: Weekly
coabitation: None
coabitation: None for males and females without evidence of copulation
Gestation: Days 0, 7, 14, 21G
Lactation: Days 0, 4L
calculation of Food: Feeders were weighed at the beginning and end of the interval.
consumption: The final weight and amount of spillage (greater than 5 g) were subtracted from initial feeder weight.

Litter observations
On lactation days 0 and 4, offspring were individually handled and examined for abnormal behavior and appearance; any dead or abnormal pups were recorded.
Day 0: Live and dead pups in each litter were counted by sex and live pups were individually weighed as soon as possible after delivery is completed.

POST-MORTEM EXAMINATIONS: Yes
Postmortem examinations (parental animals)
SACRIFICE
All P1 adult rats (48 males, 48 females) survived until the scheduled sacrifice and were euthanized by carbon dioxide anesthesia and exsanguination on days 29-30 (males) or 42-49 (females). The order of sacrifice for scheduled deaths was random among all treatment groups within a sex.
- Organs examined: The following tissues were weighed wet from all adult rats: liver, kidneys, lungs, adrenal glands, thymus, brain, spleen, heart, testes, epididymides, ovaries (with oviducts), and uterus (with cervix).
Paired organs were weighed together. Organ weight ratios (% final body weight, % brain weight) and group mean values were calculated.

Postmortem examinations (offspring)
On lactation days 0 and 4, offspring were individually handled and examined for abnormal behavior and appearance; any dead or abnormal pups were recorded. Pups in each litter were counted by sex and live pups were individually weighed and a gross external examination was performed.
F1 pup pathology data was limited to an external evaluation for abnormalities. The pups were not necropsied, organ weight data were not collected, and there was no microscopic evaluation.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes

Examinations included:
- Gravid uterus weight: No (post-partum sacrifice)
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
Fetal examinations:
No fetal examination performed (postpartum examination of offspring)
Statistics:
Male and female data were evaluated separately. For litter parameters, the proportion of affected pups per litter or the litter mean were used as the experimental unit for statistical evaluation. The level of significance selected is p < 0.05.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1. P1 Males Overall body weight gain over test days 0 – 28 was reduced 14% in 1500 ppm males
compared to the control value. While not statistically significant (p < 0.05), a similar trend was observed in the range-finding study, and this reduction was considered to be test substance related; although, not biologically adverse. Body weight and overall body weight gain for males exposed to 60 and 300 ppm were within 90% of the control value.
2. P1 Females – Premating Test substance-related, statistically significant reduction (p < 0.05) in
body weight gain occurred in during test days 0 – 7 of the premating period for 1500 ppm females.
However, since this reduction was transient, and overall weight gain was similar to control values, it
was not considered to be biologically adverse. Body weight and overall weight gain for 60 and 300
ppm females were similar to control values.
3. P1 Females – Gestation Test substance-related, statistically significant reduction in body weigh
t gain occurred in during test days 0 – 7 of gestation for 1500 ppm females. However, since this re
duction was transient, and overall weight gain was similar to control values, it was not considered to
be biologically adverse. Body weight and overall weight gain for 60 and 300 ppm females were sim
ilar to control values.
4. P1 Females – Lactation There were no test substance-related or statistically significant differences in body weight or weight gain exposed to any concentration of the test substance.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
1. Male Rats There were no test substance-related or statistically significant differences in food
consumption or food efficiency for P1 males exposed to any concentration of the test substance.
2. P1 Females – Premating
Test substance-related, statistically significant reductions (p<0.05) in food consumption and food e
fficiency occurred in 1500 ppm females. During test days 0 – 7, food consumption and food efficiency were decreased 11% and 90%, respectively, compared to the control values. However, these reductions were transient, and recovery occurred during test days 7 – 14 such that food consumption and food efficiency values over the entire premating period (test days 0 - 14) were similar to the control values. There were no test substance-related effects or statistically significant differences on food consumption or food efficiency in females exposed to 60 or 300 ppm.
3. P1 Females – Gestation Test substance-related reductions (p<0.05) in food consumption and
food efficiency occurred in 1500 ppm females. During test days 0 – 7, food consumption and food efficiency were decreased 8% and 25%, respectively, compared to the control values. However, the se reductions were transient, and recovery occurred during gestation days (GD) 7 – 14 such that food consumption and food efficiency values over the entire gestation period (GD 0 – 21) were similar to the control values. There were no test substance-related effects or statistically significant differences on food consumption or food efficiency in females exposed to 60 or 300 ppm.
4. P1 Females – Lactation There were no test substance-related or statistically significant differences (p<0.05) on food consumption or food efficiency in females for any exposure concentration.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
see above
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The following statistically significant change in a mean hematology parameter was not considered to be adverse:
White blood cell count was minimally decreased at test day 14 in female rats exposed to 1500 ppm
(mean was 80% of the control group mean). The decrease in white blood cell count was due primarily to a minimal decrease in lymphocyte counts (not statistically significant). Similar findings were not observed in male rats at any dose. Decreased white cell count may have been related to treatment because the consistency in the white counts of the 5 females in this group. However, this change was considered to be non-adverse because of the minimal nature of the change.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Description (incidence and severity)
There were no adverse changes in clinical chemistry parameters in male or female rats.
The following statistically significant changes in mean clinical chemistry parameters were not adverse or not related to exposure to the test substance:
- Bilirubin was minimally increased at test day 14 in male rats exposed to 1500 ppm (mean was 122% of control group mean). This change was due to minimally increased bilirubin in one male (animal #403) and was considered to be unrelated to treatment and thus non-adverse.
- Albumin was minimally increased at test day 14 in female rats exposed to 1500 ppm (mean was
111% of the control group mean). This change may have been related to treatment because of the
consistency in the albumin concentrations of the 5 females in this group. However, increased albumin was considered to be non-adverse because of the minimal degree of change.
- Alkaline phosphatase was mildly increased at test day 14 in females exposed to 60 ppm (mean was 153% of the control group mean). This change was considered to be unrelated to treatment because it did not occur in a concentration-related pattern.
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
A test substance-related increase (in P 1 adult females, mean absolute and relative (% body weight) kidney weights were increased 9% and 15%, respectively in the 1500 ppm exposure group, as compared to control values) was observed in female rats exposed to 1500 ppm.
There was no test substance-related organ weight effect in male rats.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test substance-related gross observations in any of the P1 adults. All gross observat
ions, recorded at necropsy, were consistent with normal background lesions that occur in rats of this
age and strain
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Daily inhalation exposure of P1 adult rats to 1500 ppm of the test substance, for approximately 28 d
ays (males) or 42 days (females), resulted in minimal regeneration of renal tubular epithelium.
Regeneration of the renal tubular epithelium was observed in 10/12 males and 9/12 females exposed to 1500 ppm of the test substance. It was not observed at lower exposures. The regeneration was characterized by an increase in the number of cells in the lining epithelium of the tubules and a decrease in the average cell size. An increase in mitotic figures or associated epithelial degeneration was not observed. The change was confined to the outer medulla, was usually diffuse, and was graded as minimal (grade 1 of 4) in all instances. A slight increase in kidney weight parameters was observed at the same dose in females only. There were no test substance-related microscopic or organ weight effects at exposures ≤ 300 ppm in either sex.
There were no test substance-related effects on causes of death, gross pathology, or reproductive failures at any exposure (≤ 1500 ppm).
Under the conditions of this study, the no-observed-effect concentration (NOEC) for pathology for
male and female P1 adult rats was 300 ppm.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
Post-implantation loss was not significantly different between treatment groups.
One male pup was found dead at first litter check (PND0) in the control group.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEC
Remarks:
Systemic toxicity
Effect level:
300 ppm (analytical)
Based on:
test mat.
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There were no test substance-related or statistically significant differences in number of litters born,
number of pups born or born alive, live born index, viability index
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
No change was observed in mean offspring body weight on postnatal days 0 or 4 for any exposure concentration
External malformations:
no effects observed
Skeletal malformations:
not examined
Visceral malformations:
not examined

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Effect level:
>= 1 500 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
(Based on external parameters assessed (postnatal development) in the current screening study)

Fetal abnormalities

Abnormalities:
not examined

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, the No-Observed-Adverse-Effect Concentration (NOAEC) for
reproduction and offspring development was 1500 ppm, the highest concentration tested.
Executive summary:

A combined repeated exposure toxicity study with reproduction/developmental toxicity screening test was conducted with the test material. Crl:CD(SD) rats (12/sex/concentration) were exposed whole body to 0, 60, 300, or 1500 ppm of perfluoromethylvinyl ether. Exposures for males and females were conducted for 6 hours per day, 5 days per week from the initiation of the study through the
14-day premating period. Exposure to the test substance did not result in adverse clinical signs or mortality. Test substance-related reductions in weight gain, food consumption, and/or food efficiency occurred in 1500 ppm parental males and females; however, they were transient and did not adversely affect the health or reproductive function of the animals. There were no adverse or test substance-related effects on reproductive function, clinical pathology parameters, and no effects on offspring body weight, clinical observations, or survival. Test substance related effects were a minimal and fully reversible regeneration of renal tubular epithelium that was observed at 150 ppm in males and females and was accompanied by increased absolute and relative kidney weights in 1500 ppm females (in P1 adult females, mean absolute and relative (% body weight) kidneys weight were increased 9% and 15%, respectively, in the 1500 ppm exposure group, as compared to the control values) which showed that the test substance shall not be classified according to CLP (Regulation EC No. 1272/2008).