ENVIRONMENTALLY ACCEPTABLE FLAME EXTINGUISHANTS 

NGP ELEMENT: 4D/6/23 

J. Douglas Mather, Ph. D. 

Chemical Development Studies, Inc. 

7636 William Moyers Ave. NE 

Albuquerque, NM 87122 

505-797-9706 

DougMather@speakeasy.net 

Robert E. Tapscott, Ph.D., 

GlobeTech, Inc. 

8200 Montgomery Blvd. NE, #218 

Albuquerque, NM 87109 

505-883-9399 

GlobeTech@speakeasy.net

INTRODUCTION 

In work sponsored by the National Institute of Standards and Technology and the NextGeneration Fire Suppression Technology Program, this research effort is directed toward the 

continued study of promising sources of Halon 1301 replacement compounds for aircraft 

applications. This effort continues the study of tropodegradable alkenes and ethers as well as 

efforts to identify screening methods for cardiac sensitization. 

NIST Technical Note 1443, "Alternative Fire Suppressant Chemicals: A Research Review with 

Recommendations", provided the basis for this project through its systematic evaluation and 

prioritization of a broad range of chemical families for further study [1]. This research review 

surveyed five major chemical family types and individually evaluated fifty subgroups of 

compounds. While many of the chemical family subgroups were culled from further 

consideration, several were identified for continued research. The promising chemical families, 

prioritized into “High Priority”, “Further Study”, and “Quick Look” categories, are listed in 

Table 1. Chemical families in the “Quick Look” category generally represent those that have not 

as yet been studied but appear to be promising based on chemical, toxicological, and physical 

data. 

The research review identified goals for evaluating and identifying chemical families that merit 

further research and, of those, the ones that are the most promising for aircraft applications. 

• Fire suppression and reignition quenching efficiency comparable to halon 1301 and 

higher than the hydrofluorocarbons (HFCs). 

• Atmospheric lifetime short, on the order of a month, to keep ozone depletion, global 

warming, and any future adverse contributions to a minimum. 

• Toxic potency of agent and combustion byproducts sufficiently low that brief exposure to 

an extinguishing concentration does not result in an unrecoverable injury; 

• No serious interaction of the agent or its byproducts with contacted aircraft materials; 

• Availability of compatible storage container components; and

• Boiling point sufficiently high that a suppressing volume fraction of 5 % (at thermal 

equilibrium) exists at -40 °C, the minimal design temperature for aircraft suppression 

system performance. This boiling point is about 25 to possibly 35 oC. 

Highly effective agents that might require a smaller concentration for suppression increase the 

boiling point cut-off proportionately. Engine heating of the interior engine nacelle surfaces 
2

along with the feasibility of warming the agent storage container are considerations in setting 

boiling point limits. Agents dispensed as a mist/powder or in particular by a solid propellant gas 

generator (SPGG), whose high temperatures and gas flow rates ensure complete volatilization 

and dispersion, could have considerably higher limiting boiling points. 

Table 1.NIST Technical Note 1443 - Prioritized Listing 

Recommendation 

Chemical Family High Priority Further Study Quick Look

Iodinated alkanes & alkenes X 

Brominated alkenes X 

Iodinated ethers X 

Brominated ethers X 

Brominated alcohols X 

Fluorinated aldehydes & ketones X 

Nitriles X 

Fluoroamines & bromofluoroamines X 

Sulfoxides X 

Phosphorus- acids and esters X 

Phosphonitriles & phosphorus halides X 

Copper-containing compounds X 

Manganese or tin compounds X 

Iron-containing compounds X 

Identifying a compound whose cardiac sensitization properties approximate the LOAEL and 

NOAEL values of Halon 1301 is a fundamental progammatic goal; therefore, refinement in the 

methods employed in the estimation and ranking of a compound's cardiac sensitization properties 

continue to be of great interest and are an ongoing effort. 

DOWN-SELECT OF CHEMICAL FAMILIES 

Of the fourteen general chemical families identified as worthy of additional testing and study six 

were identified for priority investigation based on their likely application in either volatile agent 

application or as enhanced flame suppressing additives in solid propellant gas generator designs. 

The bromofluoroalkenes, bromofluoroethers, bromofluoroamines, fluoroamines, fluoronitriles, 

and bromofluoronitrile chemical families as well as a very limited number of compounds from 

the fluoroalkylphosphorus chemical family have potential as volatile agents, 
3

Table 2. The brominated and phosphorus containing compounds are expected to have the best 

fire suppression efficiency. The non brominated fluoroamines may overall be low in toxicity. 

Compounds based on the metals manganese, copper, and tin are all expected to have high boiling 

points and as such are only likely to be of use in solid propellant gas generator extinguishers as 

additives to increase flame suppression efficiency. 
4

Table 2. Current down select of chemical families 

Chemical 

Family 

Bromofluoro 

alkenes 

Bromofluoro 

ethers 

Bromofluoroamines & 

Fluoroamines 

Examples 

CBrF=CHCHF2

CFBr=CFCFH2

CHBr=CFCHF2

CF2=CHCFBrH 

CFH=CFCFBrH 

CF2=CFCBrH2 

CFH=CBrCF2H 

CF2=CBrCFH2

CF2=CFCFHBr 

CFBr=CFCF2H 

CF2=CBrCF2H

CF3CN 

CF2BrCN 

CF3CFBrCN 

CF2BrCF2CN

CF2Br-O-CH2F 

CHFBr-O-CHF2 

CF2Br-O-CHF2 

CHFBr-O-CF3

CF2=CFI 

CF2=CHI 

CFH=CFI 

CFH=CHI 

CH2=CFI 

(CF3)2NCFHBr 

(CF3)(CF2H)NCF2Br 

(CF3)(CF2H)NCFHBr 

(CF2H)(CF2H)NCF2Br 

(CFH2)(CF3)NCF2Br 

(CF2H)(CF2H)N(CFHBr) 

(CFH2)(CF3)N(CFHBr) 

(CF3)(CF2H)N(CH2Br) 

(CH3)(CF3)N(CF2Br)

P(OCFH2)(CF3)2

P(OCHF2)(CF3) 

O=P(CF3)2(CF2H) 

O=P(CF3)(CF2H)2

O=P(CF2H)3

O=P(CFH2)3

Following further review of the chemical family recommendations and with input on aircraft 

application requirements an abbreviated list of compounds was selected, Table 3. To this listing 

the chemical family of bromofluoropropene oxides (oxiranes) was added. The three carbon 

bromofluoro-propene oxides may well have low boiling points and may well be environmentally 

acceptable. 

Table 3. Principal chemical families of interest 

Chemical Family – Focus List 

Brominated alkenes 

Brominated ethers 

Nitriles – fluorinated and brominated 

Fluoroamines & bromofluoroamines 

Bromofluoropropene oxides (oxiranes) 

Acquired compounds will have their cup-burner flame suppression performance determined. 

Synthesis evaluation and compound sourcing is ongoing and several compounds are either on 

order and being synthesized or in the process of being quoted. The boiling points of some 

targeted bromine containing compounds are predicted to be in the 0 °C to 10 oC range; 

representing some of the lowest boiling brominated compounds yet tested. 

Chemicals are being acquired for the following families; 

• Fluoronitiriles and bromofluoronitriles. Trifluoroacetonitrile (CF3CN) has a boiling 

point of -64 oC. Its fire suppression is expected to reflect a non-chemical extinguishment 

mechanism. On the other hand bromodifluoroacetonitrile (CF2BrCN), boiling point 3 oC, 

and may have a suppression efficiency comparable to halon 1301. The atmospheric 
5

lifetimes of all the nitriles are expected to be limited by hydrolysis of the CN group and 

rainout. These compounds are being acquired for cup-burner testing. 

• Bromofluoropropene oxides (oxiranes) are a newly identified chemical family. Their 

atmospheric lifetimes are expected to be short, but this needs to be confirmed. Cup 

burner values for the monobrominated compounds should be similar to the 

bromofluoropropenes. Boiling points for these compounds are estimated to be between 0 

°C and 10 oC. Their synthesis has been studied and 2-bromo-1,2-perfluoropropene oxide 

is being acquired for cup-burner testing. 

• Bromofluoropropenes: The atmospheric lifetimes of these compounds should be low 

since the double bond is reactive in the troposphere. Log KOW values were calculated, 

using several available modeling methods, for the 35 possible penta-, tetra- and 

trifluorinated bromofluoropropenes. Overall, the calculated log KOW values ranged from 

1.4 to 2.5. Using experimental KOW values of 1.84 for Halon 1301 and 2.3 for Halothane 

(CF3CHBrCl) as guides, a list of compounds whose low calculated values predicted a 

possibly equivalent or higher LOAEL was prepared and promising compounds selected 

for acquisition. Of particular interest are the bromotetrafluoropropenes listed as these 

compounds are generally of lower boiling point and may well have higher LOAEL 

values. 

• Bromofluoroethers: These compounds are expected to have relatively low toxicity and 

good flame extinguishment properties but unless they prove sufficiently polar they will 

require some degree of hydrogenation to minimize ODP impact. Two of the simplest 

brominated ethers are CBrH2-O-CF3 (39 oC) and CBrF2-O-CF3, (boiling point estimated 

between -30 °C and -8 °C). The tetrafluorinated C2 bromoethers CBrHF-O-CF3

(bromofluoromethyl trifluoromethyl ether) and CBrF2-O-CHF2 (bromodifluoromethyl 

difluoromethyl ether) are predicted to boil in the range 5 °C to 15 oC and are being sought 

for testing. Bromodifluoromethyl trifluoromethyl ether is also being sought. 

• Bromofluoroamines: There a number of derivatives of tris-trifluoromethyl amine being 

sought. 

SELECTION CRITERIA 

Selection criteria focus on obtaining compounds predicted to be effective extinguishants with 

acceptable boiling points and toxicity. 

Boiling point and ambient pressure criteria 

The ability to affect a flame extinguishing atmosphere in the fire zone or in the volume being 

protected is essential. A physical chemistry based estimate [2] of the maximum boiling point a 

compound may have and still achieve the extinguishment concentration provides some guidance 

to compound selection, Table 4. 
6

Table 4. Estimates of Maximum Boiling Points for Fire Suppression at 760 mmHg 

Conc. Ambient Temperature, °C 

% -60 -50 -40 -30 -20 -10 0 10 20 30 

1 33 47 61 76 90 105 119 133 148 162 

2 19 33 46 60 74 87 101 115 128 142 

3 11 24 37 51 64 77 91 104 117 130 

4 5 18 31 44 57 70 83 96 109 122 

5 0 13 26 39 52 65 77 90 103 116 

Example: A 4 vol.% air concentration at -20°C may be achieved by agents boiling at 57°C or 

less. 

For aircraft in-flight as well as non sea level fire suppression applications the effects of lower 

atmospheric pressure contribute favorably to agent vaporization, Figure 1. 

300

350

400

450

500

550

600

650

700

750

800

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49

Altitude (100 Meters)

Ambient Pressure (mmHg)

 

Figure 1. Ambient pressure at altitude 

While the lower atmospheric pressure at higher altitude is accompanied by markedly cooler air 

temperatures lower air pressure also depresses the boiling points of chemicals, Figure 2, which 

may help higher boiling compounds achieve sufficient volatility to function as fire suppressants 

and also avoid condensation on cold aircraft surfaces. Figure 2 depicts the effect of altitude on 

the sea level boiling point 32 oC of a compound. Assuming a heat of vaporization of 23 Kj/mole 

the estimated boiling point at an altitude of 5,000 meters is only 12 oC. 
7

200

300

400

500

600

700

800

4 8 12 15 19 21 24 27 29 32

Boiling Point (C)

Air Pressure (mmHg)

Figure 2. Boiling point estimate at low pressure 

Toxicity estimates - Cardiac sensitization 

Fire suppressing events expose by-standers and firefighters briefly to the suppressant chemical. 

This type of exposure is categorized as an acute event. While chronic exposure is a serious 

consideration initial studies of toxicity are, for the most part, focused on acute effects and 

toxicity. Typical initial screens are the Ames test, mouse micronucleus, and inhalation toxicity 

assessments. 

If initial testing is successful, a compound advances in consideration to testing that, in part, 

determines an agents uses in occupied and non-occupied application areas. The principal test 

here is the determination of a compounds ability to cause cardiac sensitization (cardiac 

arrhythmia) under conditions of an epinephrine challenge. In real life exposure situations these 

premature ventricular contractions (PVC’s) can cause immediate death. The cost of the standard 

dog exposure test to determine a compound's cardiac sensitization LOAEL is approximately 

$100 k. Cardiac arrhythmia is recognized as the primary (but not only) toxic effect of the 

halogenated compounds that dominates the search for halon alternatives. 

A wide range of chemically diverse compounds are known to induce cardiac arrhythmia. This 

situation has led to the hypothesis that the mechanism involved is not a chemical (reactivity 

based) toxicity but instead a generalized physical property effect, Table 5, that just happens to 

cause cardiac arrhythmia when sufficient chemical is absorbed into heart nerve and muscle cells 

membranes [3]. Halothane, CF3CHClBr, is amongst the compounds listed and Clark and 

Tinston’s determined EC50 level of 2.0 vol.% is similar to that of the structurally and 

compositionally and structurally similar halon 1211, CF2BrCl, whose LOAEL is 1.0 vol. %. 

It is interesting to note the relative consistency of the Relative Saturation Values in the righthand column of Table 5 and in view of the wide range of compounds listed to consider the 

possibility that if a chemical mechanism was the determining factor in cardiac sensitization, the 

Relative Saturation for Cardiac Sensitization values would be expected to be far less consistent 

and instead would exhibit a much wider range of values. The fact that these values are so 
8

consistent suggests that the predominant cardiac sensitization mechanism is the same for all of 

the compounds and compound types listed and is physical in nature. 

Table 5. Clark and Tinston data on cardiac sensitization in dogs [3]. 

Compound Vol. % at 

EC50

Partial pres at 

EC50 mmHg 

Vapor 

pressure at 

37C, mm Hg 

Relative 

Saturation for 

Cardiac 

Sensitization 

CFCl2CFCl2 0.12 2.0 99 0.02 

CCl4 0.5 4.0 190 0.02 

CH3CCl3 0.75 6.0 210 0.03 

CCl2FCF2Cl 1.0 8.0 524 0.02 

CFCl3 1.25 10 524 0.02 

CF3CHClBr 2.0 15.0 1186 0.01 

CH2Cl2 2.4 18 480 0.03 

CHFCl2 2.5 19 661 0.03 

CH2=CHCl 5 38 2052 0.01 

CF2Cl2 8 61 4218 0.01 

CF2ClCF2Cl 10 76 6764 0.01 

CH3CH2CH3 20 153 2310 0.03 

CF3Br 20 153 9538 0.01 

CF3Cl 80 610 15276 0.01 

The “physical effect” conclusions of Clark and Tinston are consistent with recent research that 

has also shown, using differential scanning calorimetry, that the inhalation anesthetic agent 

halothane (CF3CHClBr) decreases some cell membrane protein thermal unfolding temperatures 

[4]. The authors of this study reported that low, millimolar, concentrations of halothane produce 

significant destabilization of proteins [4]. Investigation of the effects of volatile anesthesia agent 

on voltage gated ion channels is also provides evidence for their inhibition of voltage-gated ion 

channels and to a greater extent on ligand-gated ion channels [5]. These same researchers report 

that “we can summarize these findings with the generalization that volatile anesthetics have 

high-efficacy on ligand-gated ion channels, whereas they have relatively low potency and high 

efficacy effects on voltage-gated ion channels”. 

Existing limited cardiac sensitization data for halogenated and non-halogenated volatile 

hydrocarbons provide few trends. The data compiled, 
9

Table 6, include non-halogenated compounds whose LOAEL values are considerably higher than 

those of halons. 
10

Table 6. Hydrocarbon, fluorocarbon and hyrofluorocarbon cardiac sensitization values 

Chemical formula NOAEL 

(vol. %) 

LOAEL (vol. 

%) 

CH3OCH3 10 20 

CH3CH2CH3 5 10 

CH2=CHCH3 - 15 

CF3CF2CF2CF3 40 >40 

CF3CF2CF3 30 >30 

CF3CHFCHF2 2.5 3.5 

CF3CHFCF3 9 10.5 

CF3CH2CF3 10 15 

CH2F2 20 25 

CHF3 30 >50 

CH2FCF3 4 8 

CH3CF3 4 8 

CHF2CF3 7.5 10 

CH3CF2H 5 15 

CF2ClH 2.5 5 

CF2Cl2 2.5 5 

CFCl3 0.5 

CH2=CClH 2.5 5 

CCl3CH3 0.25 0.5 

CF2ClCH3 2.5 5 

CFCl2CH3 0.5 

CF3CF2Cl - 15 

CF3CCl2H 1 2 

CFCl2CH3 - 1 

CF2ClCF2Cl - 2.5 

CClF2CFCl2 0.25 0.5 

CF2ClCF2CFHCl 2.0 

The fluorocarbons and hydrofluorocarbons listed, 
11

Table 6, demonstrate a wide range of LOAEL values. Degree of fluorination or total lack of 

fluorination appears to not be a determining factor in the LOAEL value. Limited data for 

partially fluorinated methane compounds demonstrate a relatively low tendency to induce 

cardiac sensitization. Limited hydrofluoropropane data fail to demonstrate increasing LOAEL 

values with increasing fluorination. Limited hydrofluoropropane data as well as 

hydrofluoroethane data demonstrate no correlation between degree of fluorination and LOAEL 

value but do suggest that fluorine (or conversely, hydrogen) position may be a strong factor in 

determining cardiac sensitization effects in these HFCs. 

Iodofluorocarbons, bromofluorocarbons, and bromochlorofluorocarbons listed in Table 7 reflect 

increasing LOAEL values where bromine is replaced by iodine. While the impact of iodine on 

cardiac sensitization LOAEL values might, based on the relative LOAEL’s of CF3Br and CF3I, 

be interpreted as high similarly low 0.1% LOAEL performances of CF3CF3CF2I and 

CF2BrCF2Br seem to suggest a more subtle mechanism. 

Table 7. Bromo, chloro and iodofluorocarbon cardiac sensitization values 

Chemical formula NOAEL 

(vol. %) 

LOAEL 

(vol. %) 

CF3I 0.2 0.4 

CF3Br 5.0 7.5 

CF2HBr 2 3.9 

CF2Br2 - - 

CF2BrCl 0.5 1.0 

CF2BrCF2Br - 0.1 

CBrClFCBrF2 0.5 

CF3CF2CF2I - 0.1 

Of the medical research areas impacted by phenomenon of cardiac sensitization, surgical 

anesthesia agents and pharmaceutical development are two areas that stand out. Published work 

in these areas provides an opportunity to gain additional insight into the phenomenon of cardiac 

sensitization and possibly some guidance for the development of a screening method. While 

literature is abundant in the general research areas of anesthesiology and cardiac 

electrophysiology and arrhythmia there was found, not surprisingly, no information or 

commercial laboratory services describing the approaches and methods employed by major 

pharmaceutical companies in their drug development research related to avoiding cardiac 

sensitizing or arrhythmia inducing drugs. 

Medical research in the areas of anesthesiology and cardiac arrhythmia does report links between 

a compounds physical properties and cardiac arrhythmia in clinical settings [6]. A primary 

difference of course being that the clinical setting reflect surgical anesthesia of humans with no 

epinephrine challenge while the cardiac sensitization test involves a dog’s exposure to the 

chemical, at levels that are just below the level at which the compound alone causes arrhythmia, 

with epinephrine challenge. While the clinical setting seeks to avoid the chemical induction of 

arrhythmia in patients, dog exposure studies seek to determine an extreme lower bound to ensure 

that chemicals employed in commercial settings do not put people in any danger of PVC induced 

sudden cardiac arrest. Clinical data presented by medical researchers seems to provide a 

reasonable basis for their observation that a relatively basic physical property, water/oil 
12

partitioning, and cardiac arrhythmia may be linked [6]. This relationship could well form the 

basis for a QSAR type of an approach to compound screening for cardiac sensitization. 

Anesthesia is the condition of loss of consciousness, usually coupled with the loss of response to 

pain and other stimuli. General anesthesia results from a depression of the central nervous 

system (CNS), which can be exerted by a wide range of chemicals. Anesthetic potency or mild 

CNS depression can also be observed in humans using performance decrement studies. 

Structure-activity relationships have been developed for predicting anesthetic effects [7]. 

The study of anesthesia is an active area of research with considerable published data on the 

influence of various compounds on human systems [6]. Published studies includes data on the 

relative tendencies of a wide range of current and former anesthesia agents to induce cardiac 

arrhythmia as well as comparison molecular property data, toxicity information and models for 

agent uptake to target tissues. Reviews covering cell membrane ion gate channel effects and the 

effects of molecular structure can be found in studies of pharmacokinetics and molecular 

physiology [8, 9]. Data presented relate uptake of anesthesia agents and physical properties such 

as blood gas ratios (partitioning) of the anesthesia agent based on relative solubility in the two 

media. 

Volatile anesthesia agents are not unlike halons in elemental composition. Anesthesia agents are 

represented by lower molecular weight brominated and chlorinated hydrofluoro alkanes and 

ethers. Some are chlorinated fluorocarbons. What may be more useful are studies of the 

minimum alveolar concentration (MAC) values determined for anesthesia agents [5,10] and 

clinical observations of the tendency of volatile anesthetics to induce cardiac arrhythmia or 

PVC’s [11]. These are summarized in a listing of the more common volatile anesthesia agents is 

presented in Table 8. These data demonstrate a correlation between the tendency of a compound 

to induce PVC’s and the Log(KOW) of the anesthesia agent. Halothane is notable for its greater 

tendency to induce PVC’s as compared to the other anesthesia agents listed. 

The search for a screening method that would provide an easy, low cost, method of guiding 

compound selection within a family of chemicals has thus far been unsuccessful. Past clinical 

research on anesthesia agents may provide guidance [12,11]. Clinical observations reported in 

medical research literature suggest a possible link between a compounds oil/water partitioning 

and its tendency to initiate PVC’s under normal surgical anesthesia, Table 8. 

Table 8. Anesthesia Compounds – Partitioning and Arrhythmia Properties 

Property Halothane Enflurane Isoflurane Desflurane Sevoflurane 

Formula CF3CHBrCl CF3-OCF2CHFCl 

CF3-OCHCl-CF3CHF2-OCHF-CF3CH2F-OCH(CF3)2

Blood-gas 

Ratio a 2.5 1.9 1.4 0.42 0.6 

Oil-water 

Ratio b 220 120 170 19 55 

Arrhythmia c +++ + + ~ ~ 

MAC d 0.74 % 1.68 % 1.15 % 6.3 % 2.0 % a

 Ratio - (blood anesthesia agent concentration)/(air concentration). 

b

 The "oil" phase is commonly, but not exclusively, octanol. 
13

c

 The symbols "+++," "+," and "~" reflect, in order, a decreasing tendency of the 

anesthetic to induce PVC’s in human patients during anesthesia. “~” indicates only a slight 

tendency. 

d

 Minimum Alveolar (air) Concentration (MAC) is a measure of the anesthetic potency of 

the compound, i.e., the air concentration where 50 % of patients don't have a motor 

response to a pain stimulus. 

Halothane (CF3CBrClH) is very prone to causing premature ventricular contractions (PVC’s). 

The alternative anesthetics listed above have progressively lower tendencies to induce PVC’s 

and also progressively lower oil-water distribution ratios when compared to halothane. This 

correlation is worth further study and at least preliminary examination as a means of guiding the 

selection of halon replacement candidate compounds. 

Intriguingly, the Meyer-Overton hypothesis predicts that the potency of conventional inhaled 

anesthetics correlates inversely with lipophilicity: minimum alveolar anesthetic concentration 

and the olive oil/gas partition coefficient [13]. 

Though limited in potential this approach may offer a near term means of screening and ranking 

the current candidate halon replacement candidates propensity to induce cardiac arrhythmia. 

There are similarities between the compounds used in anesthesia, representing a variety of 

fluorinated, chlorinated, and brominated agents from the alkane and ether families, and the 

families of current interest as halon replacement, 

CARDIAC SENSITIZATION SCREENING OPTIONS 

Two options for screening compounds for the purpose of identifying the most promising 

compounds for testing have been identified. Both of these approaches are in their infancy and 

need varying degrees of work in order to be of use. In both cases though, progress is hindered by 

the lack of cardiac sensitization test data for similar compounds - bromofluoroalkenes or ethers 

for instance. QSAR method development relies on a training set of data. The training set would 

link compounds, with known cardiac sensitization values and similar to those under 

consideration, to one or more attributes or physical properties in order to develop a predictive 

model. 

In vitro cardiac sensitization screening 

While the potential for developing an in vitro cardiac sensitization toxicity screen appears to be 

good it is likely to be a longer term research effort. In contrast, the development of a method 

based on one or more physical attributes of the compounds under consideration offers some 

promise. 

To be of greatest use to the halon replacement community, an in vitro-based test protocol (or a 

QSAR method) capable of at least differentiating between Halon 1301 (LOAEL 7.5 vol. %) and 

Halon 1211 (LOAEL 1.0 vol. %) or trifluoromethyliodide (LOAEL 0.4 vol. %) is a basic goal. 

This is due in part to the need to identify compounds whose fire suppression design air 

concentrations are expected to be in the range of 3 to 4 vol.% and whose LOAEL values are 

likely to be only two or three % higher. These tight air concentration constraints mandate the 

development of a protocol and test apparatus capable of closely controlling chemical exposure 

levels and durations. Future models would have to be able to distinguish between compounds 
14

whose LOAEL values differ by 1 to 2 vol. % in order to be of much use in final compound 

selection. 

Structure property relationships as cardiac sensitization models 

Hydrophobic hydrophilic partition coefficients have previously been identified as a possible 

property for inclusion in a QSPR approach [14] means of assessing oil/water partitioning 

properties are typically measured experimentally by shake flask or RP-HPLC methods. Of these 

two methods, the RP-HPLC based determination has the greater potential to yield a correctly 

ordered relative assessment of compound chromatographic retention times and therefore 

Log(KOW) values. 

Existing methods for calculating Log(KOW) values generally lack both experimentally 

determined values needed to yield models capable of yielding accurate estimates for similar 

compounds. 

Anecdotal reports, presumably referring to shake flask based (water/octanol) KOW 

determinations, suggest no relationship between partition coefficients and cardiac sensitization 

exists. This conclusion seems at odds with the clinical anesthetic discussed earlier, Table 8. 

Given the shake flask experimental accuracy requirement of 0.3 Log units [15] it is not 

surprising that no relationship was identified. Without a more precise Log(KOW) experimental 

method evaluating the link between compounds with known LOAEL values and their 

experimental Log(KOW) values is likely to be inconclusive. 

Calculated Log(KOW) estimates, Table 9, for an incomplete list of the tri and tetra fluorinated 

bromopropenes do not reflect the cis and trans structural isomerism of alkenes. 

Table 9. Representative calculated Log(KOW) estimates for bromofluoropropenes 

Estimation Method 

Compound KOWWIN CLogP XLogP A Log P IA Log 

P 

Average* 

CF2=CBrCF3 2.46 2.41 1.90 2.10 2.88 2.32 

CFBr=CFCF3 2.46 2.41 1.90 2.10 2.89 2.32 

CF2=CBrCF2H 1.85 1.75 1.85 1.93 2.65 1.88 

CFH=CBrCF3 2.41 2.16 2.11 2.14 2.86 2.24 

CFBr=CFCF2H 1.85 1.75 1.85 1.87 2.62 1.86 

CFBr=CHCF3 2.41 2.16 2.11 2.15 2.52 2.24 

CHBr=CFCF3 2.41 2.16 2.11 2.17 2.61 2.25 

CHF=CFCF2Br 2.47 1.93 1.95 2.15 2.82 2.19 

CF2=CFCFHBr 1.92 1.64 1.69 1.79 2.72 1.80 

CF2=CHCF2Br 2.47 1.69 1.95 2.25 2.51 2.22 

CF2=CBrCFH2 1.99 1.60 1.71 2.03 2.23 1.91 

CFH=CBrCF2H 1.80 1.50 2.06 1.91 1.89 1.87 

CHBr=CHCF3 2.35 1.90 2.33 2.38 2.00 2.23 

CH2=CBrCF3 2.49 2.5 1.86 2.16 2.78 2.38 
15

* Average – not including high and low values 

When compared to experimental Log(KOW) data for Halon 1301 and halothane the 

bromotrifluoropropenes and bromotetrafluoropropenes reveal one aspect in common. In both 

cases the modeling programs, on the average, rank compounds with a terminal CF3 higher (more 

hydrophobic) than compounds with a terminal -CFHBr, -CF2H, or -CFH2 group, Figures 2 and 3. 

The lower range of compound estimated Log(KOW) values in both cases are consistently similar 

to that of Halon 1301’s experimental value while the higher range of Log(KOW) values are 

consistently in the range of halothane – a known cardiac sensitizer in clinical settings, Figures 2 

and 3. 

0.00

0.50

1.00

1.50

2.00

2.50

CBrF=CHCHF2

Halon 1301 (exp)

CFBr=CFCFH2

CFH=CBrCF2H

CFH=CFCFBrH

CF2=CFCBrH2

CF2=CHCFBrH

CHBr=CFCHF2

CF2=CBrCFH2

CHF=CHCF2Br

CHBr=CHCF3

CH2=CFCF2Br

Halothane (exp)

CH2=CBrCF3

Average calculated Log(KOW)

Figure 3. Calculated Log(KOW) values for bromo-trifluoropropenes 

The available cardiac sensitization LOAEL results demonstrating a LOAEL of 1.0 vol % for 

CH2=CBrCF3, Clark and Tinstons observed 2.0 vol. % cardiac sensitization level for Halothane, 

the failure to observe PVC’s at 1.5 vol % in the dogs exposed to CHBr=CHCF3 in the recent 

AAWG sponsored study of this compound, and the 7.5 vol. % LOAEL of halon 1301 and the 

calculated Log(KOW) values seem to correlate relatively well and indicates that there are several 

trifluorinated bromopropenes whose cardiac sensitization properties are worthy of further 

investigation. 

While there are no tetrafluorinated bromopropenes for which LOAEL values have been 

determined to aid in the comparison of known LOAEL to calculated Log(KOW) the calculated 

Log(KOW) data and relative performance of halon 1301 and halothane in Figure 4 suggests that 

there are several tetrafluorinated bromopropenes worthy of acquisition and testing. 
16

0.00

0.50

1.00

1.50

2.00

2.50

CF2=CFCFHBr

Halon 1301 (exp)

CFBr=CFCF2H

CF2=CBrCF2H

CHF=CFCF2Br

CFBr=CHCF3

CFH=CBrCF3

CHBr=CFCF3

Halothane (exp)

Average calculated Log(KOW) value

Figure 4. Calculated Log(KOW) values for bromo-tetrafluoropropenes 

Near term screening approach to screening compounds for testing 

High Pressure Liquid Chromatography (HPLC) employing reverse-phase C18 stationary phase 

chromatography columns and gradient elution programming has the potential to quickly, 

accurately and relatively inexpensively provide the high resolution (0.05 Log (KOW) units) 

determinations needed to further investigate relationships between compounds LOAEL values 

and water/octanol partitioning property. Derivatives of this method are applied to model bloodbrain, blood-air, blood-tissue and other chemical uptake interfaces. This approach typically 

allows several compounds to be simultaneously injected along with standards (internal 

references of known Log(KOW)) enabling the comparative and reliable determination of 

experimental Log(KOW) values for a number unknown compounds as illustrated in Figure 5. 

Accuracy and reproducibility for this method are much higher than protocols based on the shake 

flask method [15]. Using an HPLC based method, the Log(KOW) of many compounds of 

interest as Halon 1301 replacements could be easily employed to generate a LOAEL prediction 

and identify the most promising halon replacement candidate(s). 

Several commercial pharmaceutical testing laboratories, where this testing is commonly done, 

have been identified and a preliminary estimate of laboratory cost is considerably less than 

$7,000. In addition, once experimental Log(KOW) values have been determined by RP-HPLC 

for available compound these values could be input into online models, incorporated in the 

models predictive “training sets”, with the result that additional un-synthesized compounds 

calculated Log(KOW) could be more accurately estimated. 
17

Figure 5. Illustration of RP-HPLC characterization of chromatographic retention times 

for use in estimating Log(KOW) values (x-axis is time).[16] 

These more accurate estimates could greatly enhance future compound selection. 

Summary 

Future progress in the study of the chemical families discussed here is expected to soon yield a 

clearly identified set of options. Cardiac sensitization screens are still needed and the study of 

potential relationships of hydrophobicity and lipophilicity may provide a reliable, time and 

resource saving approach to selection of the optimum compounds from the many 

bromofluropropene, bromofluoroether, and bromofluoroamine candidates. 

ACKNOWLEDGEMENTS 

This research is sponsored by the US Department of Defense’s Next Generation Fire 

Suppression Technology Program and funded by the DoD Strategic Environmental Research and 

Development Program. The Project Leader is Richard G. Gann, Ph.D., Senior Research Scientist 

- Building and Fire Research Laboratory, National Institute of Standards and Technology, 

Gaithersburg, MD. 

REFERENCES 

 

1 Tapscott, R.E., Sheinson, R.S., Babushok, V., Nyden, M.R., Gann, R.G., "Alternative 

Fire Suppressant Chemicals: A Research Review with Recommendations," NIST Technical Note 

1443, National institute of Standards and Technology, Gaithersburg MD, December 2001. 

2 Brabson, G.D., Garcia, M.M., Heinonen, E.W., Juarez, G., “Main Group Compounds as 

Extinguishants”, Final Report May 2001, NMERI 98/8/33380. 

3 Clark, D.G., Tinston, D.J., “Correlation of the Cardiac Sensitizing Potential of 

Halogenated Hydrocarbons With Their Physicochemical Properties”, British Journal of 

Pharmacology, Vol.49, 355-357, 1973. 
18

 

4 Tanner, Liebman & Eckenhoff, Toxicology Letters 100-101:387-391, 1998. 

5 Hemmings, H. C., and Hopkins, P. M., “Foundations of Anesthesia Basic and Clinical 

Science”, Chapter 22 Mechanisms of Anesthesia, 2000, Harcourt 

6 Hemmings, H. C., and Hopkins, P. M., “Foundations of Anesthesia Basic and Clinical 

Science”, 2000, Harcourt. 

7 Larsen, E. R., “Fluorine Compounds in Anesthesiology,” in Fluorine Chemistry Reviews, 

P. Tarrant, editor, Marcel Dekker, New York, pp. 1-44, 1969. 

8 Hemmings, H. C., and Hopkins, P. M., “Foundations of Anesthesia Basic and Clinical 

Science”, Chapter 5 Molecular Physiology, 2000, Harcourt 

9 Hemmings, H. C., and Hopkins, P. M., “Foundations of Anesthesia Basic and Clinical 

Science”, Chapter 8 Pharmacokinetics of Inhalation Anesthetics, 2000, Harcourt. 

10 Hemmings, H. C., and Hopkins, P. M., “Foundations of Anesthesia Basic and Clinical 

Science”, Chapter 24 - Inhalational Anesthetic Agents, 2000, Harcourt 

11 www.virtual-anaesthesia-textbook.com/vat/volatile.htm . A tutorial website with a wide 

variety of anesthesia agents clinical human exposure and cardiac effects information as well as 

further reference citations. 

12 Hemmings, H. Jr., and Hopkins, P., Foundations of Anesthesia - Basic and Clinical 

Sciences, Chapters 24 and 41, Harcourt Publishers Ltd., 2000. 

13 Eger EI; Ionescu P; Laster MJ; Gong D; Hudlicky T; Kendig JJ; Harris RA; Trudell JR; 

Pohorille A., “Minimum alveolar anesthetic concentration of fluorinated alkanols in rats: 

relevance to theories of narcosis,”Anesthesia and Analgesia, 1999 Apr, 88(4):867-76. 

14 Skaggs, S. R., Tapscott, R. E., Heinonen, E.W., Advanced Agent Program: Toxicological 

Screening Methods,” NMERI 95/48/31882, Wright Laboratories (WL/FIVCF), Tyndall Air 

Force Base, Florida, December 1996. 

15 EPA – Product Properties Test Guidelines, OPPTS 830.7550, Partition Coefficient ( nOctanol/Water), Shake Flask Method, Prevention, Pesticides and Toxic Substances (7101), EPA 

712–C–96–038, August 1996 

16 The reader is directed to the following internet site for additional examples and 

discussion of the application of RP-HPLC to comparison of compound retention times 

www.limathon.com/