U.S. Environmental Protection Agency
Hazard Characterization Document
September, 2014
SCREENING-LEVEL HAZARD CHARACTERIZATION
SPONSORED CHEMICAL
Vinyl Fluoride (CASRN 75-02-5)
SUPPORTING CHEMICAL
Vinyl Chloride (CASRN 75-01-4)
The High Production Volume (HPV) Challenge Program1 was conceived as a voluntary initiative
aimed at developing and making publicly available screening-level health and environmental
effects information on chemicals manufactured in or imported into the United States in quantities
greater than one million pounds per year. In the Challenge Program, producers and importers of
HPV chemicals voluntarily sponsored chemicals; sponsorship entailed the identification and
initial assessment of the adequacy of existing toxicity data/information, conducting new testing if
adequate data did not exist, and making both new and existing data and information available to
the public. Each complete data submission contains data on 18 internationally agreed to "SIDS"
(Screening Information Data Set1'2) endpoints that are screening-level indicators of potential
hazards (toxicity) for humans or the environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is
evaluating the data submitted in the HPV Challenge Program on approximately 1400 sponsored
chemicals by developing hazard characterizations (HCs). These HCs consist of an evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions.
They are not intended to be definitive statements regarding the possibility of unreasonable risk of
injury to health or the environment.
The evaluation is performed according to established EPA guidance2'3 and is based primarily on
hazard data provided by sponsors; however, in preparing the hazard characterization, EPA
considered its own comments and public comments on the original submission as well as the
sponsor's responses to comments and revisions made to the submission. In order to determine
whether any new hazard information was developed since the time of the HPV submission, a
search of the following databases was made from one year prior to the date of the HPV
Challenge submission to the present: (ChemID to locate available data sources including
Medline/PubMed, Toxline, HSDB, IRIS, NTP, AT SDR, IARC, EXTOXNET, EPA SRS, etc.),
STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS,
Merck, etc.), Science Direct and ECHA4. OPPT's focus on these specific sources is based on
their being of high quality, highly relevant to hazard characterization, and publicly available.
OPPT does not develop HCs for those HPV chemicals which have already been assessed
internationally through the HPV program of the Organization for Economic Cooperation and
1	U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2	U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3	U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
4	European Chemicals Agency, http://echa.europa.eu.

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Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment
Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are
presented in an international forum that involves review and endorsement by governmental
authorities around the world. OPPT is an active participant in these meetings and accepts these
documents as reliable screening-level hazard assessments.
These hazard characterizations are technical documents intended to inform subsequent decisions
and actions by OPPT. Accordingly, the documents are not written with the goal of informing the
general public. However, they do provide a vehicle for public access to a concise assessment of
the raw technical data on HPV chemicals and provide information previously not readily
available to the public.
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Chemical Abstract Service Registry Number
(CASRN)
Sponsored Chemical
75-02-5
Supporting Chemical
75-01-4
Chemical Abstract Index Name
Sponsored Chemical
Ethene, fluoro-
Supporting Chemical
Ethene, chloro-

Sponsored Chemical


Structural Formula
SMILES: FCC
Supporting Chemical
-^^ci
SMILES: C=CC1
Summary
Vinyl fluoride is a clear, colorless gas with high vapor pressure and high water solubility. It is
expected to have high mobility in soil. Volatilization of vinyl fluoride is high. The rate of
hydrolysis is expected to be negligible. The rate of atmospheric photooxidation is slow. Vinyl
fluoride is not readily biodegradable. Vinyl fluoride is expected to have moderate persistence
(P2) and low bioaccumulation potential (Bl).
Acute inhalation toxicity of vinyl fluoride to mice is low. In 90-day repeated inhalation toxicity
studies in rats and mice, vinyl fluoride showed concentration-related increases in cell
proliferation in livers of all treated mice and rats, and in olfactory mucosa of mice at >
200 ppm; the NOAEC was not established. No specific reproductive toxicity studies are
available with vinyl fluoride; however, no effects on the reproductive organs were seen in the
90-day inhalation study in rats. In an inhalation two-generation reproductive toxicity study in
rats with the supporting chemical, vinyl chloride, no effects on reproductive parameters were
observed at any concentration; the NOAEC for reproductive toxicity is 1100 ppm (highest
concentration tested). No developmental toxicity studies are available for vinyl fluoride. In
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prenatal inhalation developmental toxicity studies in rats and mice with the supporting chemical,
vinyl chloride, the following treatment-related developmental effects were observed at 500 ppm
and above: increased fetal resorption, decreased corpora lutea/dam in rats, decreased live
fetuses/litter in mice, increased fetal loss or pregnancy wastage in rats, decreased fetal body
weight in rats and mice, increased fetal crown-rump length in rats, increased incidences of rib
spurs and dilated ureters in rats, increased incidences of unfused or delayed ossification of
sternebrae in mice and an increased incidence of delayed ossification of the skull in mice. The
NOAEC for maternal and developmental toxicity was not established in rats; the NOAEC for
maternal and developmental toxicity in mice is 50 ppm and 500 ppm, respectively. In rabbits
exposed to the supporting chemical vinyl chloride, decreased feed consumption, number of
corpora lutea per dam, number of implantations per dam and number of live fetuses per litter
and an increase in the incidence of delayed ossification were seen at 500 ppm but not at 2500
ppm; the NOAEC for maternal and developmental toxicity was 2500 ppm (highest
concentration tested). Vinyl fluoride is mutagenic in bacteria and mammalian cells in vitro and
it induced chromosomal aberrations in vitro and in vivo. Vinyl fluoride showed no effects on
spermatocytes or germ cells in the unscheduled DNA synthesis and dominant lethal assays in
rats, respectively. Vinyl fluoride increased the incidence of tumors in rats and mice. The
International Agency for Research on Cancer (IARC) states that "for practical purposes, vinyl
fluoride should be considered to act similarly to the human carcinogen vinyl chloride".
The 96-h LCso value for fish exposed to vinyl fluoride is 210 mg/L, based on the supporting
chemical (vinyl chloride). Adequate aquatic invertebrate and algal toxicity test data are not
available for vinyl fluoride or vinyl chloride.
Data gaps for the acute toxicity to aquatic invertebrates and toxicity to aquatic plants endpoints
were identified under the HPV Challenge Program.
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The sponsor, E.I. Du Pont de Nemours & Company, Inc., submitted a Test Plan and Robust
Summaries to EPA for vinyl fluoride (CASRN 75-02-5; CA Index name: ethene, fluoro-) on
December 18, 2003. EPA posted the submission on the ChemRTK HPV Challenge website on
February 18, 2004 (http://www.epa.gov/oppt/chemrtk/pubs/summaries/fluretln/cl4972tc.htm).
EPA comments on the original submission were posted to the website on December 22, 2004.
Public comments were also received and posted to the website. The sponsor submitted
updated/revised documents on April 14, 2005, which were posted to the ChemRTK website on
January 31, 2007.
Justification for Supporting Chemical
Studies on vinyl chloride (CASRN 75-01-4), a proposed supporting chemical of vinyl fluoride,
were used to address the aquatic toxicity (e.g., fish, aquatic invertebrates and aquatic plants) and
developmental toxicity endpoints. The use of data on vinyl chloride for aquatic toxicity
endpoints was supported by ECOSAR data, which indicated that vinyl chloride was estimated to
be slightly more toxic, and thus a conservative supporting chemical.
The biotransformation pathway for vinyl fluoride is thought to be similar to that of vinyl
chloride, that is, cytochrome P-450 mediated oxidation to the haloethylene oxide (fluoroethylene
oxide), followed by rearrangement to the haloacetaldehyde (2-fluoroacetaldehyde), which
is oxidized to fluoroacetic acid (10th RoC, 2002). Based on similar metabolic pathways and
comparable toxicity data (e.g. liver toxicity) the use of data for vinyl chloride to address human
health endpoints for vinyl fluoride is considered appropriate for this hazard characterization.
Vinyl chloride has been assessed in several programs: OECD HPV program (US SIAM 13:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/VINYLCIIL.pdf).
EPA IRIS (http://www.epa.gov/iris/subst/1001 .htm) ,
AT SDR (2006: http://www.atsdr.cdc.gov/ToxProfiles/tp20.pdf) and
AEGL (http://www.epa.gov/oppt/aegl/pubs/results74.htm).
1. Chemical Identity
1.1	Identification and Purity
Vinyl fluoride is a clear, colorless gas with high vapor pressure and high water solubility.
1.2	Physical-Chemical Properties
The physical-chemical properties of vinyl fluoride are summarized in Table 1.
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Table 1. Physical-Chemical Properties of Vinyl fluoride1
Property
Value
CASRN
75-02-5
Molecular Weight
46.04
Physical State
Clear, colorless, liquefied gas
Melting Point
-160.5°C (measured)
Boiling Point
-72°C (measured)
Vapor Pressure
1.98x 104 mm Hg at 25°C (extrapolated)
43. 65 mm Hg at -111.9°C (measured)4
Dissociation Constant
(pKa)
Not applicable
Henry's Law Constant
0.12 atm-m3/mole (estimated)2
Water Solubility
9,400 mg/L at 3.4 MPa and 80°C (measured)1'3;
15,400 mg/L 6.9 Mpa and 80°C (measured)1'3
Log Kow
1.19 (estimated)2
'DuPont Corporation. 2005. Revisions to Test Plan and Robust Summary for Fluoroethylene. Available online at
http://www.epa. gov/chemrtk/pubs/summaries/fluretln/c 14972tc.htm as of April 16, 2012.
2U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental
Protection Agency, Washington, DC, USA. Available online at
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of April 16, 2012.
3Although the water solubility was measured at extremely high pressures and elevated temperature, it is unlikely
that any reasonable measurement can be obtained at standard temperature and pressure. A value of 1.18/10 '
mg/L at STP was estimated.
4 Beilstein, E4, Volume 1, part 2 page 694.
2. General Information on Exposure
2.1	Production Volume and Use
Vinyl fluoride had an aggregated production and/or import volume in the United States between
1 to 10 million pounds during calendar year 2005.
Industrial processing and uses for the chemical were claimed confidential. No commercial and
consumer uses were reported for the chemical.
2.2	Environmental Exposure and Fate
Vinyl fluoride is expected to have high mobility in soil. No biodegradation was available for the
sponsored substance; however, a structural analog, vinyl chloride (CASRN 75-01-4) achieved 3-
16% of its theoretical biochemical oxygen demand (BOD) using a closed bottle (OECD 301D)
test for volatile substances over a 4-week incubation period. Volatilization of vinyl fluoride is
high given its Henry's Law constant. The rate of hydrolysis is expected to be negligible. The
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rate of atmospheric photooxidation is slow. Vinyl fluoride is expected to have moderate
persistence (P2) and low bioaccumulation potential (Bl). The environmental fate characteristics
of vinyl fluoride are summarized in Table 2.
Table 2. Environmental Fate Properties of Vinyl fluoride1
Property
Value
CASRN
75-02-5
Photodegradation Half-life
1.9 days (estimated)2
Hydrolysis Half-life
Stable
Biodegradation
3-16% after 28 days (not readily biodegradable)3'4
Bioaccumulation Factor
BAF = 2.3 (estimated)2
Log Koc
1.3 (estimated)2
Fugacity

(Level III Model)2

Air (%)
32.7
Water (%)
65.8
Soil (%)
1.3
Sediment (%)
0.2
Persistence5
P2 (moderate)
Bioaccumulation5
Bl (low)
1 DuPont Corporation. 2005. Revisions to Test Plan and Robust Summary for Fluoroethylene. Available online at
http://www.epa.gov/chemrtk/pubs/summaries/fluretln/cl4972tc.htm as of April 16, 2012.
2U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental
Protection Agency, Washington, DC, USA. Available online at
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of April 16, 2012.
3National Institute of Technology and Evaluation. 2002. Biodegradation and Bioaccumulation of the Existing
Chemical Substances under the Chemical Substances Control Law. Available online at
http://www.safe.nite.go.ip/english/kizon/KIZON start hazkizon.html as of April 16, 2012.
4Data for structural analog, vinyl chloride (CASRN 75-01-4).
5Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal
Register 64, Number 213 (November 4, 1999) pp. 60194-60204.
Conclusion: Vinyl fluoride is a clear, colorless gas with high vapor pressure and high water
solubility. It is expected to have high mobility in soil. Volatilization of vinyl fluoride is high.
The rate of hydrolysis is expected to be negligible. The rate of atmospheric photooxidation is
slow. Vinyl fluoride is not readily biodegradable. Vinyl fluoride is expected to have moderate
persistence (P2) and low bioaccumulation potential (Bl).
3. Human Health Hazard
A summary of health effects data for SIDS and other endpoints is provided in Table 3. The table
also indicates where data for supporting chemical(s) are read-across (RA) to the sponsored
substance. For complete SIDS data set for the supporting chemical, vinyl chloride
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(CASRN 75-01-4), see human health data at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/VINYLCHL.pdf
Acute Inhalation Toxicity
Several studies are available for acute inhalation toxicity. The study summarized in the HPV
Challenge submission is presented here.
Vinyl fluoride (CASRN 75-02-5)
Mice (strain, sex and group number size not specified) were exposed via inhalation to a "gaseous
mixture" of vinyl fluoride. In the first of two experiments, mice were exposed to 45, 66, 70 or
100% vinyl fluoride in air for 4 hours and observed for up to 24 hours post-exposure. The
mortality rate was 17, 31 and 100% at 45, 66 and 70% exposure concentrations, respectively.
The median lethal concentration was 69%. In the second experiment, concentrations of 80 and
90% vinyl fluoride were mixed with pure oxygen and mice were exposed for an unspecified
duration. The study authors concluded that in the first experiment, deaths occurred at all
concentrations due to suffocation (lack of oxygen) rather than vinyl fluoride poisoning. In the
second experiment, the summary noted that the vinyl fluoride did not oxidize and the results
were similar to those obtained with tests in air.
LCso = 690,000 ppm
Repeated-Dose Toxicity
Vinyl fluoride (CASRN 75-02-5)
In a 90-day study, Crl:CD BR rats (15/sex/concentration) and Crl:CD-l(ICR)BR mice
(15/sex/concentration) were exposed (whole-body) to vinyl fluoride vapors at concentrations of
0, 200, 2000 or 20,000 ppm (mean measured concentrations of 0, 198.2, 2005.1 and 19,841.2
ppm) for 6 hours/day, 5 days/week. The following parameters were evaluated: clinical signs,
body weight, food consumption, ophthalmological examination, hematology, clinical chemistry
and urinalyses parameters, organ weights, gross and histopathology. In addition, cell
proliferation was evaluated in liver, kidney, lung, and nasal cavity tissues. Effects were limited
to a concentration-related increase in cell proliferation in livers of all treated mice and rats and in
olfactory mucosa of mice at all test concentrations. No effects were seen following clinical and
ophthalmological examination; there were also no effects on body weights, food consumption or
hematology and clinical chemistry.
LOAEC = 200 ppm (based on cell proliferation in the liver of mice and rats and in the olfactory
mucosa of mice)
NOAEC = Not established
Reproductive Toxicity
Vinyl fluoride (CASRN 75-02-5)
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No specific reproductive toxicity studies are available for vinyl fluoride.
(1)	In the 90-day inhalation toxicity study mentioned previously, there were no effects on
reproductive organs in rats (testes, epididymides, prostate, seminal vesicles, mammary gland,
ovaries, uterus and vagina were examined histologically and testes and ovaries were weighed).
(2)	No effects were seen on reproductive organs in the inhalation carcinogenicity studies of vinyl
fluoride in rats. However, in mice, an increased incidence of mammary gland adenocarcinoma
and hyperplasia were observed.
(3)	Vinyl fluoride did not induce mutations in a dominant lethal mutation assay (see details
below) in rats.
(4)	Vinyl fluoride did not induce unscheduled DNA synthesis (see details below) in rat
spermatocytes.
Vinyl chloride (CASRN 75-01-4, supporting chemical)
In a two generation reproductive toxicity study via inhalation, Sprague-Dawley rats
(30/sex/concentration) were exposed to vinyl chloride at 0, 10, 100 or 1100 ppm, 6 hours/day,
5days/week during premating and 6 hours/day, 7 days/week during gestation, lactation and
postweaning. Evaluation for the parental animals included body weights, food consumption, and
estrous cycling as well as fertility, reproductive performance, and sperm assessments. Both F1
and F2 pups were examined and weighed at birth and on several days during lactation. At
weaning, one pup/sex/litter was randomly selected, sacrificed, and given a macroscopic
examination. No adverse effect of the measured parameters was seen in the parental generations
and no adverse effect of treatment was indicated in the F1 and F2 pups. Liver effects typical of
vinyl chloride (increased weights, hypertrophy, and occurrence of altered hepatocellular foci)
were noted in parental animals at 1100 and 100 ppm, but not at 10 ppm, with increased incidence
occurring in the P2 as opposed to the PI animals. Whether this increased incidence in P2 animals
was due to in utero or juvenile susceptibility (the PI animals were not exposed during these
periods whereas the P2 animals were) or to a longer duration (P2 animals were exposed longer
than were PI animals) is not clear. However, tumor incidence has been documented to increase
at maturity among laboratory animals treated with vinyl chloride during the first 6 months of life
when compared with those exposed during the second or third 6-month period of life. No effects
on reproductive parameters were observed. See human health data at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/VINYLCHL.pdf and IRIS evaluation at:
http ://www. epa. gov/iri s/ sub st/1001 .htm
NOAEC (reproductive toxicity) = 1100 ppm (highest concentration tested)
Developmental Toxicity
Vinyl chloride (CASRN 75-01-4, supporting chemical)
(1) In a prenatal developmental toxicity study done in conjunction with the 2-generation
reproduction toxicity study, pregnant Sprague-Dawley rats (25/concentration) were exposed
(whole-body) via inhalation to vinyl chloride at 0, 10, 100 or 1100 ppm (approximately 0, 26,
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256 or 2816 mg/m3) for 6 hours/day on gestation days (GDs) 6 through 19. In dams, increased
relative kidney weights were seen at 100 or 1100 ppm. Changes in body weight gain were not
considered treatment-related. No statistically significant fetal malformations were observed, nor
were developmental parameters affected. See human health data at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/VINYLCHL.pdf
LOAEC (maternal toxicity) = 100 ppm (based on kidney effects)
NOAEC (maternal toxicity) = 10 ppm
NOAEC (developmental toxicity) = 1100 ppm (based on no effects at the highest concentration
tested)
(2)	In two separate prenatal developmental toxicity studies, pregnant Sprague-Dawley rats (16 -
31/concentration) were exposed to vinyl chloride via inhalation to concentrations of 0 (air) and
500 ppm or o (air) and 2500 ppm (with or without 15% ethanol in drinking water) for 7
hours/day, from GD 6 through 15. Decreased weight gain, decreased number of corpora
lutea/dam and pregnancy wastage (the number of corpora lutea minus the number of implants)
were found in dams exposed to 500 ppm. Decreased feed consumption and increased absolute
and relative liver weight were found in animals exposed to 2500 ppm. A decrease in fetal body
weight, an increase in crown-rump length and a significantly (p < 0.05) increased incidence of
rib spurs were observed in fetuses exposed to 500 ppm, but not 2500 ppm. A significant (p <
0.05) increase in the incidence of unilateral or bilateral dilated ureters was found in fetuses
exposed to 2500 ppm. In general, the presence of ethanol increased the incidence of observed
effects. See human health data at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/VINYLCIIL.pdf
LOAEC (maternal toxicity) = 500 ppm (based on decreased body weight gain, decreased
number of corpora lutea/dam and pregnancy wastage)
NOAEC (maternal toxicity) = Not established
LOAEC (developmental toxicity) = 2500 ppm (based on decreased fetal body weight,
increased crown-rump length and increased incidence of rib spurs)
NOAEC (developmental toxicity) = 500 ppm
(3)	In two separate prenatal developmental toxicity studies, pregnant CF-1 mice (7 -
26/concentration) were exposed to vinyl chloride via inhalation at 0 (air) and 50 (with and
without 15% ethanol) or 0 (air) and 500 ppm (with and without 15% ethanol in drinking water)
for 7 hours/day, from GD 6 through 15. Dams exposed to 500 ppm exhibited decreased weight
gain, decreased feed consumption, decreased absolute liver weight and 17% mortality. There
was an increase in the incidence of resorptions in dams exposed to 500 ppm. The total number
of live fetuses/litter and fetal weights was significantly (p < 0.05) reduced in dams exposed to
500 ppm. Fetal crown-rump length was significantly (p < 0.05) increased at 50 ppm but not at
500 ppm. Statistically significant (p < 0.05) fetal skeletal tissue anomalies at
500 ppm included increased incidences of unfused or delayed ossification of sternebrae and
delayed ossification of the skull; however, the authors concluded that these changes were within
historical controls. In general, the presence of ethanol increased the incidence of observed
effects. See human health data at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/VINYLCIIL.pdf
LOAEC (maternal toxicity) = 500 ppm (based on mortality, decreased weight gain, decreased
feed consumption, decreased absolute liver weight)
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NOAEC (maternal toxicity) = 50 ppm
LOAEC (developmental toxicity) = 2500 ppm (based on increased incidence of resorptions,
decreased live fetuses/litter, decreased fetal weights and increased incidences of unfused or
delayed ossification of sternebrae and delayed ossification of the skull)
NOAEC (developmental toxicity) = 500 ppm
(4) In two separate prenatal developmental toxicity studies, pregnant New Zealand White rabbits
[5 (high dose) or 20 (low dose)/group] were exposed to vinyl chloride via inhalation at
concentrations of 0 (air) and 500 ppm or 0 and 2500 ppm (with or without 15% ethanol in
drinking water) for 7 hours/day from GD 6 through 18. The percentage of pregnant females was
100, 95 and 86% at 0, 500 and 2500 ppm, respectively. Decreased (p < 0.05) feed consumption,
number of corpora lutea per dam, number of implantations per dam and number of live fetuses
per litter was seen in animals exposed to 500 ppm but not at 2500 ppm. A statistically
significant (p < 0.05) increase in the incidence of delayed ossification of the 5th sternebra was
seen at 500 ppm but not at 2500 ppm. See human health data at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/VINYLCHL.pdf
NOAEC (maternal and developmental toxicity) = 2500 ppm (based on no dose-response of
adverse effects observed)
Genetic Toxicity — Gene Mutation
In vitro
Vinyl fluoride (CASRN 75-02-5)
(1)	In a reverse-mutation assay modified for gaseous mixtures, Salmonella typhimurium strains
TA1535, TA1537, TA1538, TA98 and TA100 were exposed to vinyl fluoride at concentrations
of 0, 1,5, 10 or 25% in the presence and absence of metabolic activation. Study details absent
from the summary included information about cytotoxicity, criteria for determining positive and
negative findings and statistical methods. Data for strain TA1538 were excluded due to
contamination of culture. A slight increase in the frequency of histidine revertants was observed
in the TA100 culture; however, the increase was less than 2-fold and was not concentration-
related. No cytotoxicity or precipitation was observed at any concentration tested. Positive and
negative controls were tested concurrently and produced an appropriate response.
Vinyl fluoride was not mutagenic in this assay.
(2)	In several reverse-mutation assays of vinyl fluoride, various strains of Salmonella
typhimurium were exposed up to concentrations of 52%. Vinyl fluoride induced statistically
significant increases (P < 0.01) in mutation frequency (1.4 to 2.1 times
negative control mutation frequencies) in three of the five assays in strain TA1535 with
metabolic activation. VF did not induce reverse mutations in strains TA98, TA100, or
TA1537 in the presence of metabolic activation, nor in any strain in the absence of
metabolic activation (10th RoC, 2002).
Vinyl fluoride was mutagenic in the presence of metabolic activation but not in the absence
of metabolic activation.
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(3) In mammalian cell gene mutation test, Chinese hamster ovary (CHO)/HPRT cells were
exposed to vinyl fluoride at concentrations of 0, 20, 40, 60, 80 or 100% in triplicate in the
presence and absence of metabolic activation. Preliminary studies were conducted to determine
cytotoxicity. Although no statistically significant increases in mutant frequencies were
demonstrated in either trial with activation when analyzed separately, combined analyses
indicated a statistically significant (p < 0.01) increase at the 60% level. A large standard
deviation between the negative control values in the second trial made interpretation of the
results difficult. Therefore, a third trial was conducted. The combined statistics of all three trials
indicated significant increases in mutant frequencies at all concentrations (20 - 100% vinyl
fluoride). A positive quadratic dose-response was also statistically evident.
Vinyl fluoride was mutagenic in this assay.
Genetic Toxicity — Chromosomal Aberrations
In vitro
Vinyl fluoride (CASRN 75-02-5)
In mammalian cell chromosome aberration test, CHO cells were exposed to vinyl fluoride at
concentrations of 0, 23, 48, 71.5 or 96.3% in the non-activated cytotoxicity assessment; 0, 27,
52.1, 61.3 or 97% in the activated cytotoxicity assessment; 0, 8.1, 42.9, 72.3 or 104.1%) in the
non-activated chromosome aberration trial 1; 0, 8.8, 46.5, 77.8 or 111.4% in the non-activated
chromosome aberration trial 2; 0, 8.3, 25.9, 49.6 or 75.1%> in the activated chromosome
aberration trial 1; and 0, 12.3, 35.4, 63.3 or 91.3%> in the activated chromosome aberration trial 2.
The negative control contained nitrogen and the positive control agents were ethylmethane
sulfonate (EMS) and vinyl chloride. Cell cycle delay was seen following exposure to 96.3%
vinyl fluoride (in nitrogen) without activation. With activation, moderate to severe cell cycle
delay was observed at 52.1 and > 61.3%> vinyl fluoride, respectively. Equivocal chromosome
aberration results were obtained following 5-hour non-activated treatments. Chromosome
aberrations were induced after 2-hour treatments with activation at concentrations ranging from
8.3 to 63.3% vinyl fluoride.
Vinyl fluoride induced chromosomal aberrations in this assay.
In vivo
Vinyl fluoride (CASRN 75-02-5)
In mammalian bone marrow chromosome aberration test, Crl:CD-l(ICR)BR mice (15 -
18/sex/concentration) were exposed to atmospheres of vinyl fluoride gas in air at concentrations
of 0, 94, 376 or 753 mg/L for 6 hours. Cyclophosphamide, dosed by intraperitoneal injection,
served as the positive control. Approximately 24, 48 and 72 hours after initiation of exposure,
mice were sacrificed (five per sex per time period for the control, low and intermediate dose
groups, six per sex per time period for the high group). Immediately following sacrifice, the
marrow from both femurs of each animal was excised and slides were prepared and examined.
One thousand polychromatic erythrocytes (PCEs) per animal were scored for the presence of
micronuclei. No clinical signs were observed prior to sacrifice. Male mice of the low and high
exposure groups and female mice of the high exposure group exhibited weight loss. At the 24-
hour sacrifice time, females showed a concentration-related trend in the proportion of
micronucleated PCEs, although no single test concentration gave increases over controls.
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Females exposed to the intermediate (94 mg/L) and high (753 mg/L) concentrations of vinyl
fluoride showed increases in the frequency of micronucleated PCEs as compared to controls with
a concentration-related trend. Males also showed increased frequencies of PCEs; however, these
increases were considered equivocal due to the sponsor's indication that the effect was not
statistically significant.
Vinyl fluoride induced chromosomal aberrations in this study.
Genetic Toxicity — Other
In vivo
Vinyl fluoride (CASRN 75-02-5)
(1)	In the rodent dominant lethal test, male Crl:CD rats (40/group) were exposed to atmospheres
of vinyl fluoride gas in air at concentrations of 0, 200, 2000 or 20,000 ppm for 6 hours/day for 5
days. A positive control group was exposed to triethylenemelamine. Males were mated with
unexposed females beginning 2 days following exposure. This procedure was repeated weekly,
using different females, for 8 consecutive weeks. Females were weighed and clinical signs
recorded on GDs 0 and 14 and sacrificed on GD 14. The numbers of total implantations,
resorptions, live and dead embryos and corpora lutea were determined, and preimplantation loss
was calculated. Males were weighed and clinical signs were recorded daily during exposure and
weekly thereafter. All males were sacrificed 10-11 days after the final day of mating. Testes
were examined for gross abnormalities, weighed and preserved in Bouin's fixative, but
microscopic examination was not performed. The vinyl fluoride exposure did not increase the
frequency of dominant-lethal mutations, indicating that it was not mutagenic to germ cells in the
male rat.
Vinyl fluoride did not induce an increase in the frequency of dominant-lethal mutations in
this assay.
(2)	In an unscheduled DNA synthesis (UDS) assay, male CDF(F-344)CrlBr rats (15/group) were
exposed (nose-only) to vinyl fluoride via inhalation at concentrations of 0 or 20,000 ppm. At
approximately 2, 6 or 24 hours after exposure, testicular cells were prepared from five animals in
both the control and treatment groups. To determine whether vinyl fluoride inhibited DNA
repair, testicular cells were cultured and incubated. Following incubation, cell viability was
determined by trypan blue exclusion. Three slides per animal and 25 cells per slide were scored
for a total of 75 cells per animal. Vinyl fluoride was not toxic to testicular cells, nor was UDS
observed.
Vinyl fluoride exposure did not induce unscheduled DNA synthesis in this assay.
Additional Information
Carcinogenicity
Vinyl fluoride (CASRN 75-02-5)
(1) In a two-year carcinogenicity study, Crl:CD BR rats (95/sex/concentration) were exposed
(whole-body) to vinyl fluoride vapors at 0, 25, 250 or 2500 ppm for 6 hours/day, 5 days/week.
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There was a statistically significant decrease in survival of male and female rats at 250 and 2500
ppm compared to controls. The decrease in survival in male rats at 25 ppm was statistically
significant while that in female rats was not statistically significant.. Slight decreases in mean
body weight gain (6 - 15%) were observed in rats at 25 and 250 ppm, along with increased
incidence of "weak" and "colored discharged eye(s)," as stated by the sponsor, in female rats at
25 ppm. At necropsy, concentration-related lesions included masses, nodules, discoloration and
hemorrhage of the liver; mass/nodules and discoloration and hemorrhage of the lungs, and fluid
in the peritoneal cavity; masses of the head, face and periaural area; and abscesses of the face.
These lesions were attributed to secondary effects to vinyl fluoride induced neoplasms. The
combined incidences of neoplastic lesions for male and female rats at 0, 25, 250 and 2500 ppm,
respectively, were as follows: hepatic hemangiosarcoma (0/160, 13/160, 49/160 and 35/160),
hepatocellular adenoma and carcinoma (5/160, 14/160, 19/160 and 15/160), foci of clear cell
alteration (37/160, 49/160, 62/160 and 72/160), foci of basophilic alteration (35/160, 59/160,
64/160 and 90/160), sinusoidal dilatation (16/160, 65/160, 61/160, and 50/160) and Zymbal's
gland tumors (0/160, 2/160, 4/160 and 23/160). Mortality related to vinyl chloride induced
hepatic hemangiosarcoma became significant in the second year of the study. The total
incidences of rats that died of hepatic hemangiosarcoma over the course of the study were 1/80,
2/80, 25/80 and 15/80 for male rats and 0/80, 7/80, 14/80 and 15/80 for female rat at 0, 25, 250
and 2500 ppm, respectively. Lesions secondary to hemangiosarcoma-induced hemorrhage and
hemolysis included increased erythropoiesis in the spleen and bone marrow and eosinophilic
droplets/pigment in renal tubular epithelium. Acute necrosis in the liver was likely the result of
acute tissue hypoxia following hemorrhage into the peritoneal cavity. Metastatic
hemangiosarcomas in the lungs were associated with pulmonary hemorrhage, edema and
histiocytosis.
(2) In another carcinogenicity study, Crl:CD-l(ICR)BR mice (95/sex/concentration) were
exposed (whole-body) to vinyl fluoride vapors at 0, 25, 250 or 2500 ppm for 6 hours/day, 5
days/week for 18 months. Survival was decreased in male mice at 250 and 2500 ppm and in
female mice in all treatment groups. Mean body weight gain was decreased by 17% in male
mice exposed to 2500 ppm. At necropsy, concentration-related lesions included nodules, masses
and discoloration of the lung; fluid in the pleural cavity; masses of the peritoneal cavity;
hemorrhage, cysts, masses, discoloration and nodules of the liver; and mammary gland masses.
Microscopically, these lesions were attributed to secondary effects of neoplasms; the combined
incidences for male and female mice at 0, 25, 250 and 2500 pm, respectively, are as follows:
bronchioloalveolar adenoma (20/162, 69/160, 99/160 and 109/162 ), bronchioloalveolar
hyperplasia (3/162, 22/160, 53/160 and 76/162), hepatic hemangiosarcoma (1/162, 29/161,
67/160 and 74/162), hepatocellular hyperplasia (2/162, 36/160, 80/160 and 73/162) and
mammary gland adenocarcinoma and hyperplasia (0/77, 22/76, 20/78 and 20/77). Early
mortality was primarily related to hemorrhage from hepatic hemangiosarcoma. Lesions
secondary to hemangiosarcoma-induced hemorrhage and hemolysis included increased
erythropoiesis in the spleen and bone marrow and eosinophilic droplets/pigment in renal tubular
epithelium. Acute necrosis in the liver was likely the result of acute tissue hypoxia following
hemorrhage into the peritoneal cavity. Metastatic hemangiosarcomas in the lungs were
associated with pulmonary hemorrhage, edema and histiocytosis.
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Conclusion: Acute inhalation toxicity of vinyl fluoride to mice is low. In 90-day repeated
inhalation toxicity studies in rats and mice, vinyl fluoride showed concentration-related increases
in cell proliferation in livers of all treated mice and rats, and in olfactory mucosa of mice at >
200 ppm; the NOAEC was not established. No specific reproductive toxicity studies are
available with vinyl fluoride; however, no effects on the reproductive organs were seen in the 90-
day inhalation study in rats. In an inhalation two-generation reproductive toxicity study in rats
with the supporting chemical, vinyl chloride, no effects on reproductive parameters were
observed at any concentration; the NOAEC for reproductive toxicity is 1100 ppm (highest
concentration tested). No developmental toxicity studies are available for vinyl fluoride. In
prenatal inhalation developmental toxicity studies in rats and mice with the supporting chemical,
vinyl chloride, the following treatment-related developmental effects were observed at 500 ppm
and above: increased fetal resorption, decreased corpora lutea/dam in rats, decreased live
fetuses/litter in mice, increased fetal loss or pregnancy wastage in rats, decreased fetal body
weight in rats and mice, increased fetal crown-rump length in rats, increased incidences of rib
spurs and dilated ureters in rats, increased incidences of unfused or delayed ossification of
sternebrae in mice and an increased incidence of delayed ossification of the skull in mice. The
NOAEC for maternal and developmental toxicity was not established in rats; the NOAEC for
maternal and developmental toxicity in mice is 50 ppm and 500 ppm, respectively. In rabbits
exposed to the supporting chemical vinyl chloride, decreased feed consumption, number of
corpora lutea per dam, number of implantations per dam and number of live fetuses per litter and
an increase in the incidence of delayed ossification were seen at 500 ppm but not at 2500 ppm;
the NOAEC for maternal and developmental toxicity was 2500 ppm (highest concentration
tested). Vinyl fluoride is mutagenic in bacteria and mammalian cells in vitro and it induced
chromosomal aberrations in vitro and in vivo. Vinyl fluoride showed no effects on
spermatocytes or germ cells in the unscheduled DNA synthesis and dominant lethal assays in
rats, respectively. Vinyl fluoride increased the incidence of tumors in rats and mice. The
International Agency for Research on Cancer (IARC) states that "for practical purposes, vinyl
fluoride should be considered to act similarly to the human carcinogen vinyl chloride".
Table 3. Summary of the Screening Information Data Set under the U.S. HPV Challenge
Program - Human Health Data
Endpoint
SPONSORED CHEMICAL
Vinyl fluoride
(75-02-5)
SUPPORTING CHEMICAL
Vinyl chloride
(75-01-4)
Acute Toxicity
Inhalation LCso
(ppm)
690,000

Repeated-Dose Toxicity
NOAEC/LOAEC
Inhalation (ppm)
NOAEC = Not established
LOAEC = 200

Reproductive Toxicity
NOAEC/LOAEC
(ppm)
No Data
NOAEC = 1100
(RA)
(rat; 2-gen)
NOAEC = 1100
(highest concentration tested)
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Table 3. Summary of the Screening Information Data Set under the U.S. HPV Challenge

Program - Human Health Data
Endpoint
SPONSORED CHEMICAL
SUPPORTING CHEMICAL

Vinyl fluoride
Vinyl chloride

(75-02-5)
(75-01-4)
Developmental Toxicity


NOAEC/LOAEC


Inhalation (ppm)
No Data
(rat)
Maternal Toxicity
NOAEC = Not established
NOAEC = Not established

LOAEC = 500
LOAEC = 500
Developmental Toxicity
NOAEC = 500
NOAEC = 500

LOAEC = 2500
LOAEC = 2500

(mouse)
(mouse)
Maternal Toxicity
NOAEC = 50
NOAEC = 50

LOAEC = 500
LOAEC = 500
Developmental Toxicity
NOAEC = 500
NOAEC = 500

LOAEC = 2500
LOAEC = 2500

(RA)



(rabbit)

(mouse)
NOAEC = 2500
Maternal Toxicity
NOAEC = 2500
(highest concentration tested)
Developmental Toxicity
NOAEC = 2500
NOAEC = 2500

(RA)
(highest concentration tested)
Genetic Toxicity - Gene Mutation


In vitro
Positive

Genetic Toxicity - Chromosomal


Aberrations
Positive
-
In vitro


Genetic Toxicity - Chromosomal


Aberrations
Positive
-
In vivo


Genetic Toxicity - Chromosomal


Aberrations


Other


UDS
Negative
-
Dominant Lethal
Negative
-
Additional Information


Carcinogenicity
Positive in rats and mice
-
Measured data in bold; RA = read-across; - indicates endpoint not addressed for this chemical
4. Hazard to the Environment
A summary of the ecotoxicity data for SIDS and other endpoints is provided in Table 4. The
table also indicates where data for supporting chemicals are read-across (RA) to untested
members of the category.
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Acute Toxicity to Fish
Vinyl chloride (CASRN 75-01-4, supporting chemical)
(1) Zebra fish (Brachydanio rerio) were exposed to vinyl chloride (> 99% purity) at nominal
concentrations of 0, 31, 63, 125, 250 or 500 mg/L under semi-static conditions for 96 hours.
Mean measured concentrations were 1.25, 34.9, 59.4, 128, 220 and 388 mg/L. All fish exposed
to 388 mg/L died within 48 hours and 70% of fish exposed to 220 mg/L died by 96 hours.
Aberrant behavior was observed after 3 hours of exposure to 220 and 388 mg/L.
96-h LCso = 210 mg/L
Acute Toxicity to Aquatic Invertebrates and Toxicity to Aquatic Plants
No adequate data are available for the sponsored or the supporting chemical.
Conclusion: The 96-h LCso value for fish exposed to vinyl fluoride is 210 mg/L, based on the
supporting chemical (vinyl chloride). Adequate aquatic invertebrate and algal toxicity test data
are not available for vinyl fluoride or vinyl chloride.
Table 4. Summary of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program -
Aquatic Toxicity Data
Endpoint
SPONSORED CHEMICAL
Vinyl Fluoride
(CASRN 75-02-5)
SUPPORTING CHEMICAL
Vinyl Chloride
(CASRN 75-01-4)
Fish
96-h LCso (mg/L)
No Data
210
(RA)
210
Aquatic Invertebrates
48-h ECso (mg/L)
No adequate data

Aquatic Plants
72-h ECso (mg/L)
(biomass)
No adequate data
-
Bold = experimental data (i.e., derived from testing); RA = read across; - indicates that endpoint was not
addressed for this chemical
5. References
10th Report on Carcinogens (2002) Report on carcinogens background document for vinyl
fluoride found at: http://ntp.niehs.nih.gov/ntp/newhomeroc/roclO/vf.pdf
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