Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
no additional data
Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
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:
other: guideline test with GLP
Qualifier:
according to
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:
other: Crl CD(SD)
Sex:
male/female
Details on test animals 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.
Remarks:
Doses / Concentrations:

Basis:
analytical conc.
0, 60, 300, or 1500 ppm
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:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not specified
Reproductive function: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
effects observed, treatment-related
CLINICAL SIGNS AND MORTALITY:There were no test substance-related clinical signs of toxicity observed during the daily exposures to perfluoromethylvinyl ether. Mortality did not occur at any exposure concentration.

BODY WEIGHT AND WEIGHT GAIN:
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 consumptions
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.
Reproduction toxicity:
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.

GROSS PATHOLOGY 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.

HISTOPATHOLOGY:
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.
Dose descriptor:
NOAEC
Remarks:
for systemic toxicity
Effect level:
300 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEC
Remarks:
for reproduction and offspring
Effect level:
1 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: P and F1 (migrated information)
Clinical signs:
effects observed, treatment-related
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
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.
Reproductive effects observed:
not specified
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 substanace related effects were a minimal and fully reversible regenaration 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).

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 185.4 mg/m³
Study duration:
subacute
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

As the test substance is a gas at room temperature, the test is not technically feasible through oral and dermal routes. However, detailed data through the inhalation route is available. A GLP test (Report No. DUPONT-20813, 2007) following OECD guideline 422 was performed with the test material. Crl:CD(SD) rats (12/sex/concentration) were exposed whole body to 0, 60, 300, or 1500ppm of test substance. 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 food efficiency occurred in 1500ppm 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. Based on the results above, NOAEC for reproducion and offspring was considered to be 1500ppm(10185.4mg/m3), which showed that the test substance shall not be classified according to CLP(Regulation EC No. 1272/2008).


Short description of key information:
NOAEC for reproduction and offspring was 1500 ppm (10185.4 mg/m3)

Justification for selection of Effect on fertility via oral route:
In accordance with section 1 of REACH (Regulation (EC) No 1907/2006) Annex XI the oral toxicity reproduction study (required in section 8.7.1 Annex VIII) does not need to be conducted as the test substance is a gas at the room temperature.

Justification for selection of Effect on fertility via inhalation route:
Guideline test with GLP

Justification for selection of Effect on fertility via dermal route:
In accordance with section 1 of REACH (Regulation (EC) No 1907/2006) Annex XI the dermal toxicity reproduction study (required in section 8.7.1 Annex VIII) does not need to be conducted as the test substance is a gas at the room temperature.

Effects on developmental toxicity

Description of key information
Based on the results in this reproductive/developmental screening test(according to OECD 422), there were no adverse or test substance-related effects on reproductive function, and no effects on offspring body weight, clinical observations, or survival at doses of 60, 300, 1500ppm.                       Pre-natal developmental toxicity endpoint is waived based on the consideration that PMVE is used only as monomer or intermediate substance in industrial processes therefore no exposure of consumers to PMVE is expected. There is no release of PMVE from industrial plants to the environment. 
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

A combined repeated exposure toxicity study with reproduction/developmental toxicity screening test was conducted with the test material. Crl:CD(SD) rats (12/sex/dose) were exposed whole body to 0, 60, 300, or 1500 ppm of perfluoromethyl vinyl ether, which provided some information on the developmental toxicity of test item. Based on the results in this reproductive/developmental screening test(according to OECD 422), there were no adverse or test substance-related effects on reproductive function, and no effects on offspring body weight, clinical observations, or survival at doses of 60, 300, 1500 ppm.

PMVE shall be imported or manufactured at greater than or equal to 100 tonnes/year (Annex IX) which triggers the standard data requirement of a prenatal developmental toxicity study (OECD TG 414). The prenatal developmental toxicity endpoint is waived based on the consideration that PMVE is used only as monomer or intermediate substance in industrial processes therefore no exposure of consumers to PMVE is expected. There is no release of PMVE from industrial plants to the environment.


Justification for selection of Effect on developmental toxicity: via oral route:
In accordance with section 1 of REACH (Regulation (EC) No 1907/2006) Annex XI the oral toxicity reproduction study (required in section 8.7.2 Annex VIII) does not need to be conducted as the test substance is a gas at the room temperature.

Justification for selection of Effect on developmental toxicity: via inhalation route:
In accordance with section 3 of REACH (Regulation (EC) No 1907/2006) Annex XI the developmental toxicity/teratogenicity study (required in section 7.8.2 Annex IX) does not need to be conducted based on the consideration that PMVE is used only as monomer or intermediate substance in industrial processes therefore no exposure of consumers to PMVE is expected. In addition available monitoring data confirm that no exposure of workers to PMVE is expected and there is no release of PMVE from industrial plants to the environment. There is no release of PMVE from industrial plants to the environment.

Justification for selection of Effect on developmental toxicity: via dermal route:
In accordance with section 1 of REACH (Regulation (EC) No 1907/2006) Annex XI the dermal toxicity reproduction study (required in section 8.7.2 Annex VIII) does not need to be conducted as the test substance is a gas at the room temperature.

Justification for classification or non-classification

There is adequate information available from which to assess the potential of test substance to induce reproductive effects. NOAEC for reproduction and offspring was considered to be 1500ppm (11117.41mg/m3). Based on the results in this reproductive/developmental screening test(according to OECD 422) providing some information about developmental toxicity, there were no adverse or test substance-related effects on reproductive function, and no effects on offspring body weight, clinical observations, or survival at doses of 60, 300, 1500ppm. Therefore, according to Regulation (EC) 1272/2008, PMVE does not meet the classification criteria for the hazard class “Reproductive toxicity”.