MEMORANDUM

To:
Margaret Sheppard, U.S. EPA
CC:
Bella Maranion and Melissa Fiffer, U.S. EPA
From:
Jenny Tanphanich, Kara Altshuler, Reva Rubenstein, and Mark Wagner, ICF International 
Date:
February 4, 2013 
Re:
Review and Recommendation for Response to Adverse Comment on C7 Fluoroketone as a Halon 1211 Alternative (EPA Contract Number EP-W-10-031 Task Order 105, Task 01 and Task Order 205, Task 01)

This document does not contain Clean Air Act (CAA) Confidential Business Information (CBI) and, therefore, may be disclosed to the public.


ICF has reviewed comments specific to the proposed use of C7 FK as a streaming agent in EPA's Proposed Rule: Protection of Stratospheric Ozone:  Listing of Substitutes for Ozone-Depleting Substances  -  Fire  Suppression and Explosion Protection (September 2012). This memorandum summarizes ICF's responses to these comments and suggestions for future actions by the SNAP office. 

The remainder of this memorandum is organized into the following sections: 
   * Section 1: Introduction; 
   * Section 2: Chemistry of C7 FK; 
   * Section 3: Toxicity of C7 FK;
   * Section 4: Suggestions for Further Action; and
   * Section 5: References.

Please contact Kara Altshuler at 508-540-1774 or Mark Wagner at 202-862-1155 with any questions or comments.
                                       
                                       
                                       


1.  Introduction
In July of 2012, ICF submitted risk screens on the acceptability of use of C7 FK, submitted to the SNAP office by 3M, as a substitute for Halon 1211 in fire protection streaming applications.  The final risk screen discussed the atmospheric effects of the compound, including its global warming potential (GWP), ozone depletion potential (ODP), and atmospheric lifetime (ALT), and compared those parameters with Halon 1211 and two currently acceptable substitutes (i.e., HCFC-123 and HFC-236fa).  In addition, a discussion of the potential health effects of C7 FK was presented, which included exposure assessments for varying end users, such as occupational workers.  Health effects were evaluated via a review of available toxicity studies using animal models, and an acceptable exposure limit (AEL) for occupational workers was developed based on that review and using accepted risk assessment methodologies developed by EPA.  The decision by EPA that C7 FK was acceptable for use as a streaming agent was based in part on this risk screen.

EPA's Proposed Rule: Protection of Stratospheric Ozone: Listing of Substitutes for Ozone-Depleting Substances  -  Fire Suppression and Explosion Protection (September 2012) included C7 FK for use as a streaming agent.  A public comment posted in response to this proposed rule was made which questioned the potential toxicity of C7 FK based on the ability of some fluorinated ketones to react in the aqueous layer of human or animal tissues and exert toxicity.  The remainder of this memorandum addresses the supporting scientific literature and relevant background documents germane to assessing the raised concern of potential toxicity.
2.  Chemistry of C7 FK
C7 FK is a mixture of isomers with the following chemical formula, C7F14O:3-pentanone, 1,1,1,2,4,5,5,5-octafluoro-2,4-bis(trifluoromethyl) and 3-pentanone, 1, 1, 1, 2, 4, 4, 5, 5, 6, 6, 6-undecafluoro-2,4-bis(trifluoromethyl), with the octofluoro isomer representing 60% of the total mixture by weight (ICF 2012).  

Ketones, starting with the simplest one (acetone), are susceptible to hydrolysis.  In the case of acetone, substitution of fluorines for hydrogens, giving hexafluoroacetone (HFA), makes the compound more electrophilic, shifting the equilibrium dramatically to one that favors formation of a gem-diol hydrate (equilibrium constant of 10[6] vs. 10[-3] with acetone).  This is because fluorine is highly electronegative, thereby making C-O bonds more susceptible to nucleophilic attack.  This characteristic for reactivity in halogenated ketones is cited by J.L. Adcock in a public comment in response to the proposed rule (Adcock 2012).  Adcock comments on the reactivity of C7 FK, and stresses the expected ability of its two main components (listed above) to react "...with water...to form a perfluorinated 'gem-diol' of low volatility, moderate acidity, and significant surface active behavior...."

Adcock provides two references to support this expectation of reactivity.  One of the references is Chapter VI of the textbook Aliphatic Fluorine Compounds (Lovelace et al. 1958) titled, Ketones, Aldehydes, and Acetals.  This chapter, however, focuses specifically on ways of creating fluorine-containing organic compounds, including ketones, and only says such fluorine-containing ketones have a "high percentage of enol content and they easily form stable hydrates."  Nothing more specific to the compound in question, such as stability or reactivity, is contained within.  

The second reference, Gambaryan et al. (1966) also begins by discussing the vigorous reactivity of HFA with water or alcohols, resulting in a hydrate.  The article, however, is focused on the various fluoro-organic compounds that can be synthesized from perfluorinated compounds and discusses these methodologies in greater detail.  As these reactions often require harsh methods and solvents (e.g., heat, acids and bases, and organometallics), they are not relevant to the conditions in which C7 FK is proposed as a substitute for Halon 1211 in streaming applications.  The article provides no specific information regarding the reactivity or stability of C7 FK.  In summary, ICF found that both references documented the extreme reactivity of HFA in water, a fact that is supported by other sources of chemical information.  Adcock suggests that C7 FK is expected to react vigorously in water because HFA does so, but the recommended references provide no information to support that claim.

In the SNAP materials submitted for C7 FK in the streaming end-use (3M 2010a and 2010b) and more recent comments (Schultz 2012), 3M provided information that C7 FK has a very low solubility in water (estimates are on the order of <0.2 mg/mL) and a high Henry's Law Constant of 85,100 atm-m[3]/mole. These physical-chemical characteristics indicate that the compound, upon release to the environment, will be driven into the vapor phase, staying in the atmosphere and not partitioning or dissolving into surface water.  

Very little information is available regarding the potential for hydrolysis of highly fluorinated compounds.  According to 3M, alpha-branched fluoroketones cannot easily form hydrate intermediates (e.g., gem-diols) as do smaller perfluorinated ketones, due to their structure and low water solubility (Schultz 2012).  This argument is supported by comparisons of carbon-hydrogen and carbon-fluorine bond lengths.  For example, the C-H bond length is 106-109 pm, while that of C-F is 133-142 pm.  According to Lewandowski et al. (2006), fluorine atoms "tightly screen a carbon chain" and make perfluorinated compounds highly resistant to hydrolysis, photolysis, microbial degradation, and metabolism by vertebrates.  In the case of C7 FK, the ketone group is shielded by the two -CF3 groups on either side of the oxygen atom, which indicates that this alpha-branched perfluoroketone will be similarly resistant to solubility in water (see Figure 2).

	          
 
Figure 1.  Steric effects of  -- CH2 --  and  -- CF2 --  bonds (Taken from Lewandowski et al. 2006)
	

Figure 2.  2D Image of the octofluoro isomer of C7 FK (Taken from ChemSpider 2012)

Additional support for the hydrophobicity of C7 FK is provided by knowledge of the solvent dipolarity and polarizability of a compound, which measures the ability of a solvent to stabilize a charge or a dipole by virtue of its dielectric effect.  As evaluated by Kamlet et al. (1983), perfluoro-n-hexane has a dipolarity/polarizability value of -0.4, acetone has a value of 0.4, and water has a value of 1.09.  Although an imperfect surrogate for C7 FK, perfluoro-n-hexane is highly hydrophobic. C7 FK is likely to be highly hydrophobic as well, despite the presence of an internal ketone bond (as discussed earlier, the presence of so many fluorine atoms in C7 FK should shield the ketone bond from attack).  The lack of water solubility for C7 FK indicates that it will not form gem-diol hydrates and will thus not have appreciable effects in any organisms that might be exposed to it.
3.  Toxicity of C7 FK
In the comment to the Proposed Rule, Adcock indicates that the reactivity of perfluorinated ketones in water, particularly in tissues in which there is a lung:blood air interface (e.g., nose, sinus, trachea along an inhalation portal of entry) may pose significant risks to individuals breathing the compound due to interference with proper oxygenation of the blood and/or lung edema.  Such an effect would be evident in an animal toxicity test if it occurred.  Two inhalation studies were performed for C7 FK: a 5-day repeat toxicity study in which study animals were exposed to high concentrations of the compound, and a 28-day repeat dose study in which male and female rats were exposed to concentrations <=10,000 ppm for 6 hours per day.  The reported LC50 for the study was >10,000 ppm, the highest concentration used.  More importantly, no inhalation portal-of-entry effects were noted in either study.  No other observations were reported that might indicate any other adverse effects on blood oxygenation or similar impairments.  The recommended AEL for C7 FK is 225 ppm (ICF 2011), well below the 10,000 ppm high exposure concentration used in both studies. The animal toxicity data do not support the comment by J.L. Adcock that C7 FK is expected to react with water to form a stable gem-diol that will exhibit surface active behavior and thus may cause significant risk to individuals breathing the compound.
4. Suggestions for Further Action on C7 FK
ICF believes that C7 FK is acceptable for use as a streaming agent.  ICF does not believe that the AEL or risk screen documents need to be revised to respond to the comments to the proposed rule.  However, this response document can be used by EPA to further support its decision on this proposed end use for C7 FK. 
5. References
3M. 2010a. SNAP Submission to EPA for C7 Fluoroketone. February 22, 2010.
3M. 2010b. P-10-135  -  C7 Fluoroketone Teleconference EPA/3M Summary. November 22, 2010.
Adcock JL. 2012.  Comment in response to the Proposed Rule: Protection of Stratospheric Ozone: Listing of Substitutes for Ozone-Depleting Substances  -  Fire Suppression and Explosion Protection. Document ID: EPA-HQ-OAR-2011-0111-0026. October 22, 2012.
ChemSpider. 2012.  Chemical information for 1,1,1,2,4,5,5,5-octafluoro-2,4-bis(trifluoromethyl)penan-3-one.  (Available at http://www.chemspider.com/Chemical-Structure.63134.html)
Gambaryan NP, Rokhlin EM, Zeifman YV et al. 1966.  Reactions of the carbonyl group in fluorinated ketones. Angew Chem Internat Edit 5(11):947-956.
ICF. 2011.  Determination of an Acceptable Exposure Limit for C7 Fluoroketone.  May 2011.  
Kamlet MJ, Abbout J-L.M., Abraham MH et al. 1983.  Linear solvation energy relationships. 23. A comprehensive collection of the solvatochromic parameters, PI*, α, and ß, and some methods for simplifying the generalized solvatochromic equation.   J Org Chem 48:2877-2887.
Lewandowski G, Meissner E. et al. 2006.  Special applications of fluorinated organic compounds.  J Hazard Mater 136(3): 385-391.
Lovelace AM, Rausch DA, and Postelnek W. 1958. Chapter VI. Ketones, Aldehydes and Acetals. Aliphatic Fluorine Compounds. New York: Reinhold Publishing Corporation. pp. 180-187.
Schulz JF. 2012.  Comments in response to comment submitted by JL Adcock, in response to the Proposed Rule: Protection of Stratospheric Ozone: Listing of Substitutes for Ozone-Depleting Substances  -  Fire Suppression and Explosion Protection. November 30, 2012.
