Trifluoroacetic acid (TFA) is a liquid with a sharp biting odor. It has been proposed as the product of environmental degradation of the hydrochlorofluorocarbons HCFC-123, HCFC-124, HFC-134a, and HFC-125. Compounds HCFC-141b and HCFC-142b could yield mixed fluorochloroacetic acids, for which there is no available toxicologic data. The release of hydrochlorofluorocarbons into the environment could also give rise to HF, but the additional fluoride burden (1 to 3 ppb) in rainwater is trivial compared to levels in fluoridated drinking water (1 ppm), and would provide an insignificant risk to humans. Thus, in this paper only the toxocologic data on TFA is reviewed to assess the potential risks of environmental exposure

Kaminsky, Laurence S.

English

NASA Technical Reports Server

N92-15450
TOXICOLOGY OF ATMOSPHERIC DEGRADATION PRODUCTS
OF SELECTED HYDROCHLOROFLUOROCARBONS
Laurence S. Kaminsky
Department of Environmental Health & Toxicology
School of Public Health
State University of New York at Albany
Empire State Plaza
Albany, NY 12201
PRECEDING PAGE DI.h_.',KNOT F_LMED
https://ntrs.nasa.gov/search.jsp?R=19920006232 2020-03-17T14:22:45+00:00Z

BIOLOGICAL AND HEALTH EFFECTS
EXECUTIVE SUMMARY
The potential environmental degradation products of the hydrochlorofluorocarbons are trifluoroacetic
acid (TFA), mixed fluorochloroacetic acids, and hydrofluoric acid. There is no available toxicologic data
on mixed fluorochloroacetic acids. The additional fluoride burden, arising from environmental degrada-
tion of hydrochlorofluorocarbons, (1 to 3 ppb) in rainwater is trivial compared to levels in fluoridated
drinking water (1 ppm), and would provide an insignificant risk to humans.
Overall there is sparse available toxicologic data on TFA. The acute lethality of TFA in mice suggests
that it is only slightly toxic, and that its lethal effects at high doses are not dependent on its metabolism.
While a no adverse effect level has not been determined, 240 mg TFA/kg in rats produced no bone
marrow or small intestinal effects, 25 mg TFA/kg produced no body weight gains, relative testis weight
gains, or testicular histologic changes in rats, and 2000 mg/kg every second day for 14 days in mice produced
no hepatic necrosis, or heart and kidney histological changes.
TFA at 2000 mg/kg in mice significantly decreased hepatic NADPH and reduced glutathione levels,
but after 24-hr both levels returned to normal. Administration of 150 mg TFA/kg/day for 5-6 days to
rats decreased the hepatic glycogen content by 24%, the percent liver/body weight by 43 %, hepatic pyru-
vate kinase activity by 42%, and increased hepatic glycerol l-phosphate oxidase activity by 125%. Thus
the lowest dose at which effects have been reported is 150 mg/day for 5-6 days.
TFA is not mutagenic, but no carcinogenicity data is available. However, trichloroacetic acid is hepatocar-
cinogenic in mice, although it is also not mutagenic in the Ames assay. While no chronic toxicity data
on TFA is available it appears likely that on the basis of its resistance to metabolism, rapid clearance,
lack of mutagenic potential, and low acute toxicity TFA is unlikely to exhibit significant chronic toxic
effects. For a more complete assessment of TFA toxicity chronic studies are required, as well as acute
studies in species other than the mouse. The potential for TFA to act as a peroxisome proliferator should
be investigated, to gain insight into its hepatocarcinogenic potential.
A German Senate Commission for the Evaluation of Health Hazards in the Work Environment has recom-
mended that a blood TFA level of 2.5/ag/ml is risk-free. However, the assessment has no experimental
or epidemiologic basis.
455
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BIOLOGICAL AND HEALTH EFFECTS
1. INTRODUCTION
Trifluoroacetic acid (TFA) is a liquid bp 72.4°C, mp 15.4°C, with a sharp biting odor. It has been pro-
posed as the product of environmental degradation of the hydrochlorofluorocarbons HCFC-123, HCFC-124,
HFC- 134a, and HFC- 125. Compounds HCFC- 14 lb and HCFC- 142b could yield mixed fluorochloroa-
cetic acids, for which there is no available toxicologic data. The release of hydrochlorofluorocarbons into
the environment could also give rise to HF, but the additional fluoride burden (1 to 3 ppb) in rainwater
is trivial compared to levels in fluoridated drinking water (1 ppm), and would provide an insignificant
risk to humans (Murray, 1986; World Health Organization, 1984; US EPA, 1986). Thus, in this paper
only the toxicologic data on TFA is reviewed to assess the potential risks of environmental exposure.
Pharmacokinetics
There is little or no available data on the absorption, disposition, and elimination of TFA. In healthy
human volunteers the half-life for renal excretion of TFA administered intravenously is 16 hr (Holaday
and Cummah, 1976). In patients receiving halothane anesthesia the resultant metabolically-formed TFA
had a half-life in the blood of 52-60 hr (Dallmeier and Henschler, 1977).
For rats (200-260 g) administered 1.3 mmoi TFA/kg/day (150 mg TFA/kg/day) for 5 days the plasma
TFA levels (_mol/ml blood) were 0.7 and 0.75 after 1 day, 0.8 and 1.0 after 2 days, 1.1 and 1.25 after
3 days, 1.06 and 0.6 after 4 days, and 1.3 and 1.1 after 5 days. Each value represents a single estimation
and results are for two different animals at each time point (Stier et al., 1972). The average TFA concen-
tration in the livers of these animals was 1.1 gmol/g liver. These values represent approximately 10%
of the administered dose of TFA in the liver and 10% in the plasma (Stier et al., 1972).
TFA is not metabolized to any significant extent by rats (Fraser and Kaminsky, 1988). In humans TFA
is not metabolized and is quantitatively excreted in urine (D.A. Hotaday and R. Cummah, personal com-
munication reported in Fiserova-Bergerova, 1977). Fluoro substituents, when constituents of a trifluoromethyl
group, are metabolically stable relative to monofluoro substituents. Thus TFA is not metabolically defluori-
nated, in contrast to fluoroacetic acid, which has been demonstrated to be defluorinated by the rat hepatic
microsomal system (Smith et al., 1977; Kostyniak et al., 1978).
Acute Toxicity
The majority of studies on TFA toxicity involve acute administration. Several LD50 values have been
reported. For male Swiss-Webster, albino mice administered sodium trifluoroacetate intraperitoneally,
values of > 400 mg/kg (> 2.9 mmol/kg) (Rosenberg, 1971), > 2000 mg/kg (> 14.7 mmol/kg) (Airak-
sinen and Tammisto, 1968), > 5000 mg/kg (> 37 mmol/kg) (Blake et al., 1969), and > 2000 mg/kg
(> 14.7 mmol/kg) (Airaksinen et al., 1970) were obtained. TFA itself produced death in two of five
mice treated intraperitoneally at 150 mg/kg (1.1 mmol/kg), probably as a consequence of its acidity (Blake
et al., 1969). The LDs0 of sodium trifluoroacetate when administered intravenously to mice was 1,200
mg/kg (10.5 mmol/kg) (Airaksinen and Tammisto, 1968). Preadministration of phenobarbital (40 mg/kg/day)
for three days, or L-cysteine, isoniazid, ethanol, 4-iodopyrazole, or allopurinol administration 10 min
before and 3 hr after sodium trifluoroacetate administration did not affect its LDs0, suggesting that the
acetate was not being metabolized to toxic products (Airaksinen et al., 1970). Acute lethalities of the ord-
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BIOLOGICALANDHEALTHEFFECTS
er reported for TFA, categorize it as a "slightly toxic" substance (Klaasen et al., 1986). Other toxic end-
points, primarily involving effects on metabolic activity, have also been investigated. Sodium trifluoroacetate
in saline was administered by a single injection intraperitoneally to Swiss, albino, male mice (17-20 g)
(Rosenberg, 1971). By 12-hr after administration of 2000 mg/kg (14.7 mmol/kg) the concentration of
the coenzyme NADPH in the liver was statistically significantly decreased from 0.44 to 0.25 _mol/g.
The decreased levels returned to normal by 24-hr after administration (Rosenberg, 1971 ). Reduced glutathione
levels in the livers were also statistically significantly decreased from 4.33 to 3.94 _mol/100 mg at 12-hr
after administration and by 24-hr these levels had also returned to normal (Rosenberg, 1971).
Male Wistar rats (200-260 g) were administered TFA in the drinking water for 5-6 days, equivalent
to a dose of 150 mg TFA/kg body weight/day (1.3 mmol TFA/kg body weight/day) (Stier et al., 1972).
In TFA-treated rat liver relative to untreated rat liver, the soluble protein increased by 6%, the glycogen
content decreased by 24%, the neutral fat increased by 10% and the percent liver weight to body weight
by 43 %. None of these effects were evaluated for statistical significance. A number of enzyme activities
in liver of TFA-treated animals was altered relative to control rat livers: pyruvate kinase decreased by
42 %, phosphoglycerate kinase decreased by 10%, glycerol 1-phosphate oxidase increased by 125 %, glycerol-
phosphate dehydrogenase decreased by 4%, malic enzyme increased by 4%, glucose 6-phosphate de-
hydrogenase decreased by 17%, glyceraidehyde 3-phosphate dehydrogenase decreased by 4 %, enolase
decreased by 7%, malate dehydrogenase decreased by 10%, isocitrate dehydrogenase decreased by 10 %
and NADPH-oxidase increased by 7 %. Again differences were not evaluated for statistical significance
and it is doubtful whether any of the activities, with the possible exception of pyruvate kinase and glycerol
1-phosphate oxidase, were significantly affected.
In several studies TFA has been administered to animals, but without producing the certain specific
effects which were sought. However, there has been no systematic attempt made to determine a no ad-
verse effect level for TFA. TFA was neutralized in water and administered orally in a single dose to ten-
week-old male Alpk/AP strain rats (Lloyd et al., 1988; Lloyd et al., 1986). At doses of 10 or 25 mg/kg
(0.09 or 0.22 mmol/kg) body weight gains and relative testis weight were not affected, and no histological
changes were noted in the testes relative to untreated controls (Lloyd et ai., 1988; Lloyd et al., 1986).
Equivalent doses of 2,2,2-trifluoroacetaldehyde and 2,2,2-trifluoroethanol significantly reduced body weight
gain and relative testis weight, and produced histologically-detectable testicular damage.
When TFA (240 mg/kg, 2.1 mmol/kg) was administered intravenously to male Wistar rats no bone
marrow or small intestinal toxicity was detected (Fraser and Kaminsky, 1988). The metabolic precursors
of TFA, 2,2,2-trifluoroethanol and 2,2,2-trifluoroacetaldehyde, at equimolar doses produced significant
decreases in intestinal dry weight and leukocyte counts (Fraser and Kaminsky, 1988).
Swiss male mice (17-20 g) were injected intraperitoneally with sodium trifluoroacetate at 1000 mg/kg
(7.4 mmol/kg) and killed 24 hr later, at 2000 mg/kg (14.7 mmol/kg) and killed at 12 or 24 hr later, at
2000 mg/kg (14.7 mmol/kg) every second day for 14 days and killed on the 14th day (Rosenberg and
Wahlstrom, 1971). There were no TFA-induced histological changes in hearts or kidneys of any of the
treated mice. At the lowest dose of sodium trifluoroacetate (1000 mg/kg) histological changes in the liver
were noted including a cloudy swelling of the hepatocytes with a slight fat accumulation. At the higher
dose (2000 mg/kg) vacuolization of the hepatocytes was detected at all time periods (Rosenberg and Wahl-
strom, 1971). However, even after multiple doses no hepatic necrosis was detected.
457
BIOLOGICALANDHEALTHEFFECTS
Mutagenicity
TFA has been tested for mutagenicity in the Ames bacterial assay using two histidine-dependent strains
of Salmonella typhimurium, TA98 and TA 100 (Baden et al., 1976). TFA (150 mg/plate, 1.32 mmol/plate)
was incubated in an agar-overlay assay at 37°C for 2 days without a microsomal activating system. No
indication of mutagenicity was obtained under conditions where a positive control (N-methyl-N'-nitro-N°
nitrosoguanidine) was highly mutagenic. This lack of mutagenicity of TFA was confirmed under similar
conditions (Waskell, 1978). In a third study sodium trifluoroacetate was not mutagenic with Salmonella
typhimurium TA98, TA 100, and TA 1535 at all concentrations used up to 35.7 mg/ml (0.26 mmol/ml),
in the presence or absence of polychlorinated biphenyl (Aroclor 1254)-induced rat liver or testes post
mitochondrial supernatants (Blake et al., 1981). The concentration of TFA in these assays was the maxi-
mum non-toxic concentration for the bacteria.
It is important to note that while trichloroacetic acid has also been found to be nonmutagenic in the
Ames assay (Rapson et al., 1980; Waskeli, 1978), it is a hepatocarcinogen in mice (Herren-Freund, 1987).
Trichloroacetic acid has been demonstrated to produce peroxisome proliferation in mice (DeAngelo et
al., 1986), which has been proposed as one of the mechanisms of hepatocarcinogenesis (Reddy et al.,
1980), although it is questionable whether this mechanism applies in humans (Elcombe et al., 1985). Based
on these reports the potential of TFA to act as a peroxisome proliferator should be investigated to gain
insight into its potential as a hepatocarcinogen.
In Vitro Toxicology
TFA at 4 mM (450 mg/l) reduced the binding of the drugs warfarin and phenytoin to human serum
albumin to 56% and 85 % of controls, respectively. TFA at 10 mM (1140 mg/1) correspondingly reduced
the binding to 44% and 77% (Dale, 1986). The results suggest that TFA generally affects the conforma-
tion of the albumin. The potential of TFA to produce metabolic disturbances was tested in vitro in cul-
tured Morris rat hepatoma 7288C cells (Ishii and Corbascio, 1971). TFA (2.0 mM, 230 mg/l) did not
affect uridine or thymidine uptake, while at 10 mM (1140 mg/l) leucine and acetate uptake by the cells
was not affected. Thus at these concentrations DNA, RNA, protein and lipid synthesis by the cells was
not affected.
When TFA was infused at 200/amol/hr into 100 ml of perfusion medium for an isolated perfused rat
liver the levels of lactate and pyruvate decreased after 10 min (Stier et al., 1972). TFA produced a higher
uptake and turnover of lactate and pyruvate. This result is unusual in that fluorinated compounds usually
inhibit rather than accelerate metabolic processes.
Antigenicity
Aqueous solutions of chicken serum globin (10-15 mg/ml) and TFA (1.2 M) were mixed in a ratio of
1 to 1.5 at 4°C for 15 min. The mixture was dialyzed against water and lyophilized to produce a complex
of TFA and chicken serum globin, which was used to immunize rabbits (Rosenberg and Wahlstrom, 1973).
Undep these conditions TFA acted as a hapten and elicited antibodies. The clinical significance of this
observation is unknown.
458
BIOLOGICALANDHEALTHEFFECTS
_S
Several methods are available for the analysis of TFA in biological material. In urine or serum TFA
is quantitated by neutralizing with sodium hydroxide, esterifying with 2,2,2-trichloroethanol, and gas chro-
matographic analysis with a nickel-63 electron-capture detector (Witte et al., 1977). The detection limit
is 1 /ag TFA/ml body fluid. Another method uses isotachophoresis to quantitate urinary or blood TFA
(Mario et al., 1980). In serum TFA has been methylated and the head space vapor phase analyzed by
gas chromatography on Poropak Q (Fraser and Kaminsky, 1987).
2. CONCLUSIONS
Overall there is sparse available toxicologic data on TFA. The acute lethality of TFA in mice suggests
that it is only slightly toxic, and that its lethal effects at high doses are not dependent on its metabolism.
While a no adverse effect level has not been determined, 240 mg TFA/kg in rats produced no bone
marrow or small intestinal effects, 25 mg TFA/kg produced no body weight gains, relative testis weight
gains, or testicular histologic changes in rats, and 2000 mg/kg every second day for 14 days in mice produced
no hepatic necrosis, or heart and kidney histological changes.
TFA at 2000 mg/kg in mice significantly decreased hepatic NADPH and reduced glutathione levels,
but after 24-hr both levels returned to normal. Administration of 150 mg TFA/kg/day for 5-6 days to
rats decreased the hepatic glycogen content by 24 %, the percent liver/body weight by 43 %, hepatic pyru-
vate kinase activity by 42 %, and increased hepatic glycerol 1-phosphate oxidase activity by 125 %. Thus
the lowest dose at which effects have been reported is 150 mg/day for 5-6 days.
TFA is not mutagenic, but no carcinogenicity data is available. However, trichloroacetic acid is hepatocar-
cinogenic in mice, although it is also not mutagenic in the Ames assay. While no chronic toxicity data
on TFA is available it appears likely that on the basis of its resistance to metabolism, rapid clearance,
lack of mutagenic potential, and low acute toxicity TFA is unlikely to exhibit significant chronic toxic
effects. For a more complete assessment of TFA toxicity chronic studies are required, as well as acute
studies in species other than the mouse. The potential for TFA to act as a peroxisome proliferator should
be investigated, to gain insight into its hepatocarcinogenic potential.
A German Senate Commission for the Evaluation of Health Hazards in the Work Environment has recom-
mended that a blood TFA level of 2.5/ag/ml is risk-free (Dallmeier and Henschler, 1981). However, the
assessment has no experimental or epidemiologic basis.
459



Toxicology of atmospheric degradation products of selected hydrochlorofluorocarbons

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