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AMMONIUM PERFLUOROOCTANOATE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ammonium perfluorooctanoate is the ammonium salt of perfluorooctanoic acid (PFOA), a synthetic compound. PFOA is a fluorinated organic acid.

Specific Substances

    1) Ammonium pentadecafluorooctanoate
    2) Ammonium perfluorocaprilate
    3) Ammonium perfluorocaprylate
    4) Ammonium (perfluorooctanate d')
    5) Ammoniumperfluorooctanoaat
    6) Ammoniumperfluorooctanoat
    7) Ammonium perfluorooctanoate
    8) Ammonium perfluoro-octanoate
    9) Ammoniumperfluorooktanoat
    10) APFO
    11) C8
    12) C-8
    13) DS 101
    14) FC-143
    15) Fluorad FC 143
    16) Octanoate, pentadecadluoro-, ammonium
    17) Octanoic acid
    18) Octanoic acid, pentadecafluoro-, ammonium salt
    19) Pentadecafluoro-1-octanoic acid, ammonium salt
    20) Perfluoroctanssure, ammoniumsalz
    21) Perfluorooctanate d'ammonium
    22) Perfluorooctanoic acid, ammonium salt
    23) Perfluoroammonium octanoate
    24) Pentadecafluoroammonium salt
    25) Unidyne DS 101
    1.2.1) MOLECULAR FORMULA
    1) C8-F15-O2-H4-N

Available Forms Sources

    A) FORMS
    1) Ammonium perfluorooctanoate exists as a free-flowing, white powder, which is highly soluble in water (Pohanish, 2002; Lewis, 2001).
    B) SOURCES
    1) Ammonium perfluorooctanoate is a synthetic compound that does not occur naturally in the environment. It is produced from perfluorooctanoic acid (PFOA), also a man-made chemical (68 FR 18626, 2003).
    C) USES
    1) Ammonium perfluorooctanoate is used commercially in the polymerization of fluorinated monomers, generally for emulsifier and surfactant applications (Pohanish, 2002; Lewis, 2001).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) There is little human data regarding adverse health effects from acute exposure to ammonium perfluorooctanoate (APFO). Based on animal studies, APFO is considered moderately toxic following acute exposure and is an ocular irritant. APFO may cause cough, sneezing, nasal discharge, headache, hoarseness, nasal and throat pain and other signs of upper respiratory tract irritation if inhaled. Mild skin irritation may occur following dermal contact.
    2) In biologic media, APFO quickly dissociates to perfluorooctanoate which is the anion of perfluorooctanoic acid (PFOA). This management will address APFO when possible, but because of lack of data will also include information regarding PFOA. Perfluorooctanoic acid and its salts (APFO) are commonly referred to collectively.
    3) Occupational studies in humans have found higher organic fluoride concentrations in workers exposed to ammonium perfluorooctanoate, but no adverse health effects attributable to exposure have been seen. It is thought that the general population may be exposed to low levels of APFO, but it has not yet been determined how exposure occurs.
    4) In animal studies, chronic exposure by dermal, oral or inhalation primarily affects the liver. Increased liver weights and hepatocellular changes have been observed. Leydig cell tumors, mammary fibroadenomas and pancreatic acinar cell tumors have been reported in rats, but this is thought to be related to hepatic peroxisome proliferation. Peroxisome proliferation is thought to be species specific with humans predominantly nonresponsive.
    0.2.4) HEENT
    A) Eye irritation has been reported in animal studies.
    0.2.6) RESPIRATORY
    A) Acute lung injury has been seen microscopically in rats following acute inhalation exposure.
    0.2.7) NEUROLOGIC
    A) Ataxia, hypoactivity, piloerection and decreased limb tone were seen in acute toxicity studies in rats.
    0.2.8) GASTROINTESTINAL
    A) Weight loss and reduced food consumption were early signs of toxicity in animals.
    0.2.9) HEPATIC
    A) Ammonium perfluorooctanoate is a hepatotoxin in laboratory animals. Based on limited human studies, no adverse hepatic effects have been reported.
    0.2.14) DERMATOLOGIC
    A) Conflicting findings of skin irritation have been reported.
    0.2.16) ENDOCRINE
    A) Elevated serum estradiol levels have been reported in animal studies.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation in humans.
    B) Ammonium perfluorooctanoate was not teratogenic in rat inhalation or oral studies.
    0.2.21) CARCINOGENICITY
    A) The ACGIH rates ammonium perfluorooctanoate as A3, a confirmed animal carcinogen with unknown relevance to humans.

Laboratory Monitoring

    A) Monitor serum perfluorooctanoic acid (PFOA) levels. Total organic fluorine is less specific, but may be monitored if serum PFOA is not available.
    B) Monitor vital signs following a significant exposure.
    C) Monitor CBC, liver function tests, and lipids following a significant exposure or in symptomatic patients.
    D) If severe vomiting and/or diarrhea occur following exposure to ammonium perfluorooctanoate, monitor fluid and electrolyte levels.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) At the time of this review, no human overdose information was available.
    B) Treatment is symptomatic and supportive.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists.

Range Of Toxicity

    A) The minimum lethal human dose or maximum tolerated human dose has not been delineated.
    B) Death has occurred in rats at concentrations of 800 mg/m3 by inhalation.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) There is little human data regarding adverse health effects from acute exposure to ammonium perfluorooctanoate (APFO). Based on animal studies, APFO is considered moderately toxic following acute exposure and is an ocular irritant. APFO may cause cough, sneezing, nasal discharge, headache, hoarseness, nasal and throat pain and other signs of upper respiratory tract irritation if inhaled. Mild skin irritation may occur following dermal contact.
    2) In biologic media, APFO quickly dissociates to perfluorooctanoate which is the anion of perfluorooctanoic acid (PFOA). This management will address APFO when possible, but because of lack of data will also include information regarding PFOA. Perfluorooctanoic acid and its salts (APFO) are commonly referred to collectively.
    3) Occupational studies in humans have found higher organic fluoride concentrations in workers exposed to ammonium perfluorooctanoate, but no adverse health effects attributable to exposure have been seen. It is thought that the general population may be exposed to low levels of APFO, but it has not yet been determined how exposure occurs.
    4) In animal studies, chronic exposure by dermal, oral or inhalation primarily affects the liver. Increased liver weights and hepatocellular changes have been observed. Leydig cell tumors, mammary fibroadenomas and pancreatic acinar cell tumors have been reported in rats, but this is thought to be related to hepatic peroxisome proliferation. Peroxisome proliferation is thought to be species specific with humans predominantly nonresponsive.

Heent

    3.4.1) SUMMARY
    A) Eye irritation has been reported in animal studies.
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Ammonium perfluorooctanoate (0.1 g) instilled in rabbit eyes produced moderate conjunctival and iridal irritation that lasted up to 7 days (ACGIH, 2001; Griffith & Long, 1980).
    2) Corneal opacity and corrosion were confirmed by fluorescein staining in a rat inhalation study following a single high dose (5700 mg/m3) of ammonium perfluorooctanoate (Kennedy et al, 1986).

Respiratory

    3.6.1) SUMMARY
    A) Acute lung injury has been seen microscopically in rats following acute inhalation exposure.
    3.6.2) CLINICAL EFFECTS
    A) IRRITATION SYMPTOM
    1) WITH POISONING/EXPOSURE
    a) Inhalation of APFO may cause cough, sneezing, nasal discharge, headache, hoarseness, nasal and throat pain and other signs of upper respiratory tract irritation (Dyneon, 2002).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ACUTE LUNG INJURY
    a) Acute lung injury was seen microscopically in a rat inhalation study following a single 4 hour exposure (dose range 380 to 5700 mg/m3) to ammonium perfluorooctanoate (Kennedy et al, 1986).
    b) In an oral rat toxicity study, the lungs of most rats that died were found to be congested and pitted with red foci. One surviving animal was found to have lung damage. Following an acute inhalation study, moist rales were reported in one animal. At necropsy, the only abnormal finding was bilateral mottling of the lungs in 8 of 10 rats examined (Griffith & Long, 1980).

Neurologic

    3.7.1) SUMMARY
    A) Ataxia, hypoactivity, piloerection and decreased limb tone were seen in acute toxicity studies in rats.
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ATAXIA
    a) Ataxia, hypoactivity, piloerection and decreased limb tone developed in an acute oral toxicity study in rats. Signs were intermittent and did not appear to be dose-severity related (Griffith & Long, 1980).

Gastrointestinal

    3.8.1) SUMMARY
    A) Weight loss and reduced food consumption were early signs of toxicity in animals.
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) WEIGHT LOSS FINDING
    a) Weight loss and reduced food consumption were early signs of toxicity during a study of male cynomolgus monkeys receiving 20-30 mg/kg/day of ammonium perfluorooctanoate (Butenhoff et al, 2002).
    b) Male rats exposed to inhaled APFO (84 mg/m3) were found to have lower body weights during the exposure period, but recovered by day 16 after exposure (Kennedy et al, 1986).
    2) GASTROINTESTINAL FINDING
    a) In monkeys, anorexia, black stools and emesis were seen in a 90-day oral toxicity study in the 30 and 100 mg/kg/day dose groups (Griffith & Long, 1980).

Hepatic

    3.9.1) SUMMARY
    A) Ammonium perfluorooctanoate is a hepatotoxin in laboratory animals. Based on limited human studies, no adverse hepatic effects have been reported.
    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Animal studies have shown that perfluorooctanoic acid (PFOA) produced marked hepatic effects, including hepatomegaly, focal hepatocyte necrosis, hypolipidemia and alteration of hepatic lipid metabolism. In rodent studies, PFOA is a peroxisome proliferator and induces cytochrome P450 (Biegel et al, 2001).
    b) A cross-sectional study of 115 occupationally exposed workers examined the relationship between PFOA (note: the authors measured total serum fluorine levels as a surrogate variable for PFOA exposure; its use had been previously validated) and hepatic enzymes, lipoproteins, and cholesterol. No significant clinical hepatic toxicity in humans was found at the PFOA levels observed in this study. PFOA may modulate the effect of alcohol use and obesity on hepatic lipid and xenobiotic metabolism (Gilliland & Mandel, 1996; Butenhoff et al, 2002).
    c) Another study of ammonium perfluorooctanoate workers in 1993 (n = 111), 1995 (n=80), and 1997 (n =74) found no clinically significant hepatic toxicity associated with elevated serum perfluorooctanoic acid levels. This study was limited by the cross-sectional design of only 17 common subjects, low voluntary participation rates, and only a few subjects had serum levels >10 ppm (Olsen et al, 2000).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATOMEGALY
    a) Dose-dependent increases in liver weight as a result of mitochondrial proliferation occurred in male cynomolgus monkeys treated with ammonium perfluorooctanoate in all treatment groups (Butenhoff et al, 2002).
    b) Increased liver weight and hepatic beta-oxidation activity were observed in a 2-year ammonium perfluorooctanoate feeding study using male CD rats at all time points. A 2-fold increase in serum concentrations of estradiol and a 16-fold increase in total hepatic aromatase activity were seen. Histopathological exam also revealed increases in liver, Leydig cell, and pancreatic acinar cell tumors (Biegel et al, 2001).
    c) Another 14-day rat feeding study had similar findings and the authors suggested that increased serum estradiol produced by ammonium perfluorooctanoate in rats is partly due to a direct effect on the liver to increase synthesis of estradiol through aromatase cytochrome P450 induction (Liu et al, 1996).
    d) In a male rat inhalation study, livers were enlarged after receiving a single 4 hour exposure of APFO (380 to 5700 mg/m3), but returned to normal size by the end of the 42 day recovery period. Rats exposed to a subchronic, ten-dose treatment schedule also had higher liver weights and elevated blood fluoride levels throughout the experiment. Focal or multifocal hepatocellular necrosis was seen in some of the rats. Of those rats receiving the highest dose (84 mg/m3), each developed significantly elevated serum alkaline phosphatase immediately after administration (Kennedy et al, 1986).
    e) In rats, liver enlargement and microscopic hepatic enlargement were seen following dermal application of APFO (Kennedy, 1985).
    f) Sex related differences in toxicity were evident in rodent toxicity studies. Male rats were more likely to develop hepatotoxic effects at lower levels than the females. At comparable treatment levels, males had more pronounced histopathologic effects than the females. The serum and liver concentrations of organic fluorine were much greater in males than in females.
    1) Sex related differences in the organic fluorine concentration were not seen in similar studies with rhesus monkeys (Griffith & Long, 1980).

Dermatologic

    3.14.1) SUMMARY
    A) Conflicting findings of skin irritation have been reported.
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SKIN IRRITATION
    a) Ammonium perfluorooctanoate applied as a single application of 500 mg to rabbit skin produced moderate skin irritation that was still present at 48 hours (Kennedy, 1985).
    b) In another study, ammonium perfluorooctanoate was found to be non-irritating to rabbit skin (Griffith & Long, 1980).

Endocrine

    3.16.1) SUMMARY
    A) Elevated serum estradiol levels have been reported in animal studies.
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) Increased serum estradiol concentrations were seen throughout a 2-year rat feeding study in male CD rats using 300 ppm ammonium perfluorooctanoate and another peroxisome proliferator (Wyeth-14,643). The authors suggested that elevated estradiol levels may play a role in enhancement of Leydig cell tumors in the rat (Biegel et al, 2001).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IMMUNE SYSTEM FINDING
    a) Perfluorooctanoic acid (PFOA), a potent peroxisome proliferator, caused atrophy of the thymus and spleen after administration to laboratory mice (Yang et al, 2000).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation in humans.
    B) Ammonium perfluorooctanoate was not teratogenic in rat inhalation or oral studies.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Ammonium perfluorooctanoate was not teratogenic in rats after inhalation of concentrations up to 25 mg/m3 or by oral doses up to 100 mg/kg/day throughout organogenesis. Maternal deaths occurred at the higher doses by each route. Decreased fetal weight was seen at the highest inhalation dose (Staples et al, 1984).
    2) Developmental toxicity was studied in rats administered 0-150 mg/kg/day ammonium perfluorooctanoate by gavage on gestation days 6-15. At the 150 mg/kg dose, decreased maternal body weight, ataxia and maternal death were observed. No significant differences were seen in developmental parameters between the control group and the treated group (Kudo & Kawashima, 2003).
    3.20.3) EFFECTS IN PREGNANCY
    A) ANIMAL STUDIES
    1) The potential reproductive toxicity of ammonium perfluorooctanoate (APFO) was studied across 2 generations of Sprague-Dawley rats. Both males and females were gavaged with 0, 1, 3, 10, or 30 mg/kg APFO. Fertility, mating and natural delivery were not affected in either generation. Parental and first-generation male rats showed increased liver and kidney weight and decreased body weight at all doses. Decreased birth weight was observed at the 30 mg/kg dose in first-generation pups. In first-generation pup, viability was reduced at 30 mg/kg, thought to be due to reduced body weight at birth and weaning. Although somewhat lighter, no loss in viability was observed in second-generation pups at 30 mg/kg.
    a) Preputial separation and vaginal opening were somewhat delayed in second-generation rats at 30 mg/kg, but showed normal reproductive performance. The no observed adverse effect levels for reproductive function for parental and first-generation rats were > 30 mg/kg; for first-generation pup mortality, birth weight, and sexual maturation were 10 mg/kg; and for male body-weight and organ-weight changes were < 1 mg/kg (Butenhoff et al, 2004).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS3825-26-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) The ACGIH rates ammonium perfluorooctanoate as A3, a confirmed animal carcinogen with unknown relevance to humans.
    3.21.3) HUMAN STUDIES
    A) PROSTATE CARCINOMA
    1) A retrospective occupational cohort study, consisting of 2788 male and 749 female workers employed at a perfluorooctanoic acid (PFOA) production plant, reported a 3.3-fold increase in prostate cancer mortality among PFOA exposed workers as compared to non-PFOA production workers. However, the results must be interpreted cautiously as there were only 6 prostate cancer deaths overall and four were among the exposed workers. Overall, there was no significant increase in a cause-specific standardized mortality ratio for either men or women (Gilliland & Mandel, 1993).
    3.21.4) ANIMAL STUDIES
    A) LIVER CARCINOMA
    1) In a rat study using both biphasic and triphasic modulation protocols, perfluorooctanoic acid increased the incidence of hepatocellular carcinoma (Abdellatif et al, 1991).
    2) The International Agency for Research on Cancer (IARC) concluded that liver tumors induced in rodents by peroxisome proliferation are unlikely to have the same effect in humans(Kudo & Kawashima, 2003).
    B) TESTICULAR NEOPLASM
    1) A significantly increased incidence of Leydig cell adenomas were seen in rats fed up to 300 ppm ammonium perfluorooctanoate (APFO) for 2 years. The incidence of adenomas in this study was 0% in controls, 6% at 30 ppm, and 14% at 300 ppm. The historical incidence of adenomas in this species of rats was a mean of 4.68% (ACGIH, 2001; Cook et al, 1992).
    2) MAMMARY FIBROADENOMA
    a) In a 2-year feeding study in Sprague-Dawley rats, a statistically significant increase in mammary fibroadenomas was reported in females in both treatment groups (30 ppm and 300 ppm) (Kudo & Kawashima, 2003).
    3) LACK OF EFFECT - In one study, testicular toxicity was not reported in male cynomolgus monkeys receiving oral ammonium perfluorooctanoate in doses up to 30 mg/kg/day for 26 weeks (Butenhoff et al, 2002)

Genotoxicity

    A) Ammonium perfluorooctanoate has not been found to be mutagenic in S. typhimurium or S. cerevisiae assays. It showed no evidence of cell transformation.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum perfluorooctanoic acid (PFOA) levels. Total organic fluorine is less specific, but may be monitored if serum PFOA is not available.
    B) Monitor vital signs following a significant exposure.
    C) Monitor CBC, liver function tests, and lipids following a significant exposure or in symptomatic patients.
    D) If severe vomiting and/or diarrhea occur following exposure to ammonium perfluorooctanoate, monitor fluid and electrolyte levels.
    4.1.2) SERUM/BLOOD
    A) Monitor CBC, liver function tests and lipids following a significant exposure or in symptomatic patients.
    B) Monitor serum perfluorooctanoic acid (PFOA) levels. Total organic fluorine is less specific, but may be monitored if serum PFOA is not available.

Methods

    A) High performance liquid chromatography has been used to quantify perfluorooctanoic acid in serum from employees exposed to fluorochemicals commonly used in industrial applications for polymer production (Sottani & Minoia, 2002).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor serum perfluorooctanoic acid (PFOA) levels. Total organic fluorine is less specific, but may be monitored if serum PFOA is not available.
    B) Monitor vital signs following a significant exposure.
    C) Monitor CBC, liver function tests, and lipids following a significant exposure or in symptomatic patients.
    D) If severe vomiting and/or diarrhea occur following exposure to ammonium perfluorooctanoate, monitor fluid and electrolyte levels.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) At the time of this review, no data exists on acute exposure to ammonium perfluorooctanoate (APFO) in humans. Animal studies have shown that APFO is moderately toxic following acute exposure.
    B) Observe patients with large exposures for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) DILUTION
    1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting.
    D) ACTIVATED CHARCOAL
    1) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) At the time of this review, the efficacy of activated charcoal for the treatment of APFO ingestion is not known. The use of activated charcoal in cases with known or suspected gastrointestinal tract damage is probably contraindicated.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor liver function tests.
    2) Monitor fluid and electrolyte status in patients with significant diarrhea or vomiting.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Treat dermal irritation or burns with standard topical therapy. Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines.

Range Of Toxicity

Summary

    A) The minimum lethal human dose or maximum tolerated human dose has not been delineated.
    B) Death has occurred in rats at concentrations of 800 mg/m3 by inhalation.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.
    B) ANIMAL DATA
    1) A single 4-hour inhalation exposure was lethal to rats at a concentration of 800 mg/m3 (ACGIH, 2001).
    2) In a rat inhalation study, the median lethal concentration was 980+ mg/m(3)(Kennedy et al, 1986).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.
    B) ANIMAL DATA
    1) Rats tolerated oral doses of ammonium perfluorooctanoate of up to 3000 ppm for 28 days, although doses of 1000 ppm and greater resulted in reduced body weight gain (ACGIH, 2001).

Workplace Standards

    A) ACGIH TLV Values for CAS3825-26-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Ammonium perfluorooctanoate
    a) TLV:
    1) TLV-TWA: 0.01 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: Skin
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Liver dam
    d) Molecular Weight: 431.0
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS3825-26-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS3825-26-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Ammonium perfluorooctanoate
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS3825-26-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 457 mg/kg -- tremor; changes to hair; weight loss or decreased weight gain (RTECS, 2003)
    B) LD50- (ORAL)RAT:
    1) 430 mg/kg -- ptosis; ataxia; changes to hair (RTECS, 2003)
    C) LD50- (ORAL)RAT:
    1) 540 mg/kg (ACGIH, 2001)
    D) LD50- (SKIN)RAT:
    1) 7 g/kg -- somnolence (general depressed activity) (RTECS, 2003)
    E) LD50- (SKIN)RAT:
    1) 7000 mg/kg -- male rats(ACGIH, 2001)
    F) LD50- (SKIN)RAT:
    1) >7500 mg/kg -- female rats(ACGIH, 2001)
    G) TCLo- (INHALATION)RAT:
    1) 25 mg/m(3) for 6H, female, days 6-15 of pregnancy -- fetotoxicity; affected growth statistics (RTECS, 2003)
    H) TCLo- (INHALATION)RAT:
    1) 84 mg/m(3) for 6H/2W, intermittent -- changes in liver weight; affected biochemistry, including phosphatases (RTECS, 2003)
    I) TCLo- (INHALATION)RAT:
    1) 800 mg/m(3) for 6H/12D, intermittent -- fatty liver degeneration; liver function tests impaired; changes in liver weight (RTECS, 2003)
    7.7.2) RISK ASSESSMENT VALUES
    A) LOAEL- (ORAL)PRIMATE:
    1) 3 to 10 mg/kg-day for 26W -- 30% increase in absolute liver weight (DEP, 2002)
    B) LOAEL- (GAVAGE)RAT:
    1) 1 mg/kg-day -- male rats; statistically-significant increases in relative liver and kidney weights (DEP, 2002)
    C) LOAEL- (GAVAGE)RAT:
    1) 1.6 mg/kg-day for 2Y -- female rats; ovarian stromal tubular hyperplasia (DEP, 2002)
    D) LOAEL- (GAVAGE)RAT:
    1) 14 mg/kg-day for 2Y -- male rats; increased liver weight; hepatic cystoid degeneration; increased ALT enzyme activity; testicular vascular mineralization (DEP, 2002)
    E) LOAEL- (GAVAGE)RAT:
    1) 30 mg/kg-day -- female rats; increased mortality and decreased body weight (DEP, 2002)
    F) LOAEL- (INHALATION)RAT:
    1) 84 mg/m(3) for 6H/D, 5D/W for 2W -- male rats (DEP, 2002)
    G) LOAEL- (ORAL)RAT:
    1) 1.44 mg/kg-day for 90D -- male rats; statistically-significant increases in relative liver weight and CoA oxidase activity (DEP, 2002)
    H) NOAEL- (INHALATION)RAT:
    1) 1 mg/m(3) for 6H/D, 5D/W for 2W -- male rats; for liver effects (DEP, 2002)
    I) NOAEL- (INHALATION)RAT:
    1) 7.6 mg/m(3) for 6H/D, 5D/W for 2W -- male rats; for pulmonary effects (DEP, 2002)
    J) NOAEL- (ORAL)RAT:
    1) 0.47 mg/kg-day for 90D -- male rats (DEP, 2002)
    K) NOAEL- (ORAL)RAT:
    1) 1.3 mg/kg-day for 2Y -- male rats (DEP, 2002)
    L) NOAEL- (ORAL)RAT:
    1) 10 mg/kg-day -- female rats (DEP, 2002)
    M) NOEL- (INHALATION)RAT:
    1) 1 mg/m(3) -- repeated inhalation by male rats (ACGIH, 2001)
    N) NOEL- (ORAL)RAT:
    1) 1 ppm for 13W (ACGIH, 2001)

Pharmacology Toxicology

Toxicologic Mechanism

    A) The mechanism of tumorigenesis of ammonium perfluorooctanoate is not clearly understood. Some data appears to indicate that tumor induction by APFO is due to a non-genotoxic mechanism, involving activation of receptors and perturbations of the endocrine system. There is sufficient evidence to suggest that APFO is a peroxisome proliferator activated receptor (PPAR) alpha agonist and that the liver carcinogenicity/toxicity of APFO is mediated by binding to PPAR alpha in the liver (Kudo & Kawashima, 2003).
    B) Preliminary data suggest that the pancreatic acinar cell tumors are related to an increase in serum level of the growth factor cholecystokinin (Biegel et al, 2001).

Physicochemical

Molecular Weight

    A) 431.1

References

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