gluorii/ze
`Gbemzktry
`Q3/z'ews
`
`
`
`-ume l
`
`1967
`
`Ember 2
`
`L'.\':-mr.=':-a- 3: "or:
`
`Paul
`
`rant
`
`./f.\'.Fo:‘I:1I('E:f.?!_01+‘_r,-
`._
`. Rtchardson
`_. Lagowski
`
`.
`
`a MAR-CEL DEKKER journal of advances
`
`Page 1 of 58
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`Arkema Exhibit 1140
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`

`
`FLUORINE CHEMISTRY REVIEWS
` ._j.
`
`Executive Editor
`
`PAUL TARRANT
`UNIVERSITY OF FLORIDA
`GAINESVILLE, FLORIDA
`
`Associate Editors
`
`R. D. RICHARDSON
`ORGANIC CHEMICALS DEPARTMENT
`E. I. DU PONT DE. NEMOURS 5:: COMPANY
`WILMINGTON, DELAWARE
`
`J. J. LAGOWSKI
`DEPARTMENT OF CHEMISTRY
`UNIVERSITY OF TEXAS
`AUSTIN, TEXAS
`
`Advisory Board
`
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`INORGANIC (IHEMISTRY INSTITUTE
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`RESEARCH INSTITUTE OF PHARMACY
`AND BIOCHEMISTRY, PRAGUE’.
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`INSTITUTE OF I-]E‘I‘l."I-IOORGANIC
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`PENINSULAR CHIEMRESEARCH,
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`
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`
`Pubiishcd in 2 numbers per volume at 210? N. Charles 51., Baltimore, Md. 2l2l8,
`by Marcel Dekker, Im:., 95 Madison Avenue, New York, N. Y. 10016
`
`Volume 1 (2 numbers) 196?: $16.50
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`Page 2 of 58
`
`Page 2 of 58
`
`

`
`Fluorine Chemistry Reviews. 1 (2).
`
`|97—252 (I967)
`
`FLUOROCARBON TOXICITY AND
`BIOLOGICAL ACTION
`.:_?_.
`
`J. Wesley CIayron, Jr.
`HASKELL LABORATORY FOR TOXICOLOGY AND INDUSTRIAL MEDICINE
`E. I. DU FONT DE NEMOURS AND COMPANY
`WILMINGTON, DELAWARE
`
`.
`. Introduction
`.
`.
`.
`. Fluoroalkanes
`A. Acute Inhalation Toxicity
`B. Biological Action of Fluoroalkanes
`C. Chronic Toxicity of Fluoroalkanes
`D. Toxicity—Oral. Skin, and Eye
`. Fluoroalkenes
`.
`. Fluoropolymers
`. Conclusions
`References
`
`.
`
`I. INTRODUCTION
`
`Dominant among the chemical properties of the class of chemical com-
`pounds known as the fluorocarbons is their relatively high stability, a func-
`tion of the short interatornic distance between carbon and fluorine and the
`strength of the bond joining the two. The presence of fluorine in the mole-
`cule can exert profound influence. For example, in the chlorofluorocarbons
`fluorine stabilizes adjacent C—-Cl bonds and reduces the steric strain pro-
`duced by the relatively voluminous chlorine atoms. Furthermore,
`the
`accumulation of fluorine atoms on a carbon chain culminates in a changed
`bond energy and length between carbon and fluorine. Table 1 contrasts the
`bond length and energy of the C—Cl and C——F links in a series of fluoro-
`alkanes in which fluorine replaces chlorine. The perfluorinated member of
`this series reveals a significant bond shortening and energy increase com-
`pared to the compounds with a smaller complement of fluorine.
`I91
`
`Page 3 of 58
`
`Page 3 of 58
`
`

`
`I93
`
`J. Wesley Clayton. Jr.
`
`In considering the toxicology of the fluorocarbons, it is natural to relate
`the chemical properties outlined above to the biological action resulting from
`contact with living systems, and it appears that the stability of the C——F
`bond is probably the most important consideration. There is no need in this
`context to distinguish among the various kinds of bond scission which may
`be involved in specific instances. The important feature is the relative high
`
`TABLE 1
`
`Bond Length and Energy in Chlorofiuoromethanes“
`
`Compound
`
`CCL.
`CCl3F
`CCl;F;
`CCIF3
`CF;
`
`Bond length, A
`C—F
`C-CI
`
`Bond energy, kcal
`C—F
`C—Cl
`
`—
`1.348
`1.340
`1.328
`I .3] T
`
`1.765
`[.770
`1.77?
`1.135
`—
`
`—-
`ll2.1
`112.9
`ll4.6
`l I 6.0
`
`78.3
`17.7
`77.1
`76.5
`—
`
`" Based on data from G. Gloclter. J. Chem. Phys., 63, 828 (1959).
`
`order of'C—F bond stability. This bond afiinity may be adduced to explain
`the lack of biological action or, in contrast, a positive response. Lack of
`biological activity relating to C—F stability can be demonstrated by the
`fluoroanalogues
`of
`the
`sulfur mustards,
`S(CH2—-CI-I;Cl)2
`and
`S(CH1—-CH2F)2.
`The chloro compound is a potent vesicant caused by dissociation of the
`covalently bonded labile, chlorine fragment which leaves the highly active
`halogen-free moiety (1). It should be noted that it is not the released chlo-
`rine which causes the vesicant activity. The fluoro analogue, incontrast, is
`inoffensive, owing to firm C—F bonds which do not easily dissociate.
`Illustrating a positive response is the now classical lethal synthesis in
`which the C——-F bond of cu-fluoroacetate is refractory to enzymatic dehalo-
`genation. Fluoroacetate enters the tricarboxylic acid cycle with the C——F
`bond intact and passes without detectable interference to fiuorocitric acid
`(Fig. 1). At this point evidently steric hindrance precludes the action of the
`enzyme aconitase so that the next step in the chain, conversion to aconitic
`acid, is blocked. A major part of the toxicity of w-fluoroacetate, and com-
`pounds metabolized to it, is undoubtedly a result of blocked metabolism,
`and the strong C—-F union would seem to be the underlying cause. However,
`there is a considerable variation in the quantitative aspects and the kind of
`
`Page 4 of 58
`
`Page 4 of 58
`
`

`
`Fluorocarbon Toxicity and Biological Action
`
`ATP)
`
`ADP
`
`(HS—A(coenzvme A)
`®”—A)
`If
`(Cl-i1C00H
`F
`I
`CH ,—co-- S—A
`
`®—0H
`
`-
`
`1
`FCH
`1
`COOH
`{fluorocitrate)
`FIG. 1. Lethal synthesis. fiuoroaoetate to fluorocitrate.
`response shown by various animals which have received fiuoroacetate or its
`analogues. In the first place there is a wide range in the dose which proves
`lethal to a variety of vertebrate species. Table 2 summarizes data on acute
`toxicity of fluoroethanol, sodium fluoroacetate, or methyl fluoroacetate.
`The values for lethal dosages derived from graded intraperitoneal dosages
`range from <0.05 rngfkg for the pocket gopher to >500 mgflcg for the clawed
`TABLE 2
`
`Biological Response of Animals Receiving Intraperitoneal Injections of Fluoroethanol
`or Sodium or Methyl Fluoroaoetate
`__::
`Lethal dose,“
`
`mglkg
`Species
` _
`Pocket gopher
`<0.0S
`Kangaroo rat
`0.1
`Guinea pig
`0.35
`Ground squirrel
`0.9
`Hamster
`3.0
`Albino rat
`5.0
`Albino mouse
`10.0
`South African clawed toad
`>500
`
`" All figures represent the LDSO with the exception of the pocket gopher, which shows
`the LDm,.
`
`Page 5 of 58
`
`(fiuoroacetate)
`
`CO0!-I
`I
`+ H-OH
`(‘in
`C(0l-DCOOH
`
`CO0]-I
`
`lC
`
`H,
`
`IC
`
`(OH )COOH
`
`Page 5 of 58
`
`

`
`200
`
`J. Wesley Clayton. Jr.
`
`toad. In the second place the manner of response to administered fluoro-
`acetate is diverse among animals. The rat reflects the action of fiuoroacetate
`principally on the respiratory system, while the dog and rabbit register,
`respectively, central nervous and cardiovascular effects for the most part.
`The monkey and man show a combination of the three types of responses,
`indicating attack on several fronts. It is inferred from this diversified reac-
`tion among mammalian species that there is a generalized effect on tissue
`metabolism, with differences in prominence attributable to specific modes of
`entry or otherwise explicable at the cellular level, as disclosed by the obser-
`vations which follow.
`
`Metabolically, the Wistar rat turns over acetate at a lower rate than the
`Sprague-Dawley strain. Thus, the latter is more sensitive to alterations in
`acetate metabolism, and consequently fluoroacetate is more toxic for the
`Sprague-Dawley rat compared to the Wistar rat. The guinea pig brain
`actively oxidizes acetate; rabbit brain tissue does not. In the rabbit the heart
`takes up acetate avidly. These in vitro metabolic affinities correlate well with
`the convulsions experienced by guinea pigs and the cardiac arrest of rabbits
`given fluoroacetate.
`Additional inquiry into the biochemical pharmacology of fluoroacetate
`has been directed toward the cellular events which culminate in the animals‘
`response. In a review ofthis area Pattison and Peters (2) have considered the
`relationship between fluoroacetate and convulsions shown by some species.
`Fluoroacetate would seem not to be the direct cause ofconvulsions, as direct
`injection even of large doses into the subarachnoid space of the brain is
`without effect on the rat, pigeon, and rabbit. Fluorocitrate, however,
`is
`quite active, approximately 1.5 mg causing convulsions in the rat and 11 mg
`in the pigeon. The latter finding is consistent with the inability of pigeon
`brain tissue to convert fluoroacetate to fluorocitrate in vitro. The immediate
`cause for the convulsive response of the central nervous system has not yet
`been demonstrated. Pattison and Peters speculate that citrate accumulation
`resulting from fluorocitrate‘s inhibition ofaconitase may disturb the neural
`membrane equilibrium of divalent ions such as Ca“, with a resultant lower-
`ing of membrane potential and excitation. However, even though injected
`Ca“ depressed initial excitation induced by fluorocitrate, it was ineffective
`against subsequent severe convulsions. Thus,
`the cellular events which
`follow the interaction of fluorocitrate and aconitase, presumably the bio-
`chemical lesion, and the correlation of these with the reaction ofthe animal
`(e.g., convulsions, cardiac arrest} have yet to be elucidated.
`An important lesson from the two decades of effort that have been ex-
`pended in the attempt to explain the mechanism of fluoroacetate toxicity is
`
`Page 6 of 58
`
`Page 6 of 58
`
`

`
`Fluorocarbon Toxicity and Biological Action
`
`20I
`
`the potential amount ofwork involved in this kind of problem. With most of
`the fiuorocarbons only the first step in defining the toxicity has been taken.
`The handling of these materials by the body and the mechanisms of action
`have only recently been broached, or studies have not yet been initiated.
`Therefore, for many ofthe compounds cited in this review, as well as others
`on the same subject [Hodge et al. (3)], only preliminary toxicity data are
`available. It is a toxicological objective to understand the mode of action in
`relation to chemical constitution, and this should be a governing factor in
`future investigations on fluorocarbon toxicity.
`It is the objective of this paper to review the toxicology of the fluoro-
`carbons, including fluoropolymers, and to discuss some aspects of their bio-
`logical actions.
`
`II. FLUOROALKANES
`
`A. Acute Inhalation Toxicity
`
`This group of fluorocarbons is probably the most important at present
`from the commercial point of view. Fluoroalkanes are used as refrigerants,
`propellants, dielectric agents, fire extinguishing compounds, and food freez-
`ing materials. In general these are nonreactive compounds with high chemi-
`cal stability due to the strong C—F bond. This is undoubtedly the cause for
`the low toxicity ofthis class ofcompounds. Yet, while C—F firmness ensures
`stability and favors low toxicity, it does not imply complete lack of bio-
`logical activity. For example, trifluoroiodomethane, tagged with '3‘ I, may be
`safely used to trace the circulatory paths ofthe brain—demonstrating that,
`while the compound undergoes no detectable biological degradation, it is
`biologically active in penetrating the blood-brain barrier. A similar situation
`appears to obtain for fluorinated anesthetics in which metabolic degradation
`is not a sine qua non for the narcotic activity. The picture is much the same
`for other fluoroalkanes-—they are low in toxicity but biologically active, and
`probably for different reasons.
`Three developments reflect the increasing importance of knowledge ofthe
`toxicity of the fluoroalkanes. The first was the advent in the 19205 of
`mechanical refrigeration. After investigation ofseveral candidates possessing
`the requisite stability and physical properties, dichlorodifiuorornethane,
`CCl2F2, was prepared by Midgley and i-lenne (4), specifically for refrigerant
`use. This compound not only provided the requisite temperature-pressure
`relationships, nonflammability, but also a low degree of inhalation toxicity
`as compared to S0; and NH3.
`The second development is indicated by the publication, in I928 by F.
`
`Page 7 of 58
`
`Page 7 of 58
`
`

`
`202
`
`Wesley Clayton. Jr.
`
`Lehmann (5), of experiments on the pharmacological action and influence
`of the trifluoromethyl-CF3 group. This was the first report involving a
`number of fiuorinated compounds possessing pharmacological activity.
`The third one was the synthesis ofa number of derivatives of cu-fluoro-
`
`acetates, which resulted from chemical warfare research during World War
`11. Wartime security obscured the development of other fluorocarbons, but
`just prior to this period a significant discovery was made ofthe first fluoro-
`polymer, Tefl0n* tetrafluoroethylene resin. This resin, because of its resis-
`tance to most reagents, was largely committed to atomic energy programs.
`The postwar era saw a decline ofthe toxic fluoroacetate compounds. except
`as pesticides, and an increase in the market place ofmultifluorinated organic
`compounds having high stability and low toxicity. In this postwar develop-
`ment the major fluorocarbon contributors have been the fluoroalkanes.
`especially as aerosol propellants and refrigerants. Since these compounds
`are gases at room temperature, the chieftoxicological hazard was from inha-
`lation. Accordingly. the lirst toxicity experiments were aimed at evaluating
`the briefexposure that a householder, refrigeration repairman, or fire fighter
`might encounter. The Underwriters Laboratories designed an inhalation
`study in which groups of 12 guinea pigs were exposed to a graded series of
`concentrations of the test compound. At each sampling time of 5 min,
`30 min,
`1 hour, and 2 hours, three guinea pigs, if surviving the exposure,
`were removed from the chamber for observation or pathological examina-
`tion of vital organs within a 2- to 10-day period after exposure. This work
`also included other refrigerants in use at the time, for example, ammonia
`and sulfur dioxide. The comparison provided by their inclusion was invalu-
`able in putting candidate refrigerants and propellants in perspective with
`existing materials.
`Studies on several r_efrigerant compounds in the decade 1931-194! led to a
`classification system which has been used to grade the safety of new com-
`pounds. In this system class 1 compounds are the most toxic, causing death
`or serious injury when inhaled continuously by guinea pigs at 0.5-1 .0 vol. %
`for 5 min, e.g., sulfur dioxide. Class 2 is composed of materials which are
`lethal or injurious to guinea pigs at concentrations of 0.5-1 .0% for 30-min
`exposure, e.g., ammonia and methyl bromide. Classes 3 and 4 are distin-
`guished by an exposure which proves toxic for guinea pigs at 2.0-2.5 ‘X, for
`I hour and 2 hours, respectively, e.g., carbon tetrachloride and chloroform
`(class 3) and dichloroethylene and methyl chloride (class 4). Class 6 is de-
`fined by a 2-hour exposure at 20% which does not produce injury to the
`guinea pigs, e.g., dichlorodifluoromethane, dichlorotetrafluoroethane,
`* Registered du Pont trademark for fluorocarbon resins.
`
`Page 8 of 58
`
`Page 8 of 58
`
`

`
`Fluorocarbon Toxicity and Biological Action
`
`203
`
`monobromotrifluoromethane. Classes 4-5, 5a. and 5b are not precisely
`defined; they accommodate compounds more toxic than those in class 6 but
`less toxic than class 4 materials, e.g., trichlorotrifluoroethane and methylene
`chloride (class 4-5), trichloromonofiuoromethane, chlorodifiuoromethane,
`and C02 (class Sa), ethane, propane, and butane (class Sb}.
`The primary purpose of this system was to gauge the acute inhalation
`hazard, and it is evident that the fiuoroalkanes are low in toxicity on the
`basis ofthe above groupings. Subsequent work has been confirmatory, and
`experience in the chemical industry attests to a low order of toxicity for man.
`Toxicological data, Underwriters class, and threshold limit values (TLV) of
`the American Conference of Governmental
`Industrial Hygienists are
`summarized in Table 3 for a number of fiuoroalkanes.
`TABLE 3
`
`Inhalation Toxicity of Fluoromethanes
`
`Exposure.
`
`C‘oncn.,
`"/Q
`
`Hr
`
`+ or —
`
`2.0
`10.0
`20.0
`20.0
`2.0
`10.0
`20.0
`20.0
`20.0
`2.0
`5.0
`10
`20
`
`l\J--Id!‘-3|‘-‘I'~Jl-l|\lt~Jl‘~JI*J-dtxl
`
`Structure
`
`CI-ICI3
`CHCIEF
`Cl-lClF;
`Cl-IF;
`CCL.
`cc1,F
`CCi;F;
`CCIF3
`CF;
`04,0
`CH2Cl;
`CHCl;F
`CCIZF;
`
`U.L.
`class“
`3
`4-5
`5
`6‘
`3
`5
`6
`6"
`6!‘
`4
`4-5
`4-—5
`6
`
`TLV”
`S0
`1000
`(I000)
`(1000)
`10
`1000
`1000
`(1000)
`(1000)
`100
`500
`I000
`1000
`
`' U .L. signifies Underwriters‘ classification. The higher the value, the lower the toxicity.
`** TLV is the threshold limit value assigned by the American Conference of Govern-
`mental Industrial Hygienists. 1964 values. Figures in parentheses indicate provisional
`values.
`'= Based on data from Haskell Laboratory.
`in view of the fact that TLV‘s are often used incorrectly as toxicity indices,
`it is important to put them in perspective. The first industrial hygienic
`standards for airborne contaminants proposed for some fiuoroalkanes by
`Cook (6) ranged from 5000 ppm for dichlorofluoromethane to 100,000 ppm
`
`Page 9 of 58
`
`Page 9 of 58
`
`

`
`204
`
`]. Wesley Clayton. Jr.
`
`for dichiorodifiuoromethane. The values were subsequently lowered to
`1000 ppm, not from toxicity considerations but on the premise that proper
`engineering standards dictates that no contaminant vapor should be allowed
`to exceed 1000 ppm on an 3-hour average. Only carbon dioxide has a TLV
`greater than I000 ppm, i.e., 5000 ppm. Thus, while the TLV of 1000 ppm is
`commensurate with the low toxicity of the fluoromethanes. its purpose is
`primarily for good housekeeping. Industrial experience has established its
`validity and utility.
`Much of the early toxicity work on the fluoroalkanes was purely taxo-
`nomic—the assignment ofindividual compounds to categories. Toxicology
`has developed no sound principle whereby the toxicity of individual com-
`pounds can be determined from chemical structure or properties. This
`applies in full to the fiuorocarbons. in spite of C—-F bond strength and its
`intramolecular stabilizing influence, these are not reliable in predicting
`toxicity. As toxicity data became available, however, a general principle
`emerged. Like other generalities in biological science, this one partakes of
`the same kind oflimitations in that special cases defy the generalization. The
`data assembled in Table 3 illustrate this principle——a lower degree oftoxicity
`corresponding with an increasing number of fluorine atoms in the molecule.
`All three groups, A, B, and C, of Table 3 reveal this with the most striking
`example evident in group B, comparing CCL, with CF4. The influence of"
`fluorine and its interactions with other atoms in the molecule is also appa-
`rent in this compilation. As shown by the contrasting toxicities of CHCI3
`and CHCl2F (group A), the substitution of even a single F atom for C1
`effects a strong lowering of‘ toxicity in the chlorofiuoroalkane. It is plausible
`in this instance that the fact that the stability ofthe Cl atoms are enhanced by
`the C—F bond imposes an intractability to enzymatic dehalogenation with
`concomitant lower toxicity. Addition of additional F atoms in group A
`shows a continued decline in toxicity. Group B provides similar evidence of
`this stabilizing force of F vis it vis CI in the methane series. Yet another
`feature relating to the principle under discussion is shown by group C. This
`is the interplay of‘ hydrogen, fluorine, and chlorine. The substitution of CI
`for H appears to lower toxicity; compare CH3Cl with CH3Cl2. However.
`additional chlorination (i.e., CHCI3 and CCI4) yields compounds as toxic as
`CH3Cl. The replacement of H in CHZCI2 and CHCl2F with F to give
`CHCIZF and CCl2F2, respectively, also eventuates in lowered toxicity. Thus,
`while it is sometimes true that increasing the Cl complement favors a de-
`crease in toxicity. fluorine is far more effective than chlorine. This may also
`be illustrated by a lower toxicity for CHEF; contrasted with Cl-l2CI2.
`Henne (7) reported no toxic effects in guinea pigs inhaling 20°/,, CHEF; for
`
`Page 10 of 58
`
`Page 10 of 58
`
`

`
`Fluorocarbon Toxicity and Biological Action
`
`205
`
`hours, whereas 2 ‘X, CHZCIZ was fatal in 2 hours. The compound, CHZCIF,
`is intermediate; a few per cent is toxic. Thus, the order of toxicity would be
`CI-12Cl2 > CH3ClF > CI-121:2.
`This stabilizing attribute ofF may also be noted in connection with bromine.
`Table 4 indicates the following toxicity trend: CBr2F2 > CBrC1F, > CBrF3.
`TABLE 4
`
`Acute Inhalation Toxicity ofFluoromet]1anes Containing Bromine
`
`Exposure
`
`Compound
`
`Animal
`
`CBrgF3
`CBl'C]Fg
`CB1'F3
`
`Rat
`Rat
`Rat
`
`Time,
`min.
`
`15
`1 5
`l 5
`
`Lethal concn.."
`vol. "/1,
`
`5.5
`32
`83
`
`" Vapor mixed with air.
`
`From this sequence it can be inferred that the brominated compounds are
`more toxic than chlorinated and that those highly fluorinated are least toxic.
`In discussing the toxicity ofhalogenated compounds, it is to be emphasized
`that it is not the fugitive halogen which is the toxic agent. For example, the
`displacement by enzymatic dehalogenation of Br from Cl-I 3Br results in
`TABLE 5
`
`Acute Inhalation Toxicity of Several Fluoroethanes
`
`Approximate lethal concn. #
`
`Structure
`
`Vol. 7,,
`
`Exp., hr
`
`CC]1F-—CCl3F
`CClF2—-CC];
`CCl;F——CClF;
`cc1F;—ccu-3
`CHCI1-—CF3
`CClF2—CHF;._
`CCIF;-—CF3
`CHF2-—CF,
`CF,—cF,
`
`1.5
`1.5
`I0
`>20
`3.5"
`>20
`>sob
`2-I0
`>30b
`
`«F-I3-J7-I9-P-M-P-In-It
`
`Animal
`Rat
`Rat
`Rat
`Guinea pig
`Rat
`Guinea pig
`Rat
`Rat
`Rat
`
`a l..C5u.
`5 80?/,, fluorocarbon and 20° ., 03.
`
`Page 11 of 58
`
`Page 11 of 58
`
`

`
`206
`
`J. Wesley Clayton. _|r.
`
`methylation of methionine and other su1fur—containing compounds in vivo,
`thereby producing toxic elTects(1). In this regard CH3Cl is not as active as
`CI-l3Br, and, as would be anticipated, CH3}? is the least active of the three;
`thus, toxicologically the order is CH3Br > CH3CI > CH3F. Fluorination
`evidently imparts a resistance to dehalogenation, thus shielding the toxe-
`phoric part ofthe molecule.
`A correspondence oflow toxicity with increasing fluorination is disclosed
`by inhalation experiments with fiuoroalkanes of longer chain length. Table 5
`TABLE 6
`
`Comparison of Bromine and Chlorine in the Acute
`Inhalation Toxicity of Fluoroethancs
`
`Compound
`
`CH zCl—-C F 3
`CH2Cl—CI-IF;
`CH2Br—CF_,
`CH3Bt‘—CHFg
`
`" Mice exposed for I0 min.
`
`Lethal concn..°'
`vol. °/,,
`
`25.0
`1,5
`ll.7
`4.6
`
`summarizes relevant data on fluoroethanes, several having a chlorine com-
`plement, and Table 6 depicts the comparative roles of Cl and Br for fluoro-
`ethanc [compare CH2Cl—CF_; with CH2Br—CF3). In Table 6 the relation
`ofhydrogen and F is also evident from the comparison of'CH3Cl—CF3 with
`CHZCI-—CHF2 and CH2Br—CF3 with CH;,Br—CHF2. Table 7 summarizes
`the acute inhalation toxicity for several fluoropropanes. Again, the prin-
`ciple of declining toxicity with increasing fluorination is observed. The
`
`TABLE 7
`
`Toxicity of Several Fluoropropancs for Mice (exposed for 10 min)
`
`Structure
`
`Anesthetic
`concn., ‘if,
`
`Approx. lethal
`concn., ‘K
`
`HCF;—CI-l,—-CCIF;
`HCF;—CF;._—CBrF;
`HCF;—CF;,—CHC|F
`l-lCF3—CF;—Cl-ICI3
`CC|F;—CF2—CHgF
`CClF;—C‘F;._—Cl-IF;
`
`ID
`4
`2.5
`0.5
`10
`10
`
`20
`I0
`3
`2
`15
`20
`
`Page 12 of 58
`
`Page 12 of 58
`
`

`
`Fluorocarbon Toxicity and Biological Action
`
`207
`
`toxicity of octafluoroeyclobutane with a full complement of fluorine would
`seem the epitome of toxicological inertness, as Table 8 demonstrates.
`
`TABLE 8
`
`Toxicity Studies on Octafluorocyclobutane (0FCB}
`
`Exposure
` _—
`
`OFCB concn., Duration,
`vol. ‘Z,
`hr
`
`No. of
`exposures
`
`80“
`80“
`1.0
`10
`
`10
`
`0.25
`4
`6
`6
`
`6
`
`l
`1
`19
`4
`
`90
`
`Mice
`Rats
`Rats
`Rats, mice,
`guinea pigs, dogs
`Rats, mice,
`rabbits, dogs
`
`Toxic effects
`
`None
`None
`None
`None
`
`None
`
`“ 80% OFCB + 20% oxygen.
`
`B. Biological Action of Fluoroalkanes
`While it is important to gauge the toxicity ofa material by its lethal capa-
`city, it is equally important to evaluate the clinical and systemic responses to
`the agent. From the data on fluoroalkanes it is patent that the major res-
`ponse ofthe animals is mediated by the central nervous system. Indeed, the
`fact that many fluoroalkanes have been investigated as potential anesthetics
`sufliciently points up this attribute. l-(rantz and Rude (8) have recently re-
`viewed the clinical aspects of the fiuorinated anesthetics, and the reader is
`referred to this source for details which in the present paper can only be
`highlighted.
`Sayers et al. (9), in repeated exposures of dogs, monkeys, and guinea pigs
`to CCIZFZ, observed tremors and staggering gait in dogs and monkeys at
`20%. Booth and Bixby (I0) exposed mice to CHCIEF and Cl-ICIF2 and
`reported that concentrations of4 and 16 ‘X, caused convulsions; 20 and 49 %
`were lethal. Yant et al. (I I) reported incoordination and tremors in dogs but
`not in guinea pigs exposed 8, 16, and 24 hours at 15% CCIF2-—CClF2. In
`repeated exposures to 14.2"/,, CC1F2—-CCIF2, 8 hours daily, these authors
`observed signs of tremors, incoordination, and some convulsions for 3 to 5
`days in dogs. They then appeared to have developed a tolerance while expo-
`sures continued for 21 days. At 20 %, guinea pigs, which displayed no ner-
`vous system response at 14.2 "/,,, experienced tremors and convulsions but
`
`Page 13 of 58
`
`Page 13 of 58
`
`

`
`208
`
`J. Wesley Clayton. Jr.
`
`survived. Dogs died at 20 % after showing severe convulsions. Nuckolls (12),
`studying guinea pigs exposed to several fluorinated alkanes. noted loss of
`coordination in 2-hour exposures to CCl3F at a level ofabout 5 %, and severe
`tremors, anesthesia, and convulsions at l0 "4. Less marked signs of nervous
`system reaction were observed with CCIZFZ in exposures up to 30 %.
`Robbins ()3) investigated anesthetic response by mouse exposures on 12
`fluorinated derivatives of methane and ethane. He was able to eliminate
`unsatisfactory candidate anesthetics by convulsive responses provoked by
`some. Of those inducing only anesthesia, CHClBr—CF3 ultimately saw
`commercial development as halothanc. Subsequent clinical experience has
`validated these early animal experiments on halothane as a safe anesthetic in
`terms of its low degree of activity on the nervous system. Its relation to
`hepatotoxicity is discussed below.
`Lester and Greenberg ()4) studied five fluorinated alkanes, CCIZFZ,
`CH3—CHF,,, CH3—CClF2, CCl_=,F, and Cl-l2Br—CBrF-2, and have shown
`that the dominant clinical response in rats exposed for 30 min was narcosis,
`as evidenced by a disappearance of various reflexes with increasing concen-
`trations. Death, when occurring, appeared to be due to respiratory failure.
`Tremors and pulmonary irritation at anesthetic concentrations precluded
`additional exploration ofthese compounds as anesthetics for man.
`Burn (I5), and Burn et al. (16) have studied the anesthetic properties of
`three fluoroethanes: CCl2F—CCl2F, CC'.lF2—CCl2F, and CClF2—CHClF.
`The first two produced initial excitement and convulsions in mice during
`anesthesia at 1-2 % and 5-12 %, respectively. The third compound (note the
`presence of hydrogen) caused no deleterious neurological change during
`anesthesia at concentrations up to 7 ‘X, for 1 hour.
`Dishart (17), reporting on several fluorinated propanes, has shown a
`lowered anesthetic potency in mice for compounds which have more than
`four fluorine atoms. With these compounds high concentrations were
`required to produce anesthesia, but it was accompanied by convulsions. In
`fluoropropanes which produced satisfactory anesthesia,
`two of the four
`fluorine atoms had to be located on the central carbon, a position which
`conferred stability toward alkali and lack of toxic effects on the central
`nervous
`system of mice,
`for
`example, HCFZCFECHZCI
`and
`I-ICFZCFZCHZBL A higher degree of fluorination as in HCF3CF2CH2F,
`l-lCFzCF;CF2Cl, and HCF;CF2CF3Br or a lower chemical stability as in
`CF_:,CHBrCF3 provoked convulsant activity in mice in 10-min exposures or
`toxic effects possibly related to the instability of the compound in the body.
`Karpov (.-'8) studied eflects on the central nervous system's reactivity by
`chronic exposures of rabbits, rats, and mice to 14,200 or 1980 ppm of
`
`Page 14 of 58
`
`Page 14 of 58
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`Page 16 of 58
`
`Page 16 of 58
`
`

`
`Fluorocarbon Toxicity and Biological Action
`
`III
`
`CH CIFZ. Neurological studies, including swimming endurance, number of
`subthreshold impulses to produce a reflex, and number of trials to establish
`a conditioned response, revealed effects only at the lower level.
`Gage ([9) has compared several halogenated fire-extinguishing com-
`pounds, particularly observing neurological responses. Table 9 summarizes
`his findings. The most inactive of this group was bromotrifluoromethane.
`Paulet (20) has also reported his experiments on this compound (Table 10).
`Rabbits, mice, guinea pigs, and rats showed an increasing degree of neuro-
`logical effect in 2-hour exposures as the concentration of CBrF3 reached
`60 vol. "/,, and higher. Clearly, this is a fluoroalkane of low toxicity. Paulet
`observed death only at 80 7,, and above.
`It has been known for some time that certain hydrocarbons, notably cyclo-
`propane among inhalation anesthetics, can make the heart muscle abnorm-
`ally reactive to epinephrine, resulting in arrhythmic contractions. Krantz
`and Rudo (8) note that several halogenated alkenes possess this property of
`myocardial sensitization in addition to many straight chain and cyclic
`hydrocarbons. Perfluorinated compounds studied by these workers were
`inactive, but the chlorinated ones were active. Among the fluoroalkanes,
`recent work at Haskell Laboratory has shown that dogs inhaling CBrF3
`(5-10 vol.
`24,) or CCl2F——CClF2 (0.5—l.0 "/0) evidenced cardiac arrhyth-
`mia after intravenous injection of epinephrine. It is expected that perfiuori-
`nated alkanes would be inactive.
`In summary the dominant clinical response to inhaled fiuoroalkanes is
`neurological in character, varying from anesthetic to convulsive reactions.
`When death has occurred in animal studies, the principal anatomic finding
`has been pulmonary injury. The degree of fluorination appears to be related
`inversely to the reactions in the central nervous system which the clinical
`signs indicated.
`I-lalogenated alkanes as a class are noted for their hepatotoxicity. Effects
`on other organs are minimal and outside the scope of the present review.
`Outstanding hepatotoxins are several chlorinated compounds: carbon
`tetrachloride, chloroform, 1,2-dichloroethane, and symmetrical
`tetra-
`ehloroethane. On the other hand, fluorinated alkanes would not be con-
`sidered significant hepatotoxins, as illustrated by the following discussion.
`Lester and Greenberg (14) exposed rats to several concentrations (5-80 "/D)
`of CCl_~,F and CCIZFE for 30 min and of CCl2F2 for 4 and 6 hours. Liver
`injury was not observed in rats exposed to either compound, even when
`CCIZF; was inhaled at 80 “/0 for 4 and 6 hours. Other fluoroalkanes were con-
`sidered by these authors: CH3-—Cl-IF2, CH3——CClF2, and CHgBf—-CBTF2;
`in no case was the liver of exposed rats damaged.
`
`Page 17 of 58
`
`Page 17 of 58
`
`

`
`2l2
`
`J. Wesley Clayton. Jr.
`
`The compounds of CCl_;,F, CCIF3, and CF4 have been studied at Haskell
`Laboratory by single. 4-hour. rat or guinea pig exposures, and repeated ex-
`posures. Rats exposed to vapors of CCI3F in the range of 3.6 to l 1.8 “A ex-
`hibited a noninjurious vacuolation of the liver cells, a change which