FINAL

Report on Carcinogens

Background Document for

Vinyl Fluoride

Meeting of the

NTP Board of Scientific Counselors

Report on Carcinogens Subcommittee

Prepared for the:

U.S. Department of Health and Human Services

Public Health Services

National Toxicology Program

Research Triangle Park, NC 27709

Prepared by:

Technology Planning and Management Corporation

Canterbury Hall, Suite 310

4815 Emperor Blvd

Durham, NC 27703

Contract Number NOI-ES-85421

RoC Background Document for Vinyl Fluoride

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Criteria for Listing Agents, Substances or Mixtures in the Report on Carcinogens

US Department of Health and Human Services

National Toxicology Program

Known to be Human Carcinogens:

There is sufficient evidence of carcinogenicity from studies in humans which

indicates a causal relationship between exposure to the agent, substance or

mixture and human cancer.

Reasonably Anticipated to be Human Carcinogens:

There is limited evidence of carcinogenicity from studies in humans which

indicates that causal interpretation is credible but that alternative explanations

such as chance, bias or confounding factors could not adequately be excluded; or

There is sufficient evidence of carcinogenicity from studies in experimental

animals which indicates there is an increased incidence of malignant and/or a

combination of malignant and benign tumors: (1) in multiple species, or at

multiple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusual

degree with regard to incidence, site or type of tumor or age at onset; or

There is less than sufficient evidence of carcinogenicity in humans or laboratory

animals, however; the agent, substance or mixture belongs to a well defined,

structurally-related class of substances whose members are listed in a previous

Report on Carcinogens as either a known to be human carcinogen, or reasonably

anticipated to be human carcinogen or there is convincing relevant information

that the agent acts through mechanisms indicating it would likely cause cancer in

humans.

Conclusions regarding carcinogenicity in humans or experimental animals are based on

scientific judgment, with consideration given to all relevant information. Relevant

information includes, but is not limited to dose response, route of exposure, chemical

structure, metabolism, pharmacokinetics, sensitive sub populations, genetic effects, or

other data relating to mechanism of action or factors that may be unique to a given

substance. For example, there may be substances for which there is evidence of

carcinogenicity in laboratory animals but there are compelling data indicating that the

agent acts through mechanisms which do not operate in humans and would therefore not

reasonably be anticipated to cause cancer in humans.
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RoC Background Document for Vinyl Fluoride

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Summary Statement

Vinyl Fluoride

CASRN 75-02-5

Carcinogenicity

Vinyl fluoride (VF) is reasonably anticipated to be a human carcinogen based on

evidence of tumor induction at multiple organ sites in rats and mice. Inhalation exposure

of rats to vinyl fluoride resulted in increased incidences of hepatic hemangiosarcomas,

hepatocellular adenomas or carcinomas, and Zymbal gland carcinomas; inhalation

exposure of mice to VF resulted in increased incidences of hepatic hemangiosarcomas,

bronchiolar-alveolar adenomas or adenocarcinomas, hepatocellular adenomas, mammary

gland adenocarcinomas, and Harderian gland adenomas (Bogdanffy et al. 1995; IARC

1995). The tumor response to VF in laboratory animals is similar to the responses to vinyl

chloride, a known human carcinogen (NTP 1998; IARC 1987), and to vinyl bromide, a

probable human carcinogen (IARC 1986). A unique feature of vinyl chloride

carcinogenicity is the induction of rare hepatic hemangiosarcomas in rats and mice and

the causal association in epidemiological studies between vinyl chloride exposure and

excess risk of hemangiosarcoma of the liver (NTP 1998). The fact that VF, vinyl

chloride, and vinyl bromide induce rare hemangiosarcomas of the liver in experimental

animals and induce the formation of similar DNA adducts suggests a possible common

mechanism of carcinogenicity for these vinyl halides.

No studies on the potential carcinogenicity of VF in humans have been reported.

Other Information Relating to Carcinogenesis or Possible Mechanisms of

Carcinogenesis

VF is mutagenic in Salmonella typhimurium with metabolic activation (Dupont de

Nemours and Co 1992a). In addition, VF induces gene mutations and chromosomal

aberrations in Chinese hamster ovary cells (with metabolic activation), sex-linked

recessive lethal mutations in Drosophila melanogaster, and micronuclei in bone marrow

cells of female mice (IARC 1995).

The biotransformation pathway for VF 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. Human liver microsomes metabolize VF at a rate similar

to that of rat or mouse liver microsomes (Cantoreggi and Keller 1997).

VF metabolites form covalent DNA adducts. A dose-related increase in the formation of

the promutagenic adduct N2

,3-ethenoguanine was detected in liver DNA of rats and mice

exposed to VF by inhalation (Swenberg et al. 1995).
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No data are available that would suggest that mechanisms thought to account for tumor

induction by VF in experimental animals would not also operate in humans.
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Table of Contents

Criteria for Listing Agents, Substances or Mixtures in the Report on Carcinogens........................i

Summary Statement .......................................................................................................................iii

1 Introduction ............................................................................................................................... 1

1.1 Chemical identification .............................................................................................. 1

1.2 Physical-chemical properties...................................................................................... 1

1.3 Identification of metabolites....................................................................................... 2

2 Human Exposure....................................................................................................................... 5

2.1 Use.............................................................................................................................. 5

2.2 Production .................................................................................................................. 5

2.3 Analysis...................................................................................................................... 5

2.4 Environmental occurrence.......................................................................................... 5

2.5 Environmental fate ..................................................................................................... 5

2.5.1 Air ............................................................................................................... 5

2.5.2 Water........................................................................................................... 5

2.5.3 Soil .............................................................................................................. 6

2.6 Environmental exposure............................................................................................. 6

2.7 Occupational exposure ............................................................................................... 6

2.8 Biological indices of exposure ................................................................................... 6

2.9 Regulations................................................................................................................. 6

3 Human Cancer Studies.............................................................................................................. 9

4 Studies of Cancer in Experimental Animals ........................................................................... 11

4.1 Carcinogenesis studies of VF in mice...................................................................... 11

4.2 Carcinogenesis studies of VF in rats........................................................................ 12

4.3 Additional studies of VF carcinogenicity in animals............................................... 14

4.4 Summary .................................................................................................................. 14

5 Genotoxicity............................................................................................................................ 17

5.1 Prokaryotic systems.................................................................................................. 17

5.1.1 Induction of mutation in Salmonella typhimurium................................... 17

5.2 Eukaryotic systems................................................................................................... 17

5.2.1 Mutagenicity in Drosophila melanogaster ................................................ 17

5.3 Mammalian systems................................................................................................. 17

5.3.1 In vitro assays............................................................................................ 17

5.3.2 In vivo assays............................................................................................ 18

5.4 Summary .................................................................................................................. 19

6 Other Relevant Data................................................................................................................ 21

6.1 Absorption, metabolism, and excretion of VF ......................................................... 21

6.2 Alkylating properties and DNA adduct formation................................................... 23

6.3 Effects of VF on cell proliferation ........................................................................... 24
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6.4 Structure-activity relationship.................................................................................. 24

6.5 Summary .................................................................................................................. 26

7 References ............................................................................................................................... 27

Appendix A: IARC. (1995). Dry cleaning, Some Chlorinated Solvents and Other

Industrial Chemicals. Monographs on the Evaluation of the Carcinogenic Risk to

Humans. Vol. 63. World Health Organization. Lyon, France. A-1 – A-11............................ 33

Appendix B: IARC. (1986). Some Chemicals Used in Plastics and Elastomers.

Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans—

Some Chemicals used in plastics and elastomers. Vol 39. World Health

Organization. Lyon, France. pp. B-1 – B-10........................................................................... 35

List of Tables

Table 1-1. Physical and chemical properties of VF ....................................................................... 1

Table 2-1. U.S. EPA Regulations................................................................................................... 7

Table 4-1. Incidences of primary tumors of the liver, lung, mammary gland and

Harderian gland in mice exposed to VF gas for up to 18 months................................................. 12

Table 4-2. Tumor incidences in rats exposed to VF gas for up to two years............................... 14

Table 6-1. Summary of carcinogenesis, mutagenesis, and pharmacokinetics for VF, VB,

and VC........................................................................................................................................... 25

List of Figures

Figure 1-1. Structure of VF............................................................................................................ 1

Figure 1-2. Structure of fluoroethylene oxide................................................................................ 2

Figure 1-3. Structure of fluoroacetaldehyde .................................................................................. 2

Figure 1-4. Structure of fluoroacetic acid ...................................................................................... 2

Figure 6-1. Proposed metabolic pathway of VF .......................................................................... 22
RoC Background Document for Vinyl Fluoride

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1 Introduction

Vinyl fluoride (VF) was nominated for listing in the Report on Carcinogens (RoC) by the

National Institute of Environmental Health Sciences (NIEHS) RoC Review Group (RG1)

based on review of the 1995 International Agency for Research on Cancer (IARC)

monograph (IARC 1995) which indicates that there is sufficient evidence in experimental

animals for the carcinogenicity of VF and that it is probably carcinogenic to humans

(Group 2A).

1.1 Chemical identification

VF is a member of the vinyl halide class. VF and the other vinyl halides are used

ubiquitously in industry, especially in manufacture of plastics. They are easily

polymerized and copolymerized with various materials, such as acrylonitrile, vinyl

acetate, and styrene, to form pliable lightweight plastics or thermoplastic resins (HSDB

1995). VF (C2H3F, mol wt 46.044, CASRN 75-02-5) also is known as fluoroethene. It is

a colorless gas at ambient temperature and pressure and is highly flammable. VF is used

in the production of polyvinyl fluoride and other fluoropolymers and as an intermediate

in organic synthesis. The structure of VF is illustrated in Figure 1-1.

CH2

CH

F

Figure 1-1. Structure of VF

1.2 Physical-chemical properties

VF’s RTECS number is YZ7351000, and its UN number for shipping, is 1860. The

physical and chemical properties of VF are summarized in Table 1-1.

Table 1-1. Physical and chemical properties of VF

Property Information Reference

Molecular weight 46.04 CRC (1993)

Color colorless Lewis (1993)

Odor faint ethereal odor NIOSH (1994)

Physical state flammable gas CRC (1993)

Melting point (°C) -160.5 CRC (1993)

Boiling point (°C) at 750 mm -72 CRC (1993)

Specific gravity, at 21°C 0.636 (liquid) Kirk-Othmer (1991)

Relative vapor density (air = 1) 1.58 HSDB (1995)

Solubility in:

Water at 20°C

Alcohol

Ether

Acetone

insoluble

soluble

soluble

soluble

Sax (1979)

Sax (1979)

Sax (1979)

Lide (1994)
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1.3 Identification of metabolites

The major metabolites of VF are expected to be fluoroethylene oxide and

fluoroacetaldehyde, based on indirect evidence of metabolism similar to that of vinyl

chloride (VC) and vinyl bromide (VB); fluoroacetaldehyde can be further metabolized to

fluoroacetic acid (Cantoreggi and Keller 1997). In a manner analogous to metabolism of

VC (and VB), VF may initially be oxidized by microsomal monooxygenase(s) to

fluoroethylene oxide (C2H3FO, mol wt 122.95), the structure of which is shown in Figure

1-2 (Bolt 1988; Ballering et al. 1996). The structure of fluoroacetaldehyde (C2H3FO, mol

wt 62.044) is shown in Figure 1-3, and the structure of fluoroacetic acid (C2H3FO2, mol

wt 78.043, CASRN 144-49-0) is shown in Figure 1-4.

O

F

Figure 1-2. Structure of fluoroethylene oxide

CH 2 CH

F

O

Figure 1-3. Structure of fluoroacetaldehyde

CH2

C

OH

O

F

Figure 1-4. Structure of fluoroacetic acid

VF alkylates the prosthetic heme group of cytochrome P-450, and the alkylate has been

identified as N-(2-oxoethyl)protoporphyrin IX. This observation suggests a reaction of

heme with fluoroacetaldehyde (Ortiz de Montellano et al. 1982, cited in Cantoreggi and
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Keller 1997). It also is likely that incorporation of fluoroacetate into the citric acid cycle

disrupts energy metabolism and leads to increased production of mitochondrial

acetylcoenzyme A and hence excretion of ketone bodies and free fluoride. Administration

of VF has been shown to increase acetone exhalation by rats (Filser et al. 1982).
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2 Human Exposure

2.1 Use

VF is used mainly in the production of polyvinyl fluoride and other fluoropolymers.

Polymers of VF are resistant to weather and have great strength, chemical inertness, and

low permeability to air and water. Polyvinyl fluoride is laminated with aluminum,

galvanized steel, and cellulosic materials and is used as a protective surface for the

exteriors of residential and commercial buildings. Polyvinyl fluoride laminated with

various plastics has been used to cover walls, pipes, and electrical equipment and inside

aircraft cabins (IARC 1995).

2.2 Production

 E.I. du Pont de Nemours & Co. Inc. has been identified as the major manufacturer of VF

(HSDB 1995). VF was first prepared in the early 1900s by a reaction of zinc with 1,1-

difluoro-2-bromoethane . Modern preparation of VF involves a reaction of acetylene and

hydrogen fluoride in the presence of a mercury- or aluminum-based catalyst (IARC

1995). The U.S. Environmental Protection Agency (EPA), through the Office of

Pollution Prevention and Toxics, listed VF in the high production volume (HPV)

chemical list in 1990. U.S. EPA estimated the annual production volume for 1990 at 3.83

to 6.96 x 106

 lb (U.S.EPA 1990).

2.3 Analysis

Air samples collected in polytetrafluoroethylene bags can be sampled and analyzed for

VF concentrations by gas chromatography (GC) (IARC 1995, HSDB 1995).

2.4 Environmental occurrence

VF is not known to occur naturally (IARC 1995). Industrial release of VF during its use

and production may account for its presence in the environment (HSDB 1995).

2.5 Environmental fate

2.5.1 Air

VF exists in the vapor phase in the ambient atmosphere. VF reacts with photochemically

produced hydroxyl radicals, with an estimated half-life of about 1.5 days. VF also reacts

with atmospheric ozone, leading to its atmospheric degradation (estimated half-life of

about 16 days) (HSDB 1995).

2.5.2 Water

The major fate process for VF in water is volatilization. The half-lives for volatilization

from a model river (1 m deep) and a model pond (2 m deep) are 2 and 23.5 hours,

respectively. VF has a bioconcentration factor (BCF) of 4.7, and therefore is not expected

to bioconcentrate in aquatic organisms, as a BCF of greater than 1,000 is required for

significant bioaccumulation. Adsorption to sediment is not considered to be an important

fate process for VF in water (HSDB 1995).
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2.5.3 Soil

Because VF remains a gas under normal conditions, it will evaporate to the atmosphere

when released into soil. When dissolved in an aqueous solution, VF is very mobile in

soil. There are insufficient data to predict whether biodegradation is an important fate

process in soils that preclude evaporation (HSDB 1995).

2.6 Environmental exposure

Environmental exposure to VF occurs via inhalation, because VF released into the

environment exists as a gas (IPCS 1993).

2.7 Occupational exposure

Occupational exposure to VF occurs through inhalation (HSDB 1995). Dermal and eye

contact can occur among workers handling liquid VF; this type of contact will cause

frostbite (IPCS 1993).

VF was sampled in a manufacturing and polymerization plant in the United States. In

eight personal air samples taken at the manufacturing plant, concentrations of VF

generally were < 2 ppm (3.76 mg/m3

). In one personal sample, however, the

concentration of VF was 21 ppm (39.5 mg/m3

). VF concentrations in seven personal

samples taken in the polymerization plant ranged from 1 to 4 ppm (1.88 to 7.52 mg/m3

).

In four general working areas, the VF concentrations ranged from 1 to 5 ppm (1.88 to 9.4

mg/m3

) (IARC 1995).

The National Institute for Occupational Safety and Health (NIOSH) recommended an

exposure limit of 1 ppm (1.88 mg/m3

) as an eight-hour time-weighted average (TWA),

with a ceiling value of 5 ppm (9.4 mg/m3

) for short-term (15-minute) exposures (IARC

1995).

2.8 Biological indices of exposure

Simple fluoroalkenes, such as VF, are metabolized in humans, which leads to elevated

urinary excretion of free fluoride (the mechanism is discussed in Section 1.3 and 6.1)

(HSDB 1995).

2.9 Regulations

VF is regulated by U.S. EPA under the Clean Air Act to prevent accidental releases. It

has a threshold reporting quantity of 1,000 lb. VF also is regulated by U.S. EPA under the

Toxic Substances Control Act (TSCA), which requires health and safety studies to

determine risk of injury to human health or the environment. U.S. EPA regulations are

summarized in Table 2-1.
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Table 2-1. U.S. EPA Regulations

U.S. EPA Regulations

Regulatory action Effect of regulation and other comments

40 CFR 68—PART 68—CHEMICAL ACCIDENT

PREVENTION PROVISIONS. Promulgated: 59 FR

4493, 01/31/94. U.S. Codes: 42 U.S.C. 7412(r),

7601(a)(1), 7661-7661f.

This part lists regulated substances and thresholds, the petition

process for adding or deleting substances, and specific

requirements for preventing accidental releases. VF is

regulated as a flammable substance with a threshold quantity

of 1,000 lb for accidental release prevention.

40 CFR 716—PART 716—HEALTH AND SAFETY

DATA REPORTING. Promulgated: 51 FR 32726,

09/15/86. U.S. Codes: 15 U.S.C. 2607(d). The effective

date for VF is 10/04/82. The sunset date is 10/04/92.

The provisions of this part require the submission of lists and

copies of health and safety studies on chemical substances and

mixtures selected for priority consideration for testing rules

under section 4(a) of TSCA and on other chemicals for which

U.S. EPA requires health and safety information in fulfilling

the purposes of TSCA.

40 CFR 799—PART 799—IDENTIFICATION OF

SPECIFIC CHEMICAL SUBSTANCE AND

MIXTURE TESTING. Promulgated: 49 FR 39817,

10/10/84. U.S. Codes: 15 U.S.C. 2603, 2611, and 2625.

This part identifies VF as a chemical for which data are to be

developed to determine the risk of injury to human health or

the environment presented by this chemical. All persons who

manufacture VF, other than as an impurity, from July 22,

1987, to the end of the reimbursement period shall submit

letters of intent to conduct testing or exemption applications,

submit study plans, conduct tests in accordance with the TSCA

Good Laboratory Practice Standards (40 CFR part 792), and

submit data as specified in this section.

Source: These regulations in this table have been updated through the 1998 Code of Federal Regulations

40 CFR, July 1, 1996; 21 CFR, April 1, 1996; 29 CFR, July 1, 1996.
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3 Human Cancer Studies

No studies on the relationship of VF exposure to human cancer were available.
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4 Studies of Cancer in Experimental Animals

4.1 Carcinogenesis studies of VF in mice

An inhalation study in which Crl:CD-1(ICR)BR mice were exposed to VF at

concentrations of 0, 200, 2,000, or 20,000 ppm (equivalent to 0, 376, 3,760, or 37,600

mg/m3

) six hours/day, five days/week for approximately 90 days was used to establish

doses for a cancer bioassay in mice. In the range-finding study, results of hematological

assessments (after 45 and 90 days) and histopathological assessments revealed no

evidence of VF-associated toxicity. On day 93, groups of five mice per sex per exposure

level received infusions of [3

H]thymidine followed by five additional days of VF

exposure for measurement of cell proliferation in liver, kidney, lung, and nasal cavity

tissues. Exposure to VF caused hepatocellular proliferation, as indicated by increased

incorporation of [3

H]thymidine into hepatocytes. The magnitudes of the hepatocellular

proliferative responses were similar at 2,000 and 20,000 ppm. Exposure to VF at 20,000

ppm caused increased [3

H]thymidine incorporation into nasal olfactory epithelium in

male mice (Bogdanffy et al. 1990).

In the cancer bioassay (Bogdanffy et al. 1995), groups of 80 or 81 male and female

Crl:CD-1(ICR)BR mice, approximately 47 days of age, were exposed to VF (purity >

99.94%) by inhalation at concentrations of 0, 25, 250, or 2,500 ppm (0, 47, 470, or 4,700

mg/m3

) for six hours/day, five days/week for up to 18 months. Reduced survival of

exposed mice necessitated sacrifice of mice at various times between 375 and 550 days.

Animals in the 250- and 2,500-ppm groups were sacrificed when survival of the groups

reached approximately 25% (375 and 450 days for high-dose males and females and 412

and 459 days for mid-dose males and females, respectively). Surviving control and lowdose mice of both sexes were sacrificed at the scheduled study termination, 18 months.

The approximate survival rates for the control and low-dose groups were 58% and 22%,

respectively, for both sexes. All organs of control and high-dose-group animals were

examined microscopically; only the nose, lungs, liver, kidneys, gross lesions, and target

organs of animals in the other groups were subjected to microscopic evaluation.

The mice were evaluated after necropsy at intervals of 6, 12, 17 to 18, and 19 to 24

months. An early, significant increase in the incidence of lung tumors (bronchioalveolar

adenoma) was observed in males in the 250- and 2,500-ppm groups and in females in the

2,500-ppm group sacrificed at 6 months. Statistical analyses of the overall tumor

incidences were not conducted because of the varying durations of exposure to VF;

however, observations included exposure-related increases in incidences of pulmonary,

hepatic, and Harderian gland tumors in both sexes and mammary gland tumors in

females. Although the incidence of hepatocellular adenomas did not exhibit dosedependence, the increased tumor latency, increased multiplicity, and associated increase

in putatively preneoplastic basophilic foci led to the conclusion that the tumors observed

in males in the 25-ppm group were related to VF exposure.

Overall (aggregate) incidences of tumors in the lungs, liver, Harderian gland, and

mammary gland in animals sacrificed or found dead between 7 and 18 months are

summarized in Table 4-1.
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Table 4-1. Incidences of primary tumors of the liver, lung, mammary gland and

Harderian gland in mice exposed to VF gas for up to 18 months

Tumor incidence/number examined

Tumor type Concentration (ppm)

0 25 250 2500

Males

Lungs

Primary lung tumors 11/81 45/80 52/80 56/81

Bronchioalveolar adenoma 11/81 43/80 48/80 49/81

Bronchioalveolar adenocarcinoma 1/81 1/80 4/80 4/81

Liver

Hemangiosarcoma 1/81 16/80 42/80 42/81

Hepatocellular adenoma 7/81 15/80 5/80 3/81

Hepatocellular carcinoma 2/81 2/80 1/80 0/81

Harderian gland adenoma 3/80 13/79 12/80 31/80

Females

Lungs

Primary lung tumors 9/81 24/80 47/80 53/81

Bronchioalveolar adenoma 9/81 22/80 46/80 49/81

Bronchioalveolar adenocarcinoma 0/81 1/80 1/80 3/81

Liver

Hemangiosarcoma 0/81 13/81 25/80 32/81

Hepatocellular adenoma 0/81 0/81 1/80 0/81

Mammary gland

Adenoma 0/79 0/80 0/78 1/79

Adenocarcinoma 0/79 22/80 20/78 19/79

Adenoma, adenocarcinoma, fibroadenoma (combined) 0/77 22/76 20/78 20/77

Harderian gland adenoma 1/81 7/81 6/79 12/81

Source: Bogdanffy et al. (1995)

Based on the induction of liver hemangiosarcomas and bronchioalveolar adenomas in

both sexes of mice, mammary gland tumors in females, and Harderian gland adenomas in

males by VF in this study, IARC concluded that VF is carcinogenic to mice of both sexes

(IARC 1995).

4.2 Carcinogenesis studies of VF in rats

An inhalation study in which Sprague-Dawley rats were exposed to VF at concentrations

of 0, 200, 2,000, or 20,000 ppm (equivalent to 0, 376, 3,760, or 37,600 mg/m3

) six

hours/day, five days/week for 90 days was used to establish doses for a cancer bioassay

in rats. In the range-finding study, urinary excretion of fluoride was measured after 45

and 90 days of exposure to VF. Excretion of fluoride, indicative of VF metabolism,
RoC Background Document for Vinyl Fluoride

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appeared to reach a plateau at an exposure concentration of 2,000 ppm. Urinary excretion

of fluoride was greater in both sexes after 90 days of exposure than after 45 days. Results

of clinical chemical assessments, hematological assessments (after 45 or 90 days), and

histopathological assessments revealed no evidence of VF-associated toxicity.

Biochemical evidence of hepatocellular proliferation was observed in rats exposed to VF.

On day 93, groups of five rats per sex per exposure level received infusions of

[

3

H]thymidine followed by five additional days of VF exposure for measurement of cell

proliferation in liver, kidney, lung, and nasal cavity tissues. Exposure to VF at 2,000 or

20,000 ppm caused statistically significant increases in incorporation of [3

H]thymidine

into hepatocytes in both sexes. The effect of VF on [3

H]thymidine incorporation appeared

to plateau between exposure concentrations of 2,000 and 20,000 ppm (Bogdanffy et al.

1990).

In the cancer bioassay (Bogdanffy et al. 1995), groups of 95 male and 95 female

Sprague-Dawley rats (Crl:CDBR), approximately 40 days of age, were exposed by

inhalation to VF (purity > 99.94%) at concentrations of 0, 25, 250, or 2,500 ppm (0, 47,

470, or 4,700 mg/m3

) for six hours/day, five days/week for up to two years. Ten rats per

group were sacrificed on test days 275 and 276 for interim examination. Because of high

mortality, rats in the 250- and 2,500-ppm groups were sacrificed when the percentage of

surviving animals in each group reached approximately 25% (586 days and 657 days for

all surviving animals in the 2,500-and 250-ppm groups, respectively). All surviving

control and low-dose animals were sacrificed at the scheduled termination of the study

(two years). The survival rates for control and low-dose groups at the end of the study

were 30% and 25% (males) and 25% and 15% (females), respectively.

The rats were evaluated after necropsy at intervals of 0 to 12, 13 to 18, and 19 to 24

months. An early appearance of VF-induced tumors was observed in the 12 month

evaluation. Exposure to VF at 2,500 ppm for up to 12 months was associated with the

development of Zymbal gland carcinoma in both sexes. The incidence of Zymbal gland

carcinoma in high-dose males was statistically significant (Fisher’s exact test). Although

the incidence in females (4/18, 22%) was not significantly elevated, it was unusually high

for one-year-old rats and was probably due to VF administration.

Exposure of the rats to VF for up to two years caused increased incidence of

hemangiosarcomas of the liver, hepatocellular adenomas and carcinomas, and Zymbal

gland carcinomas. VF-associated reduced survival and/or saturation of VF metabolism

likely limited the induction of neoplasms in high-dose groups. The total tumor incidences

in rats exposed to VF for up to two years are summarized in Table 4-2.
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Table 4-2. Tumor incidences in rats exposed to VF gas for up to two years

Tumor incidence/number examined

Tumor type Concentration (ppm)

0 25 250 2500

Males

Liver

Hemangiosarcoma 0/80 5/80 30/80 20/80

Hepatocellular adenoma 1/80 4/80 4/80 4/80

Hepatocellular carcinoma 4/80 6/80 6/80 3/80

Zymbal gland

Carcinoma, sebaceous/squamous cell 0/80 2/51 3/49 11/80

Females

Liver

Hemangiosarcoma 0/80 8/80 19/80 15/80

Hepatocellular adenoma 0/80 4/80 9/80 5/80

Hepatocellular carcinoma 0/80 0/80 0/80 3/80

Zymbal gland

Carcinoma, sebaceous/squamous cell 0/80 0/50 1/49 12/80

Source: Bogdanffy et al. (1995)

Based on the increased incidence of liver hemangiosarcomas and Zymbal gland tumors in

both sexes of rats and an increased incidence of hepatocellular adenomas and carcinomas

in female rats resulting from exposure to VF in this study, IARC concluded that VF is

carcinogenic to rats of both sexes (IARC 1995).

4.3 Additional studies of VF carcinogenicity in animals

Similarly to vinyl chloride, VF induces the formation of preneoplastic ATPase-deficient

foci in newborn Wistar rats (Bolt et al. 1981).

4.4 Summary

VF is closely related to VC (known to be a human carcinogen) and VB (nominated as

reasonably anticipated to be a human carcinogen). The strong structural similarity

among the vinyl halides predicts similar biological effects. That prediction is verified by

the similarity of tumor response observed in carcinogenesis experiments conducted with

these agents.

Inhalation of VF increases the incidences of hemangiosarcomas in both sexes of mice and

rats, tumors of the lung and Harderian gland in male and female mice, and mammary

gland tumors in female mice. VF also increases the incidence of Zymbal gland

carcinomas and hepatocellular neoplasms in rats of both sexes. The interpretative value

of these data is strengthened by the facts that the tumor responses are dose-related and

that the spectrum of VF-induced neoplasms closely resembles that reported for VC

(Maltoni 1974, as cited in IARC 1979) and VB (IARC 1986). These findings, particularly
RoC Background Document for Vinyl Fluoride

15

the induction of rare hemangiosarcomas of the liver by these three vinyl halides, support

the conclusion that VF is reasonably anticipated to be a human carcinogen.
RoC Background Document for Vinyl Fluoride

16
RoC Background Document for Vinyl Fluoride

17

5 Genotoxicity

5.1 Prokaryotic systems

5.1.1 Induction of mutation in Salmonella typhimurium

VF was tested for the ability to induce his gene mutations in Salmonella typhimurium. In

a series of five assays, VF was tested in various S. typhimurium tester strains at exposure

concentrations of 0 to 52% with and without exogenous metabolic activation. VF 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 (Dupont de Nemours and Co. 1992a).

5.2 Eukaryotic systems

5.2.1 Mutagenicity in Drosophila melanogaster

5.2.1.1 Sex-linked recessive lethal assay

VF caused excessive sex-linked recessive lethal mutations in Drosophila melanogaster.

Males (N = 198) were exposed to VF at air concentrations of 47.6% for 24 hours and then

mated with untreated females. The progeny exhibited a significant increase (P < 0.01) in

the frequency of sex-linked recessive lethal mutations compared with controls. VF

exposure resulted in the production of 100 lethal mutations (2.4%) in the F2 progeny,

compared with 5 lethal mutations (0.08%) among F2 progeny of flies not exposed to VF.

Survivability among the VF-exposed males was 86.4%. Fertility was unaffected in the

surviving males (CMA 1988).

In its review of an abstract of a study conducted by Bentley et al. (1992, cited in IARC

1995), IARC stated that VF induced sex-linked recessive lethal mutations in Drosophila

melanogaster at exposure concentrations of 19.1% or 38.8% for six hours.

5.3 Mammalian systems

5.3.1 In vitro assays

5.3.1.1 hprt locus forward mutation test

VF induced hprt forward mutations in Chinese hamster ovary (CHO) cells in the

presence of metabolic activation by S9 liver homogenate from rats. CHO cells in

uncapped tissue culture flasks were exposed to VF gas concentrations of 0 to 100% in the

ambient environment of glass chambers for five hours (with S9 metabolic activation) or

for 18 to 19 hours (without S9 metabolic activation). VF was not mutagenic without

metabolic activation. However, VF was mutagenic at all concentrations (from 20% to

100%), causing statistically significant dose-related increases in mutant frequencies. Cell

survival was 62% in a preliminary non-activated cytotoxicity test at the highest VF

concentration tested (100%) (Dupont de Nemours and Co. 1992b).

In its review of an abstract of a study conducted by Bentley et al. (1992, cited in IARC

1995), IARC concluded that VF induced gene mutations in Chinese hamster ovary
RoC Background Document for Vinyl Fluoride

18

(CHO) cells with metabolic activation at exposure concentrations of 19.1% or 38.8% for

six hours.

5.3.1.2 Chromosomal aberrations

CHO cells were incubated with VF at target concentrations of 0, 10%, 40%, 70%, or

100% for five hours without rat S9 metabolic activation or with VF at target

concentrations of 0, 10%, 25%, 50%, or 75% VF for two hours with rat S9 metabolic

activation. Statistically significant increases in chromosomal aberrations (CA) occurred at

VF levels of 10%, 25%, and 50% with metabolic activation. Significant increases in CA

were observed only at the highest concentration without S9 metabolic activation. A

second trial used concentrations of VF at 0, 12.3%, 35.4%, 63.3%, or 91.3% with

metabolically activated CHO cells. Statistically significant increases in CA frequency

were induced at the 35.4% and 63.3% VF concentrations (Dupont de Nemours and Co.

1986).

In its review of an abstract of a study conducted by Bentley et al. (1992, cited in IARC

1995), IARC concluded that VF induced CA in CHO cells with metabolic activation at

exposure concentrations of 19.1% or 38.8% for six hours.

5.3.2 In vivo assays

5.3.2.1 Chromosomal aberrations

Dominant lethal test (rat)

Groups of 40 male Crl:CDBR rats were exposed by inhalation to VF at concentrations

of 0, 200, 2,000, or 20,000 ppm (0, 376, 3,760, or 37,600 mg/m3

) six hours/day for five

days and then mated with unexposed females. No statistically significant treatmentrelated differences in pre- or post-implantation losses were found in females mated with

males exposed to VF at any concentration. No males died in the study (Dupont de

Nemours and Co. 1988).

Mammalian bone marrow cytogenetic test (metaphase analysis)

VF gave equivocal results in males and positive results in females for induction of

micronuclei in bone marrow polychromatic erythrocytes (PCEs) of 43-day-old CD-1

mice. The mice were exposed by inhalation to mean VF concentrations of 0, 50,100,

191,000, or 388,000 ppm (0, 94,348, 359,689, or 730,678 mg/m3

) for 24, 48, or 72 hours.

At the 24-hour sampling time, no single test resulted in a significant increase of

micronucleated PCEs above control values. However in female mice, a statistically

significant trend was observed of concentration-related increases in the proportion of

micronucleated PCEs. No statistically significant increases in micronucleated PCEs or

concentration-related trends were observed at the 48- and 72-hour sampling times.

Increases in the frequency of micronucleated PCEs in males in the 50,100- and 388,000-

ppm exposure groups at the 24-, 48-, and 72-hour sampling times were not statistically

significant. The frequency of micronucleated PCEs in female mice showed a significant

concentration-related increase at the 191,000- and 388,000- ppm exposure levels,

confirmed by scoring of additional PCEs. No significant depression of the ratio of PCEs

to normochromatic erythrocytes was seen in the VF-exposed mice (Dupont de Nemours

and Co. 1987).
RoC Background Document for Vinyl Fluoride

19

In its review of an abstract of a study conducted by Bentley et al. (1992, cited in IARC

1995), IARC concluded that VF induced micronuclei in bone marrow cells of female

mice at exposure concentrations of 19.1% or 38.8% for six hours. VF did not induce

unscheduled DNA synthesis in pachytene spermatocytes or single strand breaks or crosslinks in testicular DNA of male mice.

DNA single strand breaks

Testicular-cell DNA from groups of male Sprague-Dawley rats tested by nose-only

inhalation exposure to VF at 0 or (2%) 20,000 ppm (37,600 mg/m3

) for six hours/day for

one, two, or five consecutive days showed no significantly increased frequencies of

single strand breaks or cross-links (Dupont de Nemours and Co. 1991).

In its review of an abstract of a study conducted by Bentley et al. (1992, cited in IARC

1995), IARC concluded that VF did not induce unscheduled DNA synthesis in pachytene

spermatocytes, nor single strand breaks or cross-links in testicular DNA of male mice.

5.4 Summary

VF is mutagenic and clastogenic. VF, VC, and VB are genotoxic chemicals requiring

metabolic activation to similar DNA-reactive intermediates. VF is a base-pair substitution

mutagen in S. typhimurium strain TA1535. VF induces excessive sex-linked recessive

lethal mutations in D. melanogaster, induces hprt forward mutations in CHO cells with

rat S9 metabolic activation, and is clastogenic in CHO cells in vitro. In an assay for

induction of micronucleated PCEs in female mice in vivo, VF gave equivocal results, and

it failed to induce single strand breaks or cross-links in DNA when tested in vivo in rats.
RoC Background Document for Vinyl Fluoride

20
RoC Background Document for Vinyl Fluoride

21

6 Other Relevant Data

6.1 Absorption, metabolism, and excretion of VF

VF is readily absorbed after inhalation (Filser and Bolt 1980, 1981, cited in IARC 1995).

The metabolic process appears to be saturable and dose-dependent. An early estimate

indicated that metabolic saturation occurred at inhalation concentrations in excess of 75

ppm (140 mg/m3

) in rats (Filser and Bolt 1980, cited in IARC 1995). Pharmacokinetic

data imply that the rate of biotransformation of VF is about one-fifth that of VC (Bolt et

al. 1981). VF is metabolized faster than VB, but slower than VC (Bolt et al. 1982).

Available evidence suggests that VF is metabolized via the same pathway as VC and VB.

VC and VB are metabolized to haloacetaldehydes. Based upon VC metabolism, it also is

likely that fluoroacetaldehyde is metabolized to fluoroacetic acid, a potent inhibitor of the

Krebs cycle. Incorporation of fluoroacetate into the citric acid cycle disrupts energy

metabolism and leads to increased production of mitochondrial acetyl coenzyme A and,

hence, excretion of ketone bodies. Administration of VF has been shown to increase

acetone exhalation by rats (Filser et al. 1982). The results of experiments reported by

Cantoreggi and Keller (1997) are consistent with hepatic oxidative metabolism of VF. In

the study, mice and rats were exposed to VF in a closed chamber gas uptake system. VF

uptake was monitored from the chamber. Mice were observed to have a higher metabolic

rate for VF than rats (6.5 vs. 2.2 μmol/hr per kilogram body weight). Inhibition of the

cytochrome P-450 enzyme CYP 2E1 by administration of 4-methylpyrazole completely

impaired VF metabolism in both species. CYP 2E1 induction in rats (by administration of

ethanol) increased metabolic capacity.

The proposed metabolic pathway for VF, similar to the pathways for its vinyl halide

analogs VC and VB, is illustrated in Figure 6-1 (Bolt 1988; Ballering et al. 1996).
RoC Background Document for Vinyl Fluoride

22

X

Vinyl halide

O

X

Haloethylene oxide

N N

N

N

HN

O

(R)

Minor adduct: 3,N2-ethenoguanine

HN N

H2N N

O

CHO

N

+

DNA-d-rib-DNA

Major adduct: 7-(2-oxoethyl)-guanine

Oxidation

O

X

O

HO

O

X

DNA

O

X OH

Glycoaldehyde

GSH

C

H2

O

HO

S C

H2 OH

O

Haloacetic acid Thiodiglycolic acid-urinary metabolite

Acetylhalide Haloacetaldehyde

X= F, Br, or Cl

RNA N

N

O N

3,N4-Ethenocytosine

Rib.

+

Rib.

N

N

N

N N

1,N6-Ethenoadenosine

Figure 6-1. Proposed metabolic pathway of VF

Source: Bolt 1986, 1988 and Ballering et al. 1996.

VF toxicity is mediated via epoxide formation. Oxidative metabolism of inhaled VF in

the presence of Aroclor 1254 (a hepatic cytochrome P-450 inducer) resulted in enhanced

toxicity (Conolly et al. 1978, cited in Cantoreggi and Keller 1997). In addition,

administraton of trichloropropylene oxide (an inhibitor of epoxide hydrolase) also

increased VF toxicity (Conolly and Jaeger 1977, cited in Cantoreggi and Keller 1997).

Cantoreggi and Keller (1997) demonstrated that microsomes from mice metabolized VF

more rapidly than those from rats (Vmax = 3.5 and 1.1 nmol/hr per milligram protein,

respectively) when rat or mouse liver hepatic microsomes were exposed to VF gas in

closed chambers in the presence of an NADPH-regenerating system. Disappearance of

VF gas from the incubation headspace was monitored,which was consistent with the

results from the in vivo experiment. Microsomes from human livers were found to

metabolize VF at a rate similar to that for rat or mouse liver microsomes. Among ten

human livers tested, Vmax ranged from 0.57 to 3.3 nmol/hr per milligram protein. Vmax

values were directly related to microsomal content of CYP 2E1.

Urinary excretion of fluoride was determined in rats exposed to 0, 200, 2,000 or 20,000

ppm VF (0, 376, 3,760, or 37,600 mg/m3

) for six hours/day, five days/week, after 45 and

90 days of exposure. Urinary fluoride concentrations were dose-related at both time
RoC Background Document for Vinyl Fluoride

23

periods, but were nonlinear, with a plateau appearing at approximately 2,000 ppm (for

both sexes). The appearance of a plateau was taken as evidence of metabolic saturation. It

also was noted that urinary fluoride concentrations were consistently higher, after 90 days

of exposure to VF than after 45 days. Increased excretion of fluoride after 90 days of VF

exposure may reflect hepatic enzyme induction or saturation of deposition sites

(Bogdanffy et al. 1990).

6.2 Alkylating properties and DNA adduct formation

Although the metabolism of VF is largely unknown, it has been demonstrated that the

action of monooxygenase on VF produces fluoroethylene (fluorooxirane, a reactive

epoxide intermediate) (see Figure 6-1) (Bolt et al. 1982; Cantoreggi and Keller 1997).

This is analogous to the mechanism for the metabolic production of chloroethylene

(chlorooxirane) from the VF analog VC (Bolt et al. 1982).

Comparative molecular orbital studies show that the three-membered ring of

fluorooxirane has more tension and is less stable than that of chlorooxirane, although it is

less reactive to tissue macromolecules than chlorooxirane. The order of reactivity of vinyl

halide-derived haloethylene oxides (halooxiranes) with tissue macromolecules has been

proposed to be VC > VF > VB (Bolt et al. 1982).

VF alkylates the prosthetic heme group of cytochrome P-450, and the alkylate has been

identified as N-(2-oxoethyl)protoporphyrin IX. This observation suggests a reaction of

heme with fluoroacetaldehyde (Ortiz de Montellano et al. 1982, cited in Cantoreggi and

Keller 1997).

The VF analog VC induces the formation of DNA adducts 7-(2′-oxoethyl)guanine, N2

,3-

ethenoguanine, 3,N4

-ethenocytosine, and 1,N6-ethenoadenine (Bartsch et al. 1994,

Guengerich 1994, both cited in La and Swenberg 1996). Similarly, inhaled VF in both

rats and mice results in the formation of N2

,3-ethenoguanine in liver DNA. The formation

of this adduct reaches a plateau at exposure concentrations of approximately 250 ppm in

both species, indicating metabolic saturation at this exposure (Swenberg et al. 1995). The

transition mutation in the K-ras gene, activated by a GC to AT transition at the second

base of codon 13 in five of six VC-induced tumors in humans, is consistent with the

known miscoding properties of N2

,3-ethenoguanine and 3,N4-ethenocytosine (La and

Swenberg 1996). Accordingly, VF-DNA adducts are analogous to those identified as

promutagenic adducts resulting from exposure to VC (Bolt et al. 1982). The adduct

predominantly formed is 7-(2′-oxoethyl)guanine (over 98%). However, the mutagenic

effects of VC may be driven by the formation of the minor DNA adducts N2

,3-

ethenoguanine, 3,N4

-ethenocytosine, and 1,N6-ethenoadenine. These adducts efficiently

induce GC to AT, GC to TA, and AT to GC transitions, respectively (Barbin et al. 1981,

Spengler and Singer 1981, Singer et al. 1984, 1987, 1991, Cheng et al. 1991,

Mroczkowska and Kusmierek 1991, and Basu et al. 1993 all cited in La and Swenberg

1996). Although the major DNA adduct, 7-(2′-oxoethyl)guanine, is not involved in base

pairing, its removal may result in an apurinic site that can lead to a mutation (La and

Swenberg 1996).
RoC Background Document for Vinyl Fluoride

24

6.3 Effects of VF on cell proliferation

Male and female rats and female mice exposed to VF by inhalation exhibited small but

significantly increased rates of [3

H]thymidine incorporation into hepatocytes. This

observation indicates a proliferative response to the chemical (Bogdanffy et al. 1990).

In this experiment, animals were exposed to VF in air at concentrations of 0, 200, 2,000

or 20,000 ppm (0, 376.6, 3,766.4, or 37,664 mg/m3

) for six hours/day, five days/week for

90 days. On day 93, the animals were implanted with osmotic mini-pumps containing

[

3

H]thymidine and exposed for five more days. Tritium incorporation into trachea, lungs,

nose, liver, and kidneys was measured. High-dose female mice exhibited a significant

increase in mean labeling index of hepatocytes whereas high-dose male mice had a

significantly elevated labeling index of the olfactory nasal epithelium. Although the mean

hepatocyte-labeling index in high-dose male mice was elevated relative to controls, the

range of measurements was highly variable, and the difference was not statistically

significant. Exposure of male and female rats to VF at 2,000 or 20,000 ppm caused

significant increases in hepatocyte labeling. The magnitude of response at 20,000 ppm

was similar to that observed at 2,000 ppm.

During assessment of VF carcinogenicity, Bogdanffy et al. (1995) attempted to confirm

their earlier demonstration of the cellular proliferative effect of VF in mice and rats. In

these experiments, a pulse label with 5-bromodeoxyuridine (BrdU) revealed no evidence

of cellular proliferation. The researchers concluded that the proliferative response

reported earlier might have been too subtle for detection with the less sensitive BrdU

pulse labeling technique.

6.4 Structure-activity relationship

The metabolism of VF probably proceeds through the same pathway as that of VC (a

known human carcinogen) and the probable human carcinogen VB. VF is less rapidly

metabolized than either VC or VB (Bolt et al. 1982). The metabolic process appears to be

saturable, as observed for VC. Pharmacokinetic data imply that the rate of

biotransformation of VF in rats is about one fifth that of VC (Bolt et al. 1981).

The spectrum of neoplasms produced by the three vinyl halides in mice and rats is

strikingly similar. Table 6-1 summarizes the information available on carcinogenesis,

mutagenesis, and metabolism of the three vinyl halides.
RoC Background Document for Vinyl Fluoride

25

Table 6-1. Summary of carcinogenesis, mutagenesis, and pharmacokinetics for VF,

VB, and VC

Study VF VB VC

Animal carcinogenicity

Types of tumors formed

Hepatic hemangiosarcoma rats, micea ratsb rats, micec

Extrahepatic hemangiosarcoma   rats, miced

Hepatocellular carcinoma ratse ratsb 

Hepatocellular adenoma rats, micee  ratsd

Zymbal gland carcinoma  ratsb ratsd

Bronchioalveolar adenoma and

adenocarcinoma rats, micee  

Harderian gland adenocarcinomas micee  

Mammary gland adenocarcinomas micee  miced

Oncogene activation

Oncogenicity (formation of ATPasedeficient hepatic foci in newborn rats positivef positiveg positiveh

Mutagenicity

Prokaryotic cells in vitro positivei positivej positived

D. melanogaster in vivo positivek positivel positived

Mammalian cells in vitro positivem na positived

Mammalian bone marrow test in vivo positiven na positiveo

Pharmacokinetics

Metabolism

Metabolism by rat liver microsomes Vmax = 1.1 nmol/hr-mg

proteinp

na Vmax = 280.4

nmol/hr-mg

proteinq

Metabolism by mouse liver microsomes Vmax = 3.5 nmol/hr-mg

proteinp

na na

Metabolism by human liver microsomes Vmax = 0.5-3.3 nmol/hr-mg

proteinp

na na

Detection of free ions in urine positiver positiver positiver

Detection of acetone in exhaled air in

rats

positives positives positives

Distribution (air partition coefficients)p

Blood (rats) 0.75 ± 0.09 4.05 ± 0.16 1.68 ± 0.18

Liver (rats) 0.83 ± 0.58 3.33 ± 0.38 1.60 ± 0.17

Muscle (rats) 0.54 ± 0.28 2.26 ± 0.13 2.10 ± 0.45

Fat 1.82 ± 0.15 49.2 ± 1.3 20.0 ± 0.7
RoC Background Document for Vinyl Fluoride

26

Study VF VB VC

Alkylating properties

Reactive intermediates and formation of

DNA adducts

7-(2′-oxoethyl)guanine, N 2

, 3-ethenoguaninet

7-(2′-

oxoethyl)guanine;

N 2

, 3-ethenoguanineu

7-(2′-

oxoethyl)guanin

e;

N 2

, 3-

ethenoguaninev

;

3, N 4-

ethenocytosine;

1, N 6

-

ethenoadenineu

, Not reported; na, Not available a

Bogdanffy et al. 1995, IARC 1995 lVogel and Nivard 1993, Ballering et al. 1996. b

IARC 1986 mDupont de Nemours and Co 1992b, IARC 1995 c

IARC 1979, NTP 1998 nDupont de Nemours and Co 1987, IARC 1995 d

IARC 1979 oRichardson et al. 1983 e

Bogdanffy et al. 1995 pCantonreggi and Keller 1997 f

Bolt et al. 1981 qel Ghisassi et al. 1998 g

Bolt et al. 1979 rDilley et al. 1974 h

Laib et al. 1985 sFilser et al. 1982 i

Dupont de Nemours and Co 1992a tSwenberg et al. 1995

j

IARC 1986, Roldan-Arjona et al. 1991 uBolt et al. 1988 k

CMA 1988, IARC 1995 vSwenberg et al. 1992

6.5 Summary

The information available on VF metabolism, DNA reactivity of its metabolites, and the

spectrum of tumor induction in rats and mice suggests that VF is a genotoxic carcinogen.

The metabolism of VF probably proceeds through the same pathway as that of the known

human carcinogen VC and the probable human carcinogen VB. Metabolism of VC and

VB results in the production of reactive metabolites that bind to proteins and nucleic

acids. All three vinyl halide congeners are active in genotoxicity assays. Inhalation

exposure to each congener produces unequivocal carcinogenicity in rats and mice of both

sexes. The three vinyl halides produce a similar array of neoplasms in mice and rats.
RoC Background Document for Vinyl Fluoride

27

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28. Filser, J.G., P. Jung, and H.M. Bolt. (1982). Increased acetone exhalation induced by

metabolites of halogenated C1 and C2 compounds. Arch Toxicol 49:107-116.

29. Guengerich, F. (1994). Mechanisms of formation of DNA-adducts from ethylene

dihalides, vinyl halides, and arylamines. Drug Metab Rev 26:47-66.

30. HSDB. (1995). Hazardous Substances Data Bank -- CAS# 75-02-5. MEDLARS

Online Information Retrieval System, National Library of Medicine.

31. IARC. (1979). Some Monomers, Plastics and Synthetic Elastomers, and Acrolein.

IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to

Humans. Vol. 19. Lyon, France, World Health Organization.

32. IARC. (1986). Some Chemicals Used in Plastics and Elastomers. Vinyl Fluoride.

IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to

Humans. Vol. 39, pp. 147-154 Lyon, France, World Health Organization.

33. IARC. (1987). Overall Evaluations of Carcinogenicity: An Updating of IARC

Monographs Volumes 1 to 42. IARC Monographs on the Evaluation of the

Carcinogenic Risk of Chemicals to Humans Suppl 7. Lyon, France. World Health

Organization.

34. IARC. (1995). Dry cleaning, Some Chlorinated Solvents and Other Industrial

Chemicals. Vinyl Fluoride. IARC Monographs on the Evaluation of the Carcinogenic

Risk of Chemicals to Humans. Vol. 63, pp. 467-475. Lyon, France, World Health

Organization.

35. IPCS. (1993). Vinyl Fluoride. International Chemical Safety Cards.

http://www.cdc.gov/niosh/ipcs/ipcs0598.html , International Programme on Chemical

Safety & the Commission of the European Communities.

36. Kirk-Othmer. (1991). Kirk-Othmer Encyclopedia of Chemical Technology. 4th

ed.(1), -p.684 New York, NY., John Wiley and Sons.

37. La, D.K. and J.A. Swenberg. (1996). DNA adducts: Biological markers of exposure

and potential applications to risk assessment. Mutat Res 365:129-146.

38. Laib, R.J., K.P. Klein, and H.M. Bolt. (1985). The rat liver foci bioassay: I. Agedependence of induction by vinyl chloride of ATPase-deficient foci. Carcinogenesis

6:65-68.

39. Lewis, R. J., Sr. (1993). Hawley's Condensed Chemical Dictionary. Lewis, R. J., Sr.

12th ed. New York, Van Nostrand Reinhold.

40. Lide, D. R. (1994). CRC Handbook of Chemistry and Physics. Lide, D. R. 75th ed., -

p.163 Boca Raton, Fl, CRC Press, Inc.

41. Maltoni, C. (1974). Vinyl chloride carcinogenesis: current results and perspectives.

Med Lav 65:421-444.

42. Mroczkowska, M. and J.T. Kusmierek. (1991). Miscoding potential of n-2,3-

ethenoguanine studied in an Escherichia-coli DNA-dependent RNA-polymerase in

vitro system and possible role of this adduct in vinyl chloride-induced mutagenesis.

Mutagenesis 6:385-390.
RoC Background Document for Vinyl Fluoride

30

43. NIOSH. (1994). NIOSH Pocket Guide to Chemical Hazards. (94-116) Washington,

D.C., U.S. Department of Health and Human Services.

44. NTP. (1998). Eighth Report on Carcinogens (Summary).Vinyl Chloride (CAS No.

75-01-4). http://ntp-server.niehs.nih.gov/htdocs/8_RoC/KC/VinylChloride.html ,

National Toxicology Program.

45. Ortiz de Montellano, P., K.L. Kunze, H.S. Beilan, and C. Wheeler. (1982).

Angiosarcoma of the liver in workers exposed to vinyl chloride. First two cases found

in Italy (Ital.). Med Lav 65:445-450.

46. Richardson, C.R., J.A. Styles, and I.P. Bennett. (1983). Activity of vinyl chloride

monomer in the mouse micronucleus assay. Mutat Res 122:139-142.

47. Roldan-Arjona, T., P.M. Garcia, R.F. Luque, C. Hera, and C. Pueyo. (1991). An

association between mutagenicity of the Ara test of Salmonella typhimurium and

carcinogenicity in rodents for 16 halogenated aliphatic hydrocarbons. Mutagenesis

6:199-205.

48. Sakai, K., M. Fukuba, Y. Hasui, K. Moriyoshi, T. Ohmoto, T. Fujita, and T. Ohe.

(1998). Purification and characterization of an esterase involved in poly(vinyl

alcohol) degradation by Pseudomonas vesicularis PD. Biosci Biotechnol Biochem

62:2000-2007.

49. Sax. (1979). Dangerous Properties of Industrial Materials. Sax, N. I. and Lewis, R. J.,

Sr. 5th ed. New York, Van Nostrand Reinhold.

50. Scheller, N.A., A. Ranasinghe, S. Kim, S. Holt, M.S. Bogdanffy, and J.A. Swenberg.

(1995). High resolution GC/MS detection of N2,3-ethenoguanine in livers of control

and vinyl fluoride exposed B6C3F1 mice. Int Toxicologist 7:21.(Abstract)

51. Singer, B., L.G. Abbott, and S. Spengler. (1984). Assessment of mutagenic efficiency

of two carcinogen-modified nucleosides, 1,N6-ethenodeoxyadenosine and O4-

methyldeoxythymidine, using polymerases of varying fidelity. Carcinogenesis

5:1165-1171.

52. Singer, B., J.T. Kusmierek, W. Folkman, F. Chavez, and M.K. Dosanjh. (1991).

Evidence for the mutagenic potential of the vinyl-chloride induced adduct, n-2, 3-

etheno-deoxyguanosine, using a site- directed kinetic assay. Carcinogenesis 12:745-

747.

53. Singer, B., S.J. Spengler, F. Chavez, and J.T. Kusmierek. (1987). The vinyl chloridederived nucleoside, n2,3-ethenoguanosine, is a highly efficient mutagen in

transcription. Carcinogenesis 8:745-747.

54. Spengler, S. and B. Singer. (1981). Transcriptional errors and ambiguity resulting

from the presence of 1,N6-ethenoadenosine or 3,N4-ethenocytidine in

polyribonucleotides. Nucleic Acids Res 9:365-373.

55. Swenberg, J., T.R.F. N.Fedtke, and V.E.Walker. (1990). Relationships between

carcinogen exposure, DNA adducts and carcinogenesis. In D.B.Clayson, I.C.Munro,

P.Shubik, and J.A.Swenberg, editors. Elsevier, Amsterdam. 161-184.
RoC Background Document for Vinyl Fluoride

31

56. Swenberg, J.A., N. Fedtke, F. Ciroussel, A. Barbin, and H. Bartsch. (1992). Etheno

adducts formed in DNA of vinyl chloride-exposed rats are highly persistent in liver.

Carcinogenesis 13(4):727-729.

57. Swenberg, J.A., D.K. La, N.A. Scheller, and K.-Y. Wu. (1995). Dose-Response

Relationships for Carcinogens. Toxicol Lett 82/83:751-756.

58. U.S. EPA. (1990). Vinyl Fluoride (CAS# 75-02-5).

http://www.epa.gov/opptintr/chemrtk/opptsrch.htm Washington, DC., U.S.

Environmental Protection Agency, Office of Pollution Prevention and Toxics.

59. U.S. EPA. (1996). Toxic Release Inventory for 1996.

http://toxnet.nlm.nih.gov/servlets/simple-search?1.15.1.2358 (& type CAS# 75-02-5),

U.S. EPA TRIFacts.

60. Vogel, E.W. and M.J. Nivard. (1993). Performance of 181 chemicals in a Drosophila

assay predominantly monitoring interchromosomal mitotic recombination.

Mutagenesis 8:57-81.

61. Walles, S.A., B. Holmberg, K. Svensson, S. Osterman-Golkar, K. Sigvardsson, and

K. Lindblom. (1988). Induction of single-strand breaks in liver DNA of mice after

inhalation of vinyl chloride. IARC Sci Publ 227-231.
RoC Background Document for Vinyl Fluoride

32
RoC Background Document for Vinyl Fluoride

33

Appendix A: IARC. (1995). Dry cleaning, Some

Chlorinated Solvents and Other Industrial Chemicals.

Monographs on the Evaluation of the Carcinogenic Risk

to Humans. Vol. 63. World Health Organization. Lyon,

France. pp. 467-475.
 RoC Background Document for Vinyl Fluoride

34
–467– 

VINYL FLUORIDE

This substance was considered by previous working groups, in June 1985 and March 1987 

(IARC, 1986, 1987a). Since that time, new data have become available, and these have been 

incorporated into the monograph and taken into consideration in the present evaluation.

1. Exposure Data 

1.1 Chemical and physical data 

1.1.1 Nomenclature

Chem. Abstr. Serv. Reg. No.: 75-02-5 

Chem. Abstr. Name: Fluoroethene

IUPAC Systematic Name: Fluoroethylene

Synonyms: 1-Fluoroethene; 1-fluoroethylene; monofluoroethene; monofluoroethylene

1.1.2 Structural and molecular formulae and relative molecular mass 

C C

H

F

H

H

C2H3F Relative molecular mass: 46.04 

1.1.3 Chemical and physical properties of the pure substance 

 (a) Description: Colourless gas (Ebnesajjad & Snow, 1994) 

 (b) Boiling-point: –72.2 o

C (Lide, 1993) 

 (c) Melting-point: –160.5 oC (Lide, 1993) 

 (d) Spectroscopy data: Infrared (prism [30864]; grating [48458P]) and mass [15] spectral 

data have been reported (Sadtler Research Laboratories, 1980; Weast & Astle, 1985). 

 (e) Solubility: Slightly soluble in water (1.1% by weight) (PCR Inc., 1994); soluble in 

acetone, ethanol and diethyl ether (Sax & Lewis, 1989; Lide, 1993) 

 (f) Volatility: Vapour pressure, 370 psi [2553 kPa] at 21 o

C (Ebnesajjad & Snow, 1994); 

relative vapour density (air = 1), 1.6 (PCR Inc., 1994) 

 (g) Stability: Lower explosive limit (in air), 2.6% (PCR Inc., 1994); polymerizes freely; 

forms explosive mixtures with air (Buckingham, 1982); ignites in the presence of heat 

or sources of ignition (Sax & Lewis, 1989) 
468 IARC MONOGRAPHS VOLUME 63 

 (h) Reactivity: Reacts with alkali and alkaline earth metals, powdered aluminium, zinc and 

beryllium (PCR Inc., 1994) 

 (i) Conversion factor: mg/m3

 = 1.88 × ppm1 

1.1.4 Technical products and impurities 

Vinyl fluoride is available commercially at a purity of 99.9%; 0.1% d-limonene (see IARC, 

1993) is added as a stabilizer (PCR Inc., 1994). 

1.1.5 Analysis 

Vinyl fluoride has been determined in workplace air collected in poly(tetrafluoroethylene) 

bags and analysed by gas chromatography (Oser, 1980). Nonspecific methods involving fluorescence spectrophotometry and chemiluminescence have been reported (Quickert et al., 1975; 

Sutton et al., 1979). 

1.2 Production and use 

1.2.1 Production 

Vinyl fluoride was first prepared from 1,1-difluoro-2-bromoethane, with zinc as the catalyst, in Belgium in the early 1900s. Modern production involves direct addition of hydrogen 

fluoride to acetylene in the presence of mercury- or aluminium-based catalysts (Brasure, 1980). 

In the past, vinyl fluoride was produced by dehydrofluorination of 1,1-difluoroethane or by 

direct conversion of ethylene (see IARC, 1994) in the presence of a carbon catalyst impregnated 

with palladium and copper chloride (Brasure, 1980; Siegmund et al., 1988). Dehydrochlorination of 1-chloro-1-fluoroethane and 1-chloro-2-fluoroethane is used commercially (Siegmund 

et al., 1988). 

Vinyl fluoride is produced by one company each in Japan and the United States of America 

(Chemical Information Services, Inc., 1994). 

1.2.2 Use

The main use of vinyl fluoride is in the production of polyvinyl fluoride and other fluoropolymers. Polyvinyl fluoride was first prepared in the 1930s (Brasure, 1980) and was introduced 

commercially in the United States in 1961 (Ebnesajjad & Snow, 1994). It is converted into a thin 

film by plasticized melt extrusion (Brasure, 1980) and is sold under the trademarks Tedlar PVF 

film and Dalvor (Siegemund et al., 1988). 

Polymers of vinyl fluoride are characterized by strong resistance to weather, great strength, 

chemical inertness and low permeability to air and water. Polyvinyl fluoride laminated with 

aluminium, galvanized steel and cellulosic materials has been used as a protective surfacing for 

the exteriors of residential and industrial buildings. Laminations with various plastics have also 

_______________ 

1

 Calculated from: mg/m3 = (relative molecular mass/24.45) × ppm, assuming normal temperature (25 °C) and 

pressure (101 kPa) 
 VINYL FLUORIDE 469 

been used as protective coverings on walls, pipes and electric equipment and inside aircraft 

cabins (Cohen & Kraft, 1971; Brasure, 1980). 

Use of vinyl fluoride in the Member States of the European Union in 1991 was estimated at 

about 3600 tonnes (Environmental Chemicals Data and Information Network, 1993). 

1.3 Occurrence 

1.3.1 Natural occurrence 

Vinyl fluoride is not known to occur as a natural product. 

1.3.2 Occupational exposures 

Vinyl fluoride was determined in a manufacturing and a polymerization plant in the United 

States. The concentrations in eight samples taken at the manufacturing plant were generally 

< 2 ppm [3.76 mg/m3

], but a level of 21 ppm [39.5 mg/m3] was reported in one personal sample. 

The concentrations in seven personal samples taken in the polymerization plant were 1–4 ppm 

[1.88–7.52 mg/m3

], and those in four general area samples were 1–5 ppm [1.88–9.4 mg/m3] 

(Oser, 1980). 

1.4 Regulations and guidelines 

In most countries, exposure limits have not been recommended (ILO, 1991). The United 

States National Institute for Occupational Safety and Health (1994) recommended an exposure 

limit of 1 ppm [1.88 mg/m3

] as an 8-h time-weighted average, with a ceiling value of 5 ppm [9.4 

mg/m3

] for short-term (15-min) exposure. 

2. Studies of Cancer in Humans 

No data were available to the Working Group. 

3. Studies of Cancer in Experimental Animals 

Inhalation 

Mouse: Groups of 95 male and 95 female Swiss-derived mice, 47 days of age, were 

exposed to 0, 25, 250 or 2500 ppm [0, 47, 470 or 4700 mg/m3

] vinyl fluoride (purity, > 99.94%) 

for 6 h per day on five days per week for up to 550 days. Ten mice per group were killed at six 

months for interim evaluation. All surviving mice were killed at various times between 375 and 

550 days because of early, dose-related mortality. Animals were necropsied, and all organs were 

preserved for histological examination. All organs of control animals and those at the high dose 

were examined; only the nose, lungs, liver, kidneys, gross lesions and target organs of animals in 
470 IARC MONOGRAPHS VOLUME 63 

the other groups were examined microscopically. The overall incidences of primary lung 

tumours (predominantly alveolar–bronchiolar adenomas) were 11/81 male controls, 45/80 at 

25 ppm, 52/80 at 250 ppm and 56/81 at 2500 ppm; and 9/81 female controls, 24/80 at 25 ppm, 

47/80 at 250 ppm and 53/81 at 2500 ppm. Fatal hepatic haemangiosarcomas occurred in 1/81, 

16/80, 42/80 and 42/81 males and 0/81, 13/81, 25/80 and 32/81 females in the four groups, 

respectively. Mammary gland neoplasms (adenoma, adenocarcinoma and fibroadenoma) 

occurred in 0/77 control females, 22/76 at 25 ppm, 20/78 at 250 ppm and 20/77 at 2500 ppm. 

Harderian gland adenomas occurred in 3/66 control males, 13/68 at 25 ppm, 12/66 at 250 ppm 

and 31/62 at 2500 ppm (killed between 7 and 18 months). The authors did not perform statistical 

analyses because of the differences in the times of killing in the various groups (Bogdanffy 

et al., 1995). 

Rat: Groups of 95 male and 95 female Sprague-Dawley-derived rats, 40 days of age, were 

exposed to 0, 25, 250 or 2500 ppm [0, 47, 470 or 4700 mg/m3

] vinyl fluoride (purity, > 99.94%) 

for 6 h per day on five days per week for 725 days. Ten rats per group were killed at 271–276 

days (although the interim kill had been scheduled for 12 months), and surviving rats were killed 

at various times between 552 and 725 days. Animals were necropsied, and organs were 

preserved for histological examination. All organs of control animals and those at the high dose 

were examined; only the nose, lungs, liver, kidneys, gross lesions and target organs of animals in 

the other groups were examined microscopically. Increased incidences of tumours were seen at 

several sites (Table 1). The authors did not perform statistical analyses because of the 

differences in the times of killing in the various groups (Bogdanffy et al., 1995). 

Table 1. Tumour incidences in Fischer 344 rats exposed to vinyl fluoride by 

inhalation for two years

Sex Target organ Control 25 ppm 

[47 mg/m3

] 

250 ppm 

[470 mg/m3] 

2500 ppm 

[4700 mg/m3] 

Males Hepatic haemangiosarcomas 0/81 5/80 30/80 20/80 

 Zymbal gland tumours 0/80 2/80 3/80 11/80 

 Hepatocellular adenomas 

 and carcinomas 

5/80 10/80 10/80 7/80 

Females Hepatic haemangiosarcomas 0/80 8/80 19/80 15/80 

 Zymbal gland tumours 0/80 0/80 1/80 12/80 

 Hepatocellular adenomas 

 and carcinomas 

0/80 4/80 9/80 8/10 

From Bogdanffy et al. (1995) 
 VINYL FLUORIDE 471 

4. Other Data Relevant to an Evaluation of Carcinogenicity 

and its Mechanisms 

4.1 Absorption, distribution, metabolism and excretion 

4.1.1 Humans 

No data were available to the Working Group. 

4.1.2 Experimental systems 

The metabolism and toxicity of vinyl fluoride have been reviewed (Kennedy, 1990). 

Vinyl fluoride is readily absorbed after its inhalation and reaches a tissue concentration in 

rats that is 90% of that in the inhaled air (Filser & Bolt, 1979, 1981). The metabolism is 

saturable and dose-dependent, saturation occurring at concentrations > 75 ppm (> 140 mg/m3

) 

(Filser & Bolt, 1979). Pharmacokinetic data imply that the rate of biotransformation of vinyl 

fluoride is about one-fifth that of vinyl chloride (Bolt et al., 1981). 

Fluoride appears to be a metabolite of vinyl fluoride as it is found in the urine six days after 

exposure (Dilley et al., 1974). The fluoride concentrations in the urine of rats were found to be 

increased 45 and 90 days after exposure by inhalation to 0, 200, 2000 or 20 000 ppm [373, 3733 

or 37 333 mg/m3

] vinyl fluoride for 6 h per day, five days per week for about 90 days. A plateau 

was observed at about 2000 ppm [3733 mg/m3

], suggesting saturation of vinyl fluoride 

metabolism (Bogdanffy et al., 1990). When rats and mice were exposed to 0, 25, 250 or 

2500 ppm [0, 47, 470 or 4700 mg/m3

] vinyl fluoride for two years and 18 months, respectively, a 

plateau of urinary fluoride excretion was seen at ≥ 250 ppm (Bogdanffy et al., 1995). 

4.2 Toxic effects 

4.2.1 Humans 

Vinyl fluoride may burn the skin and eyes and may cause headache or dizziness (United 

States National Library of Medicine, 1994). 

4.2.2 Experimental systems 

The acute lethality of vinyl fluoride is so low that concentrations can be increased to the 

point at which oxygen becomes limiting (Lester & Greenberg, 1950; Kopecný et al., 1964; 

Clayton, 1967). 

Rats were exposed to vinyl fluoride at 3000 ppm [5640 mg/m3

] for 30 min and followed for 

seven days thereafter. Increased urine output and potassium excretion were observed at various 

times (Dilley et al., 1974). [The Working Group noted that the control values on some days were 

similar to those that were significantly different from control values on other days.] 

Groups of 15 male and 15 female rats and mice were exposed to vinyl fluoride at concentrations of 0, 200, 2000 or 20 000 ppm [0, 375, 3750 or 37 500 mg/m3

] for 6 h per day, on five 

days per week for 90 days. No significant changes in histopathological or haematological parameters or in clinical chemistry were found at 45 days or at the end of the 90-day exposure 
472 IARC MONOGRAPHS VOLUME 63 

(Bogdanffy et al., 1990). Rats and mice exposed to vinyl fluoride by inhalation at 0, 25, 250 or 

2500 ppm [47, 470 or 4700 mg/m3

] also showed no changes in these measures (Bogdanffy et al., 

1995). The survival of the exposed mice and rats was decreased, however, such that, after early 

sacrifices, only control animals and those receiving the lowest dose were available for clinical 

evaluation. Liver-cell proliferation, measured as the labelling index in animals implanted with 

osmotic minipumps containing 3

H-thymidine, was increased in rats and mice of each sex at all 

concentrations in one study (Bogdanffy et al., 1990) but not in a subsequent study with interim 

sampling for cell proliferation (Bogdanffy et al., 1995), owing perhaps to use of a less sensitive 

technique in the later study. 

Increased exhalation of acetone has been reported to be due to the effects of vinyl fluoride 

on intermediary metabolism (Filser et al., 1982). Intermediate metabolites of vinyl fluoride have 

been shown to alkylate the haem group of cytochrome P450 enzymes in vitro, suggesting 

potential inhibition of the metabolism of other substances (Ortiz de Montellano et al., 1982). 

Exposure of rats to vinyl fluoride at 10 000 ppm [18 800 mg/m3

] after pretreatment with 

Aroclor 1254 resulted in liver damage (Conolly et al., 1978). Treatment of newborn rats with 

2000 ppm [3760 mg/m3

] vinyl fluoride for 8 h per day, on five days per week for 14 weeks 

resulted in increased numbers of preneoplastic foci in their livers (Bolt et al., 1981). 

4.3 Reproductive and prenatal effects 

No data were available to the Working Group. 

4.4 Genetic and related effects 

As reported in an abstract, vinyl fluoride induced gene mutations and chromosomal 

aberrations in Chinese hamster ovary cells in the presence of an exogenous metabolic system, 

sex-linked recessive lethal mutations in Drosophila melanogaster and micronuclei in polychromatic erythrocytes from the bone marrow of female mice exposed to 19.1 or 38.8% vinyl 

fluoride for 6 h. No unscheduled DNA synthesis was seen in pachytene spermatocytes, no single 

strand breaks or cross-links in testicular DNA and no dominant lethal mutations in male rats 

(Bentley et al., 1992). 

4.5 Structure–activity relationship 

Vinyl fluoride bears a close structural relationship to vinyl chloride (see IARC, 1987b). 

5. Summary and Evaluation 

5.1 Exposure data 

Vinyl fluoride has been produced commercially since the 1960s for use in the production of 

polyvinylfluoride and fluoropolymers. Human exposure may occur during its production and 

use. 
 VINYL FLUORIDE 473 

5.2 Human carcinogenicity data 

No data were available to the Working Group. 

5.3 Animal carcinogenicity data 

Vinyl fluoride was tested for carcinogenicity in one experiment in mice and one experiment 

in rats by inhalation. It produced haemangiosarcomas in the liver and alveolar–bronchiolar 

adenomas in mice of each sex, mammary tumours in females and Harderian gland adenomas in 

males. In rats, it produced haemangiosarcomas of the liver and Zymbal gland tumours in animals 

of each sex and an increased incidence of hepatocellular adenomas and carcinomas in females. 

5.4 Other relevant data 

Vinyl fluoride is readily absorbed after administration by inhalation. Its metabolism is 

saturable and dose-dependent. Vinyl fluoride has very low acute toxicity. High doses produced 

no measurable toxic effects after subchronic exposure. Survival was decreased after chronic 

exposure, but no other toxic effects were seen in surviving animals. 

5.5 Evaluation1

There is inadequate evidence in humans for the carcinogenicity of vinyl fluoride. 

There is sufficient evidence in experimental animals for the carcinogenicity of vinyl 

fluoride. 

 Overall evaluation 

Vinyl fluoride is probably carcinogenic to humans (Group 2A). 

In making the overall evaluation, the Working Group took into account the following 

evidence: Vinyl fluoride is closely related structurally to the known human carcinogen, vinyl 

chloride. The two chemicals cause the same rare tumour (hepatic haemangiosarcoma) in 

experimental animals, which is also a tumour caused by vinyl chloride in humans. 

6. References 

Bentley, K.S., Mullin, L.S., Rickard, L.B., Vlachos, D.A., Sarrif, A.M., Sernau, R.C., Brusick, D.J. & 

Curren, R.D. (1992) Vinyl fluoride: mutagenic in mammalian somatic cells in vitro and in vivo and 

in Drosophila germ cells but nongenotoxic in germ cells of mammals (Abstract). Environ. mol. 

Mutag., 19 (Suppl. 20), 5 

_______________ 

1 For definition of the italicized terms, see Preamble. 
474 IARC MONOGRAPHS VOLUME 63 

Bogdanffy, M.S., Kee, C.R., Kelly, D.P., Carakostas, M.C. & Sykes, G.P. (1990) Subchronic inhalation 

study with vinyl fluoride: effects on hepatic cell proliferation and urinary fluoride excretion. 

Fundam. appl. Toxicol., 15, 394–406 

Bogdanffy, M.S., Makovec, G.T. & Frame, S.R. (1995) Inhalation oncogenicity bioassay in rats and 

mice with vinyl fluoride. Fundam. appl. Toxicol. (in press) 

Bolt, H.M., Laib, R.J. & Klein, K.-P. (1981) Formation of pre-neoplastic hepatocellular foci by vinyl 

fluoride in newborn rats. Arch. Toxicol., 47, 71–73 

Brasure, D.E. (1980) Poly(vinyl fluoride). In: Mark, H.F., Othmer, D.F., Overberger, C.G., Seaborg, 

G.T. & Grayson, N., eds, Kirk-Othmer Encyclopaedia of Chemical Technology, 3rd Ed., Vol. 11, 

New York, John Wiley & Sons, pp. 57–64 

Buckingham, J., ed. (1982) Dictionary of Organic Compounds, 5th Ed., Vol. 3, New York, Chapman 

and Hall, p. 2649 

Chemical Information Services, Inc. (1994) Directory of World Chemical Producers 1995/1996 

Standard Edition, Dallas, TX, p.706 

Clayton, J.W., Jr (1967) Fluorocarbon toxicity and biological action. Fluorine Chem. Rev., 1, 197–252 

Cohen, F.S. & Kraft, P. (1971) Vinyl fluoride polymers. In: Bikales, N.M., ed., Encyclopedia of Polymer 

Science and Technology, Vol. 14, New York, Wiley Interscience, pp. 522–540 

Conolly, R.B., Jaeger, R.J. & Szabo, S. (1978) Acute hepatotoxicity of ethylene, vinyl fluoride, vinyl 

chloride, and vinyl bromide after Aroclor 1254 pretreatment. Exp. mol. Pathol., 28, 25–33 

Dilley, J.V., Carter, V.L., Jr & Harris, E.S. (1974) Fluoride ion excretion by male rats after inhalation of 

one of several fluoroethylenes or hexafluoropropene. Toxicol. appl. Pharmacol., 27, 582–590 

Ebnesajjad, S. & Snow, L.G. (1994) Poly(vinyl fluoride). In: Kroschwitz, J.I. & Howe-Grant, M., eds, 

Kirk-Othmer Encyclopedia of Chemical Technology, 4th Ed., Vol. 11, New York, John Wiley & 

Sons, pp. 683–694 

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update: 02.09.1993 

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123–136 

Filser, J.G. & Bolt, H.M. (1981) Inhalation pharmacokinetics based on gas uptake studies. I. Improvement of kinetic models. Arch. Toxicol., 47, 279–292 

Filser, J.G., Jung, P. & Bolt, H.M. (1982) Increased acetone exhalation induced by metabolites of halogenated C1 and C2 compounds. Arch. Toxicol., 49, 107–116 

IARC (1986) IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, 

Vol. 39, Some Chemicals used in Plastics and Elastomers, Lyon, pp. 147–154 

IARC (1987a) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Suppl. 7, Overall 

Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1–42, Lyon, p. 73 

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Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1–42, Lyon, pp. 373–

376 

IARC (1993) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 56, Some 

Naturally Occurring Substances: Food Items and Constituents, Heterocyclic Aromatic Amines and 

Mycotoxins, Lyon, pp. 135–162 

IARC (1994) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 60, Some 

Industrial Chemicals, Lyon, pp. 45–71 
 VINYL FLUORIDE 475 

ILO (1991) Occupational Exposure Limits for Airborne Toxic Substances: Values of Selected Countries 

(Occupational Safety and Health Series No. 37), 3rd Ed., Geneva 

Kennedy, G.L., Jr (1990) Toxicology of fluorine-containing monomers. Crit. Rev. Toxicol., 21, 149–170 

Kopecný, J., Lúcanská, N., Šipka, F., Cerný, E. & Ambros, D. (1964) Toxicity of vinyl fluoride. Pracov. 

Lék., 16, 310–311 (in Polish) 

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methane and ethane. Arch. ind. Hyg. occup. Med., 2, 335–344 

Lide, D.R., ed. (1993) CRC Handbook of Chemistry and Physics, 74th Ed., Boca Raton, FL, CRC Press, 

pp. 3–518, B-25 

Ortiz de Montellano, P.R., Kunze, K.L., Beilan, H.S. & Wheeler, C. (1982) Destruction of cytochrome 

P-450 by vinyl fluoride, fluroxene, and acetylene. Evidence for a radical intermediate in olefin 

oxidation. Biochemistry, 21, 1331–1339 

Oser, J.L. (1980) Extent of industrial exposure to epichlorohydrin, vinyl fluoride, vinyl bromide and 

ethylene dibromide. Am. ind. Hyg. Assoc. J., 41, 463–468 

PCR Inc. (1994) Material Safety Data Sheet: Vinyl Fluoride, Gainesville, FL 

Quickert, N., Findlay, W.J. & Monkman, J.L. (1975) Modification of a chemiluminescent ozone monitor 

for the measurement of gaseous unsaturated hydrocarbons. Sci. total Environ., 3, 323–328 

Sadtler Research Laboratories (1980) 1980 Cumulative Index, Philadelphia, PA 

Sax, N.I. & Lewis, R.J. (1989) Dangerous Properties of Industrial Materials, 7th Ed., New York, Van 

Nostrand Reinhold, p. 3476 

Siegmund, G., Schwertfeger, W., Feiring, A., Smart, B., Behr, F., Vogel, H. & McKusick, B. (1988) 

Fluorine compounds. In: Gerhartz, W., Yamamoto, Y.S., Elvers, B., Rounsaville, J.F. & Schulz, G., 

eds, Ullmann’s Encyclopedia of Industrial Chemistry, 5th Ed., Vol. A11, New York, VCH 

Publishers, pp. 349–392 

Sutton, D.G., Westberg, K.R. & Melzer, J.E. (1979) Chemiluminescence detector based on active 

nitrogen for gas chromatography of hydrocarbons. Anal. Chem., 51, 1399–1401 

United States National Institute for Occupational Safety and Health (1994) NIOSH Pocket Guide to 

Chemical Hazards (DHHS (NIOSH) Publ. No. 94-116), Cincinnati, OH, pp. 330–331 

United States National Library of Medicine (1994) Hazardous Substances Data Bank (HSDB), 

Bethesda, MD 

Weast, R.C. & Astle, M.J. (1985) CRC Handbook of Data on Organic Compounds, Vols I & II, Boca 

Raton, FL, CRC Press, pp. 433, 624 (I), 591, 770 (II) 
RoC Background Document for Vinyl Fluoride

35

Appendix B: IARC. (1986). Some Chemicals Used in

Plastics and Elastomers. Monographs on the Evaluation

of the Carcinogenic Risk of Chemicals to Humans – 

Some Chemicals used in plastics and elastomers. Vol

39. World Health Organization. Lyon, France. pp. 147 – 154.
RoC Background Document for Vinyl Fluoride

36
147 

VINYL FLUORIDE

1. Chemical and Physical Data 

1.1 Synonyms and trade names 

Chem. Abstr. Services Reg. No.: 75-02-5 

Chem. Abstr. Name: Ethene, fluoroIUPAC Systematic Name: Fluoroethylene 

Synonyms: Monofluoroethylene; VF; vinyl fluoride, monomer 

1.2 Structural and molecular formulae and molecular weight 

C2H3F Mol. wt: 46.05 

1.3 Chemical and physical properties of the pure substance 

(a) Description: Colourless gas with an ethereal odour (Brasure, 1980); Sax, 1984) 

(b) Boiling-point: –72.2°C (Weast, 1984) 

(c) Melting-point: –160.5°C (Weast, 1984) 

(d) Density: Liquid density, 0.620 g/cm3

 at 25°C (Brasure, 1980) 

(e) Spectroscopy data: Infrared (Sadtler Research Laboratories,1980; prism [30864a

], 

grating [48458P]) and mass spectral data (NIH/EPA Chemical Information System, 

1983) have been reported. 

 

a

 Spectrum number in Sadtler compilation 

CH2 CH F
148 IARC MONOGRAPHS VOLUME 39 

(f) Solubility: Insoluble in water; soluble in ethanol and diethyl ether (Hawley, 1981; 

Sax, 1984, Weast, 1984); soluble in acetone (Weast, 1984) 

(g) Volatility: Vapour pressure, 25 atm (19 000 mg Hg) at 21°C (Brasure, 1980) 

(h) Stability: Polymerizes freely; forms explosive mixtures with air (Buckingham, 

1982); ignites in presence of heat or sources of ignition (Sax, 1984) 

(i) Conversion factor: mg/m3

 = 1.88 × ppma 

1.4 Technical products and impurities 

Vinyl fluoride is not available commercially in bulk quantities, although it is produced 

and used internally by one company in the USA (US Environmental Protection Agency, 

1981). It is relatively unreactive, in comparison to other monomers, and requires high 

pressure, temperatures of 60-140°C and free radical catalysts for polymerization. However, 

for storage purposes, stabilizers such as terpenes (D-limonene) are added to prevent 

spontaneous polymerization (Cohen & Kraft, 1971; Grayson, 1985). Vinyl fluoride is 

available with a purity of 99% (Weiss, 1980) 

2. Production, Use, Occurrence and Analysis 

2.1 Production and use 

(a) Production 

Vinyl fluoride is produced by the addition of hydrogen fluoride to acetylene in the 

presence of mercury catalysts. In another method, 1,1-difluoroethane (also formed by the 

addition of hydrogen fluoride to acetylene) is pyrolysed to vinyl fluoride. Vinyl fluoride has 

been produced in the USA since 1962 (US Environmental Protection Agency, 1980). No 

data were available on the quantities of vinyl fluoride produced in 1983. 

(b) Use 

Vinyl fluoride is used to produce polyvinyl fluoride and other fluoropolymers. Since 

vinyl fluoride is less reactive than vinyl chloride, free-radical polymerization with peroxidetype catalysts requires high pressures (4350-14500 psi; 300-1000 atm) and moderate 

 

a

 Calculated from: mg/m3 = (molecular weight/24.45) × ppm, assuming standard temperature (25°C) and 

pressure (760 mm Hg) 
 VINYL FLUORIDE 149 

temperatures (60-140°C) (Grayson, 1985). The introduction of commercial polyvinyl 

fluoride by E. I. duPont de Nemours, Inc. in 1962 (US Environmental Protection Agency, 

1980) was aided by the development of a Ziegler-Natta catalyst that allowed polymerization 

at lower temperatures and pressures (Cohen & Kraft, 1971). 

Homopolymers and copolymers made from vinyl fluoride show exceptional resistance to 

chemical attack and water absorption. They are quite stable at relatively high temperatures 

and are highly stable when exposed to sunlight. Polyvinyl fluoride is used as a protective 

and decorative surface for building panels and sidings, as a protective cover for pipes 

(Cohen & Kraft, 1971) and electrical equipment (US Environmental Protection 

Agency,1980), for insulating storage tanks, as a top coat on wall coverings, on interior finish 

in commercial aeroplanes, and as a surface for highway markers. Polyvinyl fluoride film 

does not fracture when the material to which it is bonded expands or contracts (Cohen & 

Kraft, 1971). 

(c) Regulatory status and guidelines 

The US National Institute for Occupational Safety and Health (1978, 1983) has 

recommended that exposure to vinyl halides be restricted to the minimum detectable level, 

with the eventual goal of zero exposure. It has recommended an exposure limit of 2 mg/m3

as an eight-hour time-weighted average, with a ceiling value of 10 mg/m3

 for any 15-min 

sampling period. 

2.2 Occurrence 

(a) Natural occurrence 

It is not known whether vinyl fluoride occurs as a natural product. 

(b) Occupational exposure 

Surveys made at a vinyl fluoride manufacturing plant and a vinyl fluoride 

polymerization plant (Table 1) showed that exposure levels for production and control 

operations were generally < 4 mg/m3

, while exposures associated with polymer operations 

ranged from 2-9 mg/m3

, with a time-weighted average of 3.6 mg/m3 (Bales, 1978; Oser, 

1980). 

2.3 Analysis 

Vinyl fluoride has been determined in workplace air (1-9 mg/m3

) by collection in 

poly(tetrafluoroethylene) bags and analysis by gas chromatography (Bales, 1978). 
150 IARC MONOGRAPHS VOLUME 39 

Table 1. Occupational exposures to vinyl fluoride at manufacturing and 

polymerization plantsa

Industry Job classification Type of sample Concentration 

(mg/m3

)

b

Manufacturing Plant operator 

Control room 

Plant operator(start-up) 

Personal 

Area 

Personal 

< 4 

< 4 

40 

Polymerization Polymer operator 

Supervisor 

Pumproom 

Personal 

Area 

Area 

2-8 

2-4 

9 a

From Bales (1978); Oser (1980) 

b

Eight-hour time-weighted average samples 

3. Biological Data Relevant to the Evaluation of 

Carcinogenic Risk to Humans 

3.1 Carcinogenicity studies in animals 

No data on the carcinogenicity of vinyl fluoride were available to the Working Group. 

3.2 Other relevant biological data 

(a) Experimental systems 

Toxic effects 

The available data indicate that the acute inhalation toxicity of vinyl fluoride in rats and 

mice cannot be determined due to the occurrence of asphyxia (Lester & Greenberg, 1950; 

Kopečný et al., 1964; Clayton, 1967). 

Rats pretreated with Aroclor 1254 for three consecutive days and then exposed to 18 000 

mg/m3

 (10 000 ppm) vinyl fluoride for 4 h had significantly increased serum levels of 

alanine-α-ketoglutarate transaminase and histological signs of acute hepatotoxicity (Conolly 

et al., 1978). 

Newborn Wistar rats exposed to 4000 mg/m3

 (2100 ppm) vinyl fluoride for 8 h per day 

on five days per week for 4-14 weeks developed ATPase-deficient foci in the liver (Bolt 

et al., 1981), but to an extent about 20-fold lower than was seen after similar exposure to 

vinyl 
 VINYL FLUORIDE 151 

chloride (Bolt et al., 1979). This may be attributable to the slower metabolism of vinyl 

fluoride under inhalation conditions. 

Effects on reproduction and prenatal toxicity 

No data were available to the Working Group. 

Absorption, distribution, excretion and metabolism 

In rats, vinyl fluoride was readily taken up via the pulmonary route and, at equilibrium, 

reached a concentration in the entire organism which was 90% of that in the gas phase. 

Metabolism was saturable after exposure to concentrations greater than 140 mg/m3

 (75 ppm) 

(Filser & Bolt, 1979, 1981) and was associated with the release of fluoride into the urine 

(Dilley et al., 1974). The rate of metabolism was much slower than that of vinyl chloride or 

vinyl bromide under similar exposure conditions (Filser & Bolt, 1979). 

When incubated with liver microsomes from phenobarbital-treated rats, vinyl fluoride 

alkylates the prosthetic group (haem) of cytochrome P-450. The alkylated moiety has been 

identified as the dimethyl ester of N-(2-oxoethyl)protoporphyrin IX (Ortiz de Montellano et 

al., 1982). 

Like other halogenated C1 and C2 compounds that are transformed to reactive 

metabolites, vinyl fluoride causes changes in rat intermediary metabolism which lead to 

increased exhalation of acetone (Filser et al., 1982). 

Mutagenicity and other short-term tests 

No data were available to the Working Group. 

(b) Humans 

No data were available to the Working Group. 

3.3 Case reports and epidemiological studies of carcinogenicity to humans 

No data were available to the Working Group. 

4. Summary of Data Reported and Evaluation 

4.1 Exposure data 

Vinyl fluoride has been produced commercially since 1962 by a single company, as an 

intermediate, for use within the company. It is used to produce polyvinyl fluoride and other 

fluoropolymers. Occupational exposure is limited to the manufacture of the monomer and 

its conversion polymers. 
152 IARC MONOGRAPHS VOLUME 39 

4.2 Experimental data 

No data were available to evaluate the carcinogenicity, reproductive effects or prenatal 

toxicity of vinyl fluoride to experimental animals or the activity of vinyl fluoride in 

short-term tests. 

4.3 Human data 

No data were available to evaluate the reproductive effects or prenatal toxicity of vinyl 

fluoride to humans. 

No case report or epidemiological study was available to evaluate the carcinogenicity of 

vinyl bromide to humans. 

4.4 Evaluation 

No data were available to evaluate the carcinogenicity of vinyl fluoride to experimental 

animals or to humans. 

5. References 

Bales, R.E. (1978) Vinyl Halides Carcinogenicity (Current Intelligence Bulletin No. 28; DHEW

(NIOSH) Pub. No. 79-102), Cincinnati, OH, National Institute for Occupational Safety and 

Health 

Bolt, H.M., Laib, R.J. & Stockle, G. (1979) Formation of pre-neoplastic hepatocellular foci by vinyl 

bromide in newborn rats. Arch. Toxicol., 43, 83-84 

Bolt, H.M., Laib, R.J. & Klein, K.-P. (1981) Formation of pre-neoplastic hepatocellular foci by 

vinyl fluoride in newborn rats. Arch. Toxicol., 47, 71-73 

Brasure, D.E. (1980) Polyvinyl fluoride. In: Mark, H.F., Othmer, D.F., Overberger, C.B. & Seaborg, 

G.T., eds, Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed., Vol. 11, New York, 

John Wiley & Sons, pp. 57-64 

Buckingham, J., ed. (1982) Dictionary of Organic Compounds, 5th ed., Vol. 3, New York, 

Chapman and Hall, p. 2649 [F-00396] 

Clayton, J.W., Jr (1967) Fluorocarbon toxicity and biological action. Fluorine Chem. Rev., 1, 

197-252 
 VINYL FLUORIDE 153 

Cohen, F.S. & Kraft, P. (1971) Vinyl fluoride polymers. In: Bikales, N.M., ed., Encyclopedia of 

Polymer Science and Technology, Vol. 14, New York, Wiley Interscience, pp. 522-540 

Conolly, R.B., Jaeger, R.J. & Szabo, S. (1978) Acute hepatotoxicity of ethylene, vinyl fluoride, 

vinyl chloride, and vinyl bromide after Aroclor 1254 pretreatment. Exp. mol. Pharmacol., 28, 

25-33 

Dilley, J.V., Carter, V.L., Jr & Harris, E.S. (1974) Fluoride ion excretion by male rats after 

inhalation of one of several fluoroethylenes or hexafluoropropene. Toxicol. appl. Pharmacol., 

27, 582-590 

Filser, J.G. & Bolt, H.M. (1979) Pharmacokinetics of halogenated ethylenes in rats. Arch. Toxicol., 

42, 123-136 

Filser, J.G. & Bolt, H.M. (1981) Inhalation pharmacokinetics based on gas uptake studies. I. 

Improvement of kinetic models. Arch. Toxicol., 47, 279-292 

Filser, J.G., Jung, P. & Bolt, H.M. (1982) Increased acetone exhalation induced by metabolites of 

halogenated C1 and C2 compounds. Arch. Toxicol., 49, 107-116 

Grayson, M., ed. (1985) Kirk-Othmer Concise Encyclopedia of Chemical Technology, New York, 

John Wiley & Sons, pp. 516-517 

Hawley, G.G., ed. (1981) The Condensed Chemical Dictionary, 10th ed., New York, Van Nostrand 

Reinhold Co., p. 1086 

Kopečný, J., Lúčanská, N., Šipka, F., Černý, E. & Ambros, D. (1964) Toxicity of vinyl fluoride 

(Pol.). Pracov. Lék., 16, 310-311 

Lester, D. & Greenberg, L.A. (1950) Acute and chronic toxicity of some halogenated derivatives of 

methane and ethane. Arch. ind. Hyg. occup. Med., 2, 335-344 

National Institute for Occupational Safety and Health (1978) Vinyl Fluoride and Vinyl Bromide 

Industrial Hygiene Survey Report (DHEW (NIOSH) Pub. No. 79-111; US NTIS PB80-190150), 

Cincinnati, OH, pp. 13-18 

National Institute for Occupational Safety and Health (1983) NIOSH recommendations for 

occupational health standards. Morb. Mortal. Wkly Rep., 32, Suppl., 22S 

NIH/EPA Chemical Information System (1983) Carbon-13 NMR Spectral Search System, Mass 

Spectral Search System and Infrared Spectral Search System, Arlington, VA, Information 

Consultants, Inc. 

Ortiz de Montellano, P.R., Kunze, K.L., Beilan, H.S. & Wheeler, C. (1982) Destruction of 

cytochrome P-450 by vinyl fluoride, fluroxene, and acetylene. Evidence for a radical 

intermediate in olefin oxidation. Biochemistry, 21, 1331-1339 

Oser, J.L. (1980) Extent of industrial exposure to epichlorohydrin, vinyl fluoride, vinyl bromide and 

ethylene dibromide. Am. ind. Hyg. Assoc. J., 41, 463-468 

Sadtler Research Laboratories (1980) The Sadtler Standard Spectra Collection, Cumulative Index, 

Philadelphia, PA 

Sax, N.I. (1984) Dangerous Properties of Industrial Materials, 6th ed., New York, Van Nostrand 

Reinhold, Co., p. 2730 
154 IARC MONOGRAPHS VOLUME 39 

US Environmental Protection Agency (1980) TSCA Chemical Assessment Series, Chemical 

Information Profiles (CHlPs), August 1976–August 1978 (EPA-560/11-80-011), Washington 

DC, Office of Pesticides and Toxic Substances, pp. 277-289 

US Environmental Protection Agency (1981) Fluoroalkenes; response to the interagency testing 

committee. Fed. Regist., 46, 53704-53708 

US International Trade Commission (1984) Synthetic Organic Chemicals, US Production and 

Sales, 1983 (USITC Publication 1588), Washington DC, US Government Printing Office 

Weast, R.C., ed. (1984) CRC Handbook of Chemistry and Physics, 65th ed., Boca Raton, FL, CRC 

Press, p. C-571 

Weiss, G., ed. (1980) Hazardous Chemicals Data Book, Park Ridge, NJ, Noyes Data Corp., p. 913