FC-~5, FC-143 and FM-3422 - 90 Day Subacute Toxicity Studies
Conducted at IRDC - Review of Final Reports and Summary
OVERALL SUMMARY AND RECOMMENDATIONS

FC-95 was the most toxic of the three compounds studied and certainly
more toxic than anticipated. It produced mortalities in rats at a dietary
dose of i00 ppm (20 mg/kg/day) and in monkeys at an oral dose of 4.5
mg/kg/day. The primary target organs in rats were the liver, hematopoietic
tissues and upper gastrointestinal tract and in monkeys, the gastrointestinal
tract although no pathological lesions were reported. FC-143 appeared to be
the least toxic of the three compounds studied and produced no mortalities
in rats at dietary doses as high as I000 ppm (~ i00 mg/kg/day). However,
definite evidence of liver toxicity was seen at the high dose. In monkeys,
FC-143 caused deaths at oral doses of i00 (4/4) and 30 (3/4) mg/kg/day and
evidence of effects on hematopoietic tissue at these lethal doses. Like
FC-95 and FM-3422, FC-143 also produced clinical evidence of gastrointestinal
toxicity but no associated pathological lesions. FM-3422 caused deaths in rats
at dietary doses of i000, 3000 and i0,000 ppm (~ I00, 300 and i000 mg/kg/day
respectively) and in monkeys (1/4) at an oral dose of 30 mg/kg/day. The primary
target organ in rats appeared to be the liver although there was some gross
evidence of kidney and upper gastrointestinal tract involvement as well. In
monkeys, the gastrointestinal tract was affected clinically, but there were
no pathological lesions reported at necropsy.
The goals of conducting these 90 day subacute toxicity studies of
i) defining doses for chronic experiments and 2) obtaining general toxicological
information on the three compounds appear to have been met. However, several
questions surfaced that deserve further clarification. The apparent effect
of FC-95 on the liver and hematopoietic system of rats should be studied for
reversibility. The question of clinical gastroinestinal signs in monkeys
with all three compounds without any gross or microscopic pathology is certainly
perplexing, but may not be worth further pursuit since the oral route is not a
likely one for man. If another study with FC-143 is conducted to help define
the gastrointestinal and hematopoietic effects, the dog should be considered.
Since the most likely route of exposure in plant workers is by inhalation, an
inhalation study, probably with FM-3422, could be useful in evaluating any
effects via pulmonary exposure. Mary Case and Bill McCormick are preparing
protocols for follow-up to the toxicity questions mentioned.
Because of the apparent persistence of these fluorochemicals in the body,
the most important question remains possible long term effects. Although
lifetime rodent studies have limitations in predicting chronic effects
(carcinogenesis) for man, they are still considered the most reliable indicators
available. Unless there are adequate data through human epidemiological evaluations that can reasonably assure relative safety of these compounds following
long term exposure, lifetime rodent studies should be undertaken as soon as
possible. It maybe possible to limit the number of compounds evaluated in lifetime rodent studies to one or two if metabolic data can be used to establish
a common linkage between compounds.

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INDIVIDUAL SUMMARIES
FC-95

Study No. 137-085 - go Day Subacute Rat Toxicity Study
Dietary levels of FC-95 were administered to five male and five female
rats/level at 30, I00, 300, i000 and 3000 ppm which approximates 3, i0, 30,
i00 and 300 mg/kg/day respectively. All rats at the three highest doses
and 5/10 at i00 ppm died during the study. Predominant signs observed included emaciation, convulsions, altered posture, ocular, oral and anal discharges, hyperreactivity and reduced motor activity. Mortalities occurred
in a sequence related to dose, with earlier deaths seen at the highest level.
There was compound and dose related evidence of reduced body weight gain and
food consumption with actual weight loss at higher lethal doses. At 30 ppm
only slight body weight effects were present. The most notable clinical
pathology effects were observed at i00 ppm (values not obtained at higher
levels) and consisted of enzyme level increases suggestive of possible liver
toxicity and decreased erythrocytic values (principally hemoglobin and hematocrit with slight lowering of red cell counts) indicating an anemia. Pathologically, the most consistent and apparent compound related effect involved
liver, hematopoietic tissues (thymus, bone marrow, spleen, mesenteric lymph
nodes), gastrointestinal tract, muscle and skin.
In summary, FC-95 was relatively toxic to rats causing mortalities at
dietary doses as low as i00 ppm (~ l0 mg/kg/day). Primary target organs
appeared to be liver, hematopoietic tissues, stomach and small intestine
with some indication of a compound related effect in muscle and skin.

Stud~. No. 137-087 - 90 Day Subacute Rhesus Monkey Toxicity Study

FC-95 was administered by gastric intubation as an aqueous suspension
to two male and two female rhesus monkeys/level at doses of I0, 30, i00 and
300 mg/kg/day for up to 20 days. Because of unexpected early mortalities in
all monkeys at all levels (days 2-4 at 300, 3-5 at i00, 7-10 at 30 and 11-20
at I0 mg/kg/day), the study was inconclusive. Prominent signs observed
consisted of anorexia, decreased activity, emesis with some diarrhea, body
stiffening, general body trembling and twitching, weakness, convulsions
and prostration. No clinical pathology work was done because of the short
study duration. The only pathological lesions reported consisted of gross
yellowish-brown liver coloration at I00 and 300 mg/kg/day but no histopathologic basis for this finding was observed.
In summary, FC-95 proved to be considerably more toxic to monkeys than
anticipated resulting in early deaths preceded by gastroinestinal and central
nervous system signs. Although far from definitive, this study suggested the
gastrointestinal tract and possibly liver as target organs.

1199.0002

 Study No. 137-092 - 90 Day Subacute Rhesus Monkey Toxicity Study (Second
Study )
Since all monkeys died in the first FC-95 study (137-087), a second
experiment was conducted using oral garage doses of 0.5, 1.5 and 4.5 mg/kg/day
a~ministered to two male and two female monkeys/dose. The controls were the
same monkeys used in the first FC-95 e~periment. All 4.5 mg/kg monkeys exhibited signs of gastrointestinal tract toxicity (anorexia, emesis, black
stools, dehydration) starting on day 1 or 2 of. the study, and all died or
were sacrificed in extremis between weeks 5-7." Prior to death, these monkeys
showed marked or severe rigidity, convulsions, general body tremors, prostration
and loss of body weight. The monkeys at lower doses all survived, but evidence
of gastrointestinal toxicity was observed both at 1.5 and 0.5 mg/kg/day. The
only consistent clinical pathology observation reported was decreased alkaline
phosphatase values at all three doses. No gross pathological lesions considered
compound related were observed and the only microscopic pathology of apparent
compound relationship consisted of lipid depletion in the adrenals, atrophy
of pancreatic exocrine cells and atrophy of the serous alveolar cells of the
submandibular salivary glands in high dose monkeys. These latter effects may
be due to general debilitation of the animals.
In summary, FC-95 was relatively toxic to rhesus monkeys producing deaths
at doses as low as 4.5 mg/kg/day in 5-7 weeks. The apparent target organ was
the upper gastrointestinal tract although no pathological lesions were reported
even at the high dose.
FC-143

Study No. 137-089 - 90 Day Subacute Rat Toxicity Study
Dietary levels of FC-143 administered to five male and five female rats/level
were 10, 30, I00, 300 and i000 ppm which approximates I, 3, i0, 30 and i00
mg/kg/day respectively. Clinically, the only effect observed was slightly
decreased body weight gains at 300 and lO00 ppm. Clinical pathology abnormalities
reported in high dose male rats only included slightly lowered erythrocyte counts,
and elevated BUN and alkaline phosphatase values. There were several other variations from control groups in the clinical pathology parameters including fairly
consistent lowering of calcium levels at all doses, but these were not considered
abnormal based on the contract laboratory’s comparison to background control data.
Pathological abnormalities were confined to the liver and included gross enlargement and discoloration at i000 ppm, increased organ weights at I000 and 300 ppm
and several microscopic changes at i000 ppm.
In summary, FC-143 was well tolerated in rats at doses up to and including
300 ppm (~ 30 mg/kg/day). There was obvious liver toxicity at I000 ppm ( ~ I00
mg/kg/day), but no mortalities occurred.

1199.0003

 -4Study No. 137-090 - 90 Day Subacute Rhesus Monkey Toxicity Study
FC-143, suspended in 0.5% methocel, was administered by gastric intubation
to two male and two female rhesus monkeys/dose at 3, i0, 30 and I00 mg/kg/day.
All high dose monkeys died during weeks 2-5 and 3/4 30 mg/kg monkeys died during
the last half of the study. All monkeys that died showed clinical evidence of
gastrointestinal toxicity (anorexia, emesis, dark stools), but there were no
associated pathological lesions found at necropsy. No mortalities occurred and
only occasional signs of gastrointestinal effects were reported at the two lower
doses except for one i0 mg/kg monkey that had signs of gastrointestinal toxicity
for several days late in the study. There were a few abnormalities reported in
clinical pathology parameters, but no consistent pattern was observed. Gross
and microscopic pathological lesions were restricted to the two highest dose
levels and consisted of lipid depletion in adrenals, hypocellularity of bone
marrow and atrophy of lymphoid follicles of the spleen and lymph nodes.

In summary, FC-143 was less toxic than FC-95 in rhesus monkeys but, at
lethal doses (i00 and 30 mg/kg/day), evidence of effects on hematopoietic
tissue was seen. Like FC-95, the gastrointestinal tract also appeared to be
a target organ although this was not confirmed on histopathological examination.
FM-3422
Stud[ No. 137-086 - 90 Day Subacute Rat Toxicity Study

FM-3422 was administered in the diet to five male and five female rats/level
at 30, i00, 300, I000, 3000 and 10,O00 ppm which corresponds to approximately
3, i0, 30, i00, 300 and I000 mg/kg/day respectively. All rats at the i000,
3000 and i0,000 ppm levels died between days 9 and 29. Prominent signs observed
in these rats included emaciation, altered posture, convulsions, reduced motor
activity and/or increased sensitivity. At 30 ppm, a slight decrease in body
weight gain in females was the only clinical effect reported. There were also
some slight abnormalities in serum enzyme levels, but no pronounced trends.
Likewise, minimal effects were seen at I00 ppm. At 300 ppm there appeared to
be increased compound related clinical signs, decreased body weight gain and food
consumption, depressed hematological parameters and several alterations in
clinical chemistry values. Pathologically, the liver was grossly enlarged with
accentuated lobulation and discoloration with the 300 ppm group being more
severely effected than the i000 or 3000 ppm rats. This apparent reversed order
of toxicity related to dose could be due to the early mortalities of the high
dose rats and, therefore, a short dosing duration. The liver abnormalities
seen grossly were associated with increased liver weights and microscopic
lesions. Some kidney discoloration and evidence of stomach irritation were also
observed grossly at 300 ppm.
In summary, FM-3422 was lethal at doses of i000, 3000 and I0,000 ppm which
is approximately i00, 300 and i000 mg/kg/day respectively. The liver appeared
to be the primary target organ, but there was gross pathological evidence of
possible kidney and stomach involvement at the 300 ppm level also.

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 -5-

Study 137-088 - 90 Day Subacute Rhesus Monkey Toxicity Study
FM-3422, suspended in propylene glycol, was administered by gavage to
two male and two female monkeys/level using doses of i, 3, i0 or 30 mg/kg/day.
The vehicle appeared to cause anorexia early in the study necessitating volume
reduction from 5 to 2 ml/kg. The only mortality occurred in one high dose
monkey the last week of dosing. Gastrointestinal signs consisting of emesis,
diarrhea and black stools with mucus or bloody mucus were seen in most monkeys
from most groups. There were no clinical pathology observations that appeared
to be significant cc~pound effects. Pathological lesions reported included
lipid depletion of adrenals and atrophy of pancreatic exocrine glands at 30
mg/kg only.
In summary, FM-3422 caused mortality at 30 mg/kg in 1/4 monkeys and
appeared to primarily effect the gastrointestinal tract although there was
no supporting microscopic evidence.

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Date
RAN/Imr

1199.0005