Registration Dossier

Diss Factsheets

Administrative data

Description of key information

- 90-day inhalation study in rats (OECD TG413, EC method B.29), NOAEC systemic effects: 1000 ppm (6790.26 mg/m3)


- 28-day repeated dose toxicity study combined with reproductive/developmental screening, by inhalation in rats (OECD TG422), NOEC systemic effects, general toxicity: 300 ppm (2037 mg/m3)

Key value for chemical safety assessment

Toxic effect type:
concentration-driven

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

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).

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-04-22 to 2016-05-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.29 (Sub-Chronic Inhalation Toxicity:90-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Age at study initiation: 38 days old at receipt, 7 weeks old at the initiation of test substance exposures
- Weight at study initiation: Individual body weights ranged from 236 g to 283 g for males and from 172 g to 214 g for females at the initiation of test substance exposures
- Housing: 2 or 3 per cage
- Diet : PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002 (meal), ad libitum, except during the exposure periods and except during the period of fasting prior to necropsy
- Water : Reverse osmosis-treated (on-site) drinking water, delivered by an automatic watering system. Ad libitum except during the exposure periods.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Actual mean daily temperature ranged from 19.0°C to 22.7°C during the study
- Humidity (%): actual mean daily relative humidity ranged from 43.0% to 55.8% during the study
- Air changes (per hr): minimum of 10 fresh air changes per hour
- Photoperiod : 12 hour light (0600 hours to 1800 hours)/12 hour dark

IN-LIFE DATES: From: 07May2015 To: 06Aug2015
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4 approximately 1000-L stainless steel and glass whole body inhalation exposure chambers
- Method of holding animals in test chamber: whole body inhalation exposure chambers
- source of air: filtered air
- Method of conditioning air: A HEPA-filter and an activated-charcoal bed were used to pre-treat room air prior to delivery to chambers.
- Temperature, humidity, pressure in air chamber: mean temperature 19 to 25°C, mean humidity 30 to 70%, under slight negative pressure.
- Air flow rate: 200 to 250 Standard liters per minute
- Air change rate: 12 to 15 ACH
- Treatment of exhaust air: Chamber exhaust was passed through the facility exhaust system consisting of redundant exhaust blowers preceded by activated-charcoal and HEPA-filter units.

TEST ATMOSPHERE
- Brief description of analytical method used: Analyzed exposure concentrations were determined at approximately 45-minute intervals using an appropriate gas chromatography (GC) method
- Samples taken from breathing zone: yes

CONTROL GROUP
Concurrent exposure to humidified, filtered air on a comparable regimen
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance usage was documented by weighing the gas cylinder prior and following exposure.
Analyzed exposure concentrations were determined at approximately 45-minute intervals using an appropriate gas chromatography (GC) method after calibration with standards prepared at 5 gas concentrations. The first sampling round initiated approximately 18 min after the start of exposure atmosphere generation.
- Homogeneity was assessed during method development: 4 remote locations.

Duration of treatment / exposure:
6 hours per day on a 5-day per week basis for 13 weeks (65 total exposures)
Frequency of treatment:
5-day per week
Dose / conc.:
0 ppm (nominal)
Dose / conc.:
80 ppm (nominal)
Dose / conc.:
81 ppm (analytical)
Dose / conc.:
280 ppm (nominal)
Dose / conc.:
279 ppm (analytical)
Dose / conc.:
1 000 ppm (nominal)
Dose / conc.:
1 004 ppm (analytical)
No. of animals per sex per dose:
10 animals
Control animals:
other: humidified, filtered air on a comparable regimen
Details on study design:
- Dose selection rationale: based on results of an OECD 422 study
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and moribundity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: detailed physical examinations were performed weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded twice weekly (± 1 day) during the first 4 weeks of the exposure period, then weekly for the remainder of the study.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Food consumption was recorded once weekly (± 2 days) beginning after randomization

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during during acclimatation period (study week 2), and near the end of the treatment period (study week 12)
- Dose groups that were examined: all the animals
All ocular examinations were conducted using an indirect ophthalmoscope and slit lamp biomicroscope preceded by pupillary dilation with an appropriate mydriatic agent.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the scheduled necropsy
- Anaesthetic used for blood collection: Yes, isoflurane
- Animals fasted: Yes
- How many animals: all
- Parameters listed in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the scheduled necropsy
- Animals fasted: Yes
- How many animals: all
- Parameters listed in table 2 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: at the scheduled necropsy
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes, overnight
- Parameters listed in table 3 were examined.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes, on all animals

HISTOPATHOLOGY: Yes, on all animals
Statistics:
All statistical tests were performed using WTDMS™. Analyses were conducted using two-tailed tests for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group by sex. Body weight, body weight change, food consumption, clinical pathology and organ weight (absolute and relative) data were subjected to a parametric one way ANOVA (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance treated groups to the control group.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Yellow material around the urogenital area in the 280 and 1000 ppm group females beginning (from day 14 throughout study period). Red material around the nose noted in the 1000 ppm group males and females at 1 hour post-exposure throughout the study period. However, this observation was considered transient and not toxicologically significant.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
3 male animals found dead during the study:
- 1 control group male found dead on study day 37,
- one 280 ppm group male found dead on study day 90, and
- one 1000 ppm group male found dead on study day 92 (day of scheduled necropsy).
The cause of death of these animals was undetermined. Deaths occurred at different days and in different groups, including one animal in the control group, and lack of histologic correlates led to conclude that the deaths were not test substance related.

In addition, 2 males were replaced after being found dead on study days 12 and 11 (control and 280 ppm group, respectively); however, no clinical findings were noted for the 280 ppm group male that would be associated with test substance exposure.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In females, there was a small effect on mean body weight in the 1000 ppm group. Although not statistically significant, body weight was 8% lower than the control group mean following 12 and 13 weeks of exposure. Mean cumulative body weight gain for this group was 16.5% lower than control group (study week 13).In males, body weights were unaffected by test substance exposure.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
There were no test substance-related alterations in hematology and coagulation parameters.
However, some statistically significant differences were observed when the control and test substance-treated groups were compared, but without an exposure-related response (increased WBC and lymphocyte counts in the 280 ppm group females and decreased platelet counts in the 280 ppm group males).
The decreased group mean value for the platelet count in this group was mainly due to 1 animal which presented with malignant lymphoma and was not test substance related.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no test substance-related alterations in serum chemistry parameters.
However, some statistically significant differences were observed when the control and test substance treated groups were compared. The mean cholesterol value was higher in the 1000 ppm group females (+27.8%) than in the control group. However, the value was within the range of values in the laboratory historical control database and lacked correlating histologic findings or changes in other related serum chemistry parameters, and therefore was considered the result of biologic variation
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Higher kidney (+12.9%) and liver weights (+14.9%) (relative to final body weight) in the 1000 ppm group females were statistically significant when compared to the control group, but were not correlated with histologic findings and were considered to be a result of a non-statistically significant, test substance-related effect on final body weight.
There were no other test substance-related effects on organ weights. However, some statistically significant differences were observed when the control and test substance treated groups were compared:
- The adrenal gland weight relative to brain weight was lower for the 1000 ppm group females than the control group, but lacked correlating histologic changes and was within the range of values in the laboratory historical control database, and therefore was considered the result of biologic variability.
- Spleen weights (absolute and relative to final body weight) were higher in the 280 ppm group females than the control group females. In the absence of an exposure-relationship or correlating histologic findings and because the values were within the range of values in the laboratory historical control database, the higher spleen weights were not considered test substance-related.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No observations that were considered to be associated with administration of the test substance.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no test substance-related microscopic findings noted in this study.
All histologic changes were considered to be incidental findings or related to some aspect of experimental manipulation other than administration of the test substance. There was no test substance related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
One male in the 280 ppm group presented with malignant lymphoma at the scheduled necropsy in the mandibular, mediastinal, and mesenteric lymph nodes, spleen, thymus, lungs, and liver, but was not test-article related because the neoplasm occurred in only 1 animal in the mid-exposure group.
Key result
Dose descriptor:
NOAEC
Effect level:
ca. 1 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Key result
Critical effects observed:
no

 

Selected Clinical Observations

Sex

Males

Females

Exposure Level (ppm)

0

80

280

1000

0

80

280

1000

Observationa

 

Dried red material around nose

 

 

 

 

1 Hour Post-Exposure

2/2

3/3

4/3

12/5

0/0

3/3

7/4

24/8

Wet yellow material urogenital area

 

 

 

 

1 Hour Post-Exposure

0/0

0/0

0/0

0/0

0/0

0/0

20/3

109/7

Dried yellow material urogenital area

 

 

 

 

Detailed Physicals

0/0

0/0

0/0

0/0

0/0

0/0

0/0

15/4

Prior to Exposure

0/0

0/0

0/0

0/0

0/0

0/0

0/0

50/4

1 Hour Post-Exposure

0/0

0/0

0/0

0/0

0/0

0/0

3/2

21/6

Non-Exposure Days

0/0

0/0

0/0

0/0

0/0

0/0

1/1

12/3

 a= Observations reported as total occurrence/number of animals.

Conclusions:
Administration of PMVE via whole-body inhalation for 6 hours per day on a 5-day per week basis for 13 weeks to Sprague-Dawley rats at exposure levels up to 1000 ppm was well tolerated. Non-adverse test substance-related effects were limited to clinical observations of yellow material around the urogenital area in the 280 and 1000 ppm group females and slightly lower mean body weights in the 1000 ppm group females. There was no remarkable histopathological findings. Therefore, the no observed adverse effect concentration (NOAEC) was 1000 ppm.
Executive summary:

The potential toxic effects of trifluoro(trifluoromethoxy)ethylene (also referred to as PMVE) were assessed in Sprague Dawley rats administered the substance via whole-body inhalation for 6 hours per day on a 5-day per week basis for 13 weeks (minimum of 65 exposures for each animal).

Trifluoro(trifluoromethoxy)ethylene was administered to 3 groups (Groups 2‑4) of Crl:CD(SD) rats. Target exposure concentrations were 80, 280, and 1000 ppm for Groups 2, 3, and 4, respectively. Analyzed exposure concentrations were 81, 279, and 1004 ppm for Groups 2, 3, and 4, respectively. A concurrent control group (Group 1) was exposed to humidified, filtered air on a comparable regimen. Each group (Groups 1-4) consisted of 10 animals/sex. Following 13 weeks of exposure, all rats/sex/group were euthanized. All standard examinations were performed. Intergroup differences were assessed using parametric one-way ANOVA test, and, when appropriate, Dunnett's test was used to compare treated groups to the control group.

There were no test substance-related effects on survival, food consumption, clinical pathology parameters, organ weights, macroscopic observations, or microscopic findings. In addition, there were no test substance-related ophthalmic lesions indicative of toxicity (examinations performed during study weeks -2 and 12).

There were 3 male animals found dead during the study: 1 control group male found dead on day 37, one 280 ppm group male found dead on day 90, and one 1000 ppm group male found dead on day 92 (day of scheduled necropsy). The cause of death of these animals was undetermined; however, the occurrence at different days and in different groups, including an animal in the control group, and lack of histologic correlates led to the determination that the deaths were not test substance‑related. In addition, 2 males were replaced after being found dead on study days 12 and 11 (control and 280 ppm group, respectively); however, no clinical findings were noted for the 280 ppm group male that would be associated with test substance exposure.

Test substance-related clinical observations of yellow material around the urogenital area were noted in the 280 and 1000 ppm group females beginning as early as study day 14 and continuing throughout study period. The test substance-related observation of red material around the nose was noted in the 1000 ppm group males and females at 1 hour post-exposure throughout the study period. However, this observation was considered transient and not toxicologically significant. In females, test substance exposure resulted in a small effect on mean body weight in the 1000 ppm group. Body weight was 8% lower than the control group mean following 12 and 13 weeks of exposure. Compared to control group mean values, higher mean kidney and liver weights (relative to final body weight) were noted in the 1000 ppm group females, but were not correlated with microscopic findings and were considered to be a result of a non-statistically significant, test substance-related effect on final body weight.

Administration of PMVE via whole-body inhalation for 6 hours per day on a 5-day per week basis for 13 weeks to Crl:CD(SD) rats at exposure levels up to 1000 ppm was well tolerated. Non-adverse test substance-related effects were limited to clinical observations of yellow material around the urogenital area in the 280 and 1000 ppm group females and slightly lower mean body weights in the 1000 ppm group females. Therefore, the no‑observed‑adverse‑effect concentration (NOAEC) was 1000 ppm.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
6 790.26 mg/m³
Study duration:
subchronic
Experimental exposure time per week (hours/week):
30
Species:
rat
Quality of whole database:
Consistent results were obtained in two good quality repeated dose studies.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-04-22 to 2016-05-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.29 (Sub-Chronic Inhalation Toxicity:90-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Age at study initiation: 38 days old at receipt, 7 weeks old at the initiation of test substance exposures
- Weight at study initiation: Individual body weights ranged from 236 g to 283 g for males and from 172 g to 214 g for females at the initiation of test substance exposures
- Housing: 2 or 3 per cage
- Diet : PMI Nutrition International, LLC, Certified Rodent LabDiet® 5002 (meal), ad libitum, except during the exposure periods and except during the period of fasting prior to necropsy
- Water : Reverse osmosis-treated (on-site) drinking water, delivered by an automatic watering system. Ad libitum except during the exposure periods.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Actual mean daily temperature ranged from 19.0°C to 22.7°C during the study
- Humidity (%): actual mean daily relative humidity ranged from 43.0% to 55.8% during the study
- Air changes (per hr): minimum of 10 fresh air changes per hour
- Photoperiod : 12 hour light (0600 hours to 1800 hours)/12 hour dark

IN-LIFE DATES: From: 07May2015 To: 06Aug2015
Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4 approximately 1000-L stainless steel and glass whole body inhalation exposure chambers
- Method of holding animals in test chamber: whole body inhalation exposure chambers
- source of air: filtered air
- Method of conditioning air: A HEPA-filter and an activated-charcoal bed were used to pre-treat room air prior to delivery to chambers.
- Temperature, humidity, pressure in air chamber: mean temperature 19 to 25°C, mean humidity 30 to 70%, under slight negative pressure.
- Air flow rate: 200 to 250 Standard liters per minute
- Air change rate: 12 to 15 ACH
- Treatment of exhaust air: Chamber exhaust was passed through the facility exhaust system consisting of redundant exhaust blowers preceded by activated-charcoal and HEPA-filter units.

TEST ATMOSPHERE
- Brief description of analytical method used: Analyzed exposure concentrations were determined at approximately 45-minute intervals using an appropriate gas chromatography (GC) method
- Samples taken from breathing zone: yes

CONTROL GROUP
Concurrent exposure to humidified, filtered air on a comparable regimen
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance usage was documented by weighing the gas cylinder prior and following exposure.
Analyzed exposure concentrations were determined at approximately 45-minute intervals using an appropriate gas chromatography (GC) method after calibration with standards prepared at 5 gas concentrations. The first sampling round initiated approximately 18 min after the start of exposure atmosphere generation.
- Homogeneity was assessed during method development: 4 remote locations.

Duration of treatment / exposure:
6 hours per day on a 5-day per week basis for 13 weeks (65 total exposures)
Frequency of treatment:
5-day per week
Dose / conc.:
0 ppm (nominal)
Dose / conc.:
80 ppm (nominal)
Dose / conc.:
81 ppm (analytical)
Dose / conc.:
280 ppm (nominal)
Dose / conc.:
279 ppm (analytical)
Dose / conc.:
1 000 ppm (nominal)
Dose / conc.:
1 004 ppm (analytical)
No. of animals per sex per dose:
10 animals
Control animals:
other: humidified, filtered air on a comparable regimen
Details on study design:
- Dose selection rationale: based on results of an OECD 422 study
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and moribundity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: detailed physical examinations were performed weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded twice weekly (± 1 day) during the first 4 weeks of the exposure period, then weekly for the remainder of the study.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Food consumption was recorded once weekly (± 2 days) beginning after randomization

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during during acclimatation period (study week 2), and near the end of the treatment period (study week 12)
- Dose groups that were examined: all the animals
All ocular examinations were conducted using an indirect ophthalmoscope and slit lamp biomicroscope preceded by pupillary dilation with an appropriate mydriatic agent.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the scheduled necropsy
- Anaesthetic used for blood collection: Yes, isoflurane
- Animals fasted: Yes
- How many animals: all
- Parameters listed in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the scheduled necropsy
- Animals fasted: Yes
- How many animals: all
- Parameters listed in table 2 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: at the scheduled necropsy
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes, overnight
- Parameters listed in table 3 were examined.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes, on all animals

HISTOPATHOLOGY: Yes, on all animals
Statistics:
All statistical tests were performed using WTDMS™. Analyses were conducted using two-tailed tests for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group by sex. Body weight, body weight change, food consumption, clinical pathology and organ weight (absolute and relative) data were subjected to a parametric one way ANOVA (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance treated groups to the control group.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Yellow material around the urogenital area in the 280 and 1000 ppm group females beginning (from day 14 throughout study period). Red material around the nose noted in the 1000 ppm group males and females at 1 hour post-exposure throughout the study period. However, this observation was considered transient and not toxicologically significant.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
3 male animals found dead during the study:
- 1 control group male found dead on study day 37,
- one 280 ppm group male found dead on study day 90, and
- one 1000 ppm group male found dead on study day 92 (day of scheduled necropsy).
The cause of death of these animals was undetermined. Deaths occurred at different days and in different groups, including one animal in the control group, and lack of histologic correlates led to conclude that the deaths were not test substance related.

In addition, 2 males were replaced after being found dead on study days 12 and 11 (control and 280 ppm group, respectively); however, no clinical findings were noted for the 280 ppm group male that would be associated with test substance exposure.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In females, there was a small effect on mean body weight in the 1000 ppm group. Although not statistically significant, body weight was 8% lower than the control group mean following 12 and 13 weeks of exposure. Mean cumulative body weight gain for this group was 16.5% lower than control group (study week 13).In males, body weights were unaffected by test substance exposure.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
There were no test substance-related alterations in hematology and coagulation parameters.
However, some statistically significant differences were observed when the control and test substance-treated groups were compared, but without an exposure-related response (increased WBC and lymphocyte counts in the 280 ppm group females and decreased platelet counts in the 280 ppm group males).
The decreased group mean value for the platelet count in this group was mainly due to 1 animal which presented with malignant lymphoma and was not test substance related.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no test substance-related alterations in serum chemistry parameters.
However, some statistically significant differences were observed when the control and test substance treated groups were compared. The mean cholesterol value was higher in the 1000 ppm group females (+27.8%) than in the control group. However, the value was within the range of values in the laboratory historical control database and lacked correlating histologic findings or changes in other related serum chemistry parameters, and therefore was considered the result of biologic variation
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Higher kidney (+12.9%) and liver weights (+14.9%) (relative to final body weight) in the 1000 ppm group females were statistically significant when compared to the control group, but were not correlated with histologic findings and were considered to be a result of a non-statistically significant, test substance-related effect on final body weight.
There were no other test substance-related effects on organ weights. However, some statistically significant differences were observed when the control and test substance treated groups were compared:
- The adrenal gland weight relative to brain weight was lower for the 1000 ppm group females than the control group, but lacked correlating histologic changes and was within the range of values in the laboratory historical control database, and therefore was considered the result of biologic variability.
- Spleen weights (absolute and relative to final body weight) were higher in the 280 ppm group females than the control group females. In the absence of an exposure-relationship or correlating histologic findings and because the values were within the range of values in the laboratory historical control database, the higher spleen weights were not considered test substance-related.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No observations that were considered to be associated with administration of the test substance.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no test substance-related microscopic findings noted in this study.
All histologic changes were considered to be incidental findings or related to some aspect of experimental manipulation other than administration of the test substance. There was no test substance related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
One male in the 280 ppm group presented with malignant lymphoma at the scheduled necropsy in the mandibular, mediastinal, and mesenteric lymph nodes, spleen, thymus, lungs, and liver, but was not test-article related because the neoplasm occurred in only 1 animal in the mid-exposure group.
Key result
Dose descriptor:
NOAEC
Effect level:
ca. 1 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Key result
Critical effects observed:
no

 

Selected Clinical Observations

Sex

Males

Females

Exposure Level (ppm)

0

80

280

1000

0

80

280

1000

Observationa

 

Dried red material around nose

 

 

 

 

1 Hour Post-Exposure

2/2

3/3

4/3

12/5

0/0

3/3

7/4

24/8

Wet yellow material urogenital area

 

 

 

 

1 Hour Post-Exposure

0/0

0/0

0/0

0/0

0/0

0/0

20/3

109/7

Dried yellow material urogenital area

 

 

 

 

Detailed Physicals

0/0

0/0

0/0

0/0

0/0

0/0

0/0

15/4

Prior to Exposure

0/0

0/0

0/0

0/0

0/0

0/0

0/0

50/4

1 Hour Post-Exposure

0/0

0/0

0/0

0/0

0/0

0/0

3/2

21/6

Non-Exposure Days

0/0

0/0

0/0

0/0

0/0

0/0

1/1

12/3

 a= Observations reported as total occurrence/number of animals.

Conclusions:
Administration of PMVE via whole-body inhalation for 6 hours per day on a 5-day per week basis for 13 weeks to Sprague-Dawley rats at exposure levels up to 1000 ppm was well tolerated. Non-adverse test substance-related effects were limited to clinical observations of yellow material around the urogenital area in the 280 and 1000 ppm group females and slightly lower mean body weights in the 1000 ppm group females. There was no remarkable histopathological findings. Therefore, the no observed adverse effect concentration (NOAEC) was 1000 ppm.
Executive summary:

The potential toxic effects of trifluoro(trifluoromethoxy)ethylene (also referred to as PMVE) were assessed in Sprague Dawley rats administered the substance via whole-body inhalation for 6 hours per day on a 5-day per week basis for 13 weeks (minimum of 65 exposures for each animal).

Trifluoro(trifluoromethoxy)ethylene was administered to 3 groups (Groups 2‑4) of Crl:CD(SD) rats. Target exposure concentrations were 80, 280, and 1000 ppm for Groups 2, 3, and 4, respectively. Analyzed exposure concentrations were 81, 279, and 1004 ppm for Groups 2, 3, and 4, respectively. A concurrent control group (Group 1) was exposed to humidified, filtered air on a comparable regimen. Each group (Groups 1-4) consisted of 10 animals/sex. Following 13 weeks of exposure, all rats/sex/group were euthanized. All standard examinations were performed. Intergroup differences were assessed using parametric one-way ANOVA test, and, when appropriate, Dunnett's test was used to compare treated groups to the control group.

There were no test substance-related effects on survival, food consumption, clinical pathology parameters, organ weights, macroscopic observations, or microscopic findings. In addition, there were no test substance-related ophthalmic lesions indicative of toxicity (examinations performed during study weeks -2 and 12).

There were 3 male animals found dead during the study: 1 control group male found dead on day 37, one 280 ppm group male found dead on day 90, and one 1000 ppm group male found dead on day 92 (day of scheduled necropsy). The cause of death of these animals was undetermined; however, the occurrence at different days and in different groups, including an animal in the control group, and lack of histologic correlates led to the determination that the deaths were not test substance‑related. In addition, 2 males were replaced after being found dead on study days 12 and 11 (control and 280 ppm group, respectively); however, no clinical findings were noted for the 280 ppm group male that would be associated with test substance exposure.

Test substance-related clinical observations of yellow material around the urogenital area were noted in the 280 and 1000 ppm group females beginning as early as study day 14 and continuing throughout study period. The test substance-related observation of red material around the nose was noted in the 1000 ppm group males and females at 1 hour post-exposure throughout the study period. However, this observation was considered transient and not toxicologically significant. In females, test substance exposure resulted in a small effect on mean body weight in the 1000 ppm group. Body weight was 8% lower than the control group mean following 12 and 13 weeks of exposure. Compared to control group mean values, higher mean kidney and liver weights (relative to final body weight) were noted in the 1000 ppm group females, but were not correlated with microscopic findings and were considered to be a result of a non-statistically significant, test substance-related effect on final body weight.

Administration of PMVE via whole-body inhalation for 6 hours per day on a 5-day per week basis for 13 weeks to Crl:CD(SD) rats at exposure levels up to 1000 ppm was well tolerated. Non-adverse test substance-related effects were limited to clinical observations of yellow material around the urogenital area in the 280 and 1000 ppm group females and slightly lower mean body weights in the 1000 ppm group females. Therefore, the no‑observed‑adverse‑effect concentration (NOAEC) was 1000 ppm.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

As the test substance is a gas at room temperature, the test is not technically feasible through oral and dermal routes; in addition, inhalation exposure is the most relevant route of exposure . In fact, detailed data via the inhalation route is available. A GLP test (Report No. DUPONT-20813, 2007) following OECD guideline 422 showed that 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 1500ppm 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 1500ppm males and females, and was accompanied by increased absolute and relative kidney weights in 1500ppm females. Based on the results above, the NOEC for systemic toxicity was 300ppm ( 2037,08 mg/m3).

In the follow-up study, a GLP 90-day inhalation study in rats conducted at the doses 0, 80, 280 and 1000 ppm, only few clinical signs were observed, and were limited to non-adverse test substance-related effects consisting of yellow material around the urogenital area in the 280 and 1000 ppm group females and slightly lower mean body weights in the 1000 ppm group females. There were no remarkable histopathological findings in males and females at the highest dose. Therefore, the no observed adverse effect concentration (NOAEC) was 1000 ppm (6790.26 mg/m3).

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
In accordance with section 1 of REACH (Regulation (EC) No 1907/2006) Annex XI the oral repeated toxicity study (required in section 8.6.1 Annex VIII) does not need to be conducted as inhalation exposure is the most relevant route of exposure. In addition PMVE is a gas at standard temperature and pressure consequently the oral toxicity test is technically not feasible.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Adverse effects were initially observed in the 28-day (OECD422) at 1500 ppm, while in the 90-day study despite a longer exposure period the highest dose 1000 ppm could be considered a NOAEC. The sub-chronic study performed according to the OECD413 Guideline and GLP was therefore selected as key study and starting point for the DNEL derivation for long-term systemic effects by inhalation.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
guideline study following GLP. There were no specific observations indicating local effects on the respiratory tract in the repeated dose-toxicity study in rats.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
In accordance with section 1 of REACH (Regulation (EC) No 1907/2006) Annex XI the dermal repeated toxicity study (required in section 8.6.1 Annex VIII) does not need to be conducted as inhalation exposure is the most relevant route of exposure. In addition PMVE is a gas at standard temperature and pressure, consequently the dermal toxicity test is technically not feasible.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
In accordance with section 1 of REACH (Regulation (EC) No 1907/2006) Annex XI the dermal repeated toxicity study (required in section 8.6.1 Annex VIII) does not need to be conducted as inhalation exposure is the most relevant route of exposure. In addition PMVE is a gas at standard temperature and pressure, consequently the dermal toxicity test is technically not feasible..

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Based on the results of the study, the No-Observed-Adverse-Effect Concentration (NOAEC) for systemic toxicity was 1000 ppm (6790.26 mg/m3). PMVE does not meet the classification criteria for hazard classes related to repeated dose exposure according to Regulation (EC) 1272/2008.