#ll.	United States
Environmental Protection
^^LbI M % Agency
EPA/690/R-04/006F
Final
12-21-2004
Provisional Peer Reviewed Toxicity Values for
Dimethylphenethylamine (Phentermine)
(CASRN 122-09-8)
Derivation of Subchronic and Chronic Oral RfDs
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms
bw - body weight
cc - cubic centimeters
CD - Caesarean Delivered
CERCLA - Comprehensive Environmental Response, Compensation, and Liability Act of 1980
CNS - central nervous system
cu.m - cubic meter
DWEL - Drinking Water Equivalent Level
FEL - frank-effect level
FIFRA - Federal Insecticide, Fungicide, and Rodenticide Act
g - grams
GI - gastrointestinal
HEC - human equivalent concentration
Hgb - hemoglobin
i.m. - intramuscular
i.p. - intraperitoneal
i.v. - intravenous
IRIS - Integrated Risk Information System
IUR - Inhalation Unit Risk
kg - kilogram
L - liter
LEL - lowest-effect level
LOAEL - lowest-observed-adverse-effect level
LOAEL(ADJ) - LOAEL adjusted to continuous exposure duration
LOAEL(HEC) - LOAEL adjusted for dosimetric differences across species to a human
m - meter
MCL - maximum contaminant level
MCLG - maximum contaminant level goal
MF - modifying factor
mg - milligram
mg/kg - milligrams per kilogram
mg/L - milligrams per liter
MRL - minimal risk level
MTD - maximum tolerated dose
MTL - median threshold limit
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NAAQS - National Ambient Air Quality Standards
NOAEL - no-observed-adverse-effect level
NOAEL(ADJ) - NOAEL adjusted to continuous exposure duration
NOAEL(HEC) - NOAEL adjusted for dosimetric differences across species to a human
NOEL - no-observed-effect level
OSF - Oral Slope Factor
p-RfD - provisional Oral Reference Dose
p-RfC - provisional Inhalation Reference Concentration
p-OSF - provisional Oral Slope Factor
p-IUR - provisional Inhalation Unit Risk
PBPK - physiologically based pharmacokinetic
ppb - parts per billion
ppm - parts per million
PPRTV - Provisional Peer Reviewed Toxicity Value
RBC - red blood cell(s)
RCRA - Resource Conservation and Recovery Act
RGDR - Regional deposited dose ratio (for the indicated lung region)
REL - relative exposure level
RGDR - Regional gas dose ratio (for the indicated lung region)
RfD - Oral Reference Dose
RfC - Inhalation Reference Concentration
s.c. - subcutaneous
SCE - sister chromatid exchange
SDWA - Safe Drinking Water Act
sq.cm. - square centimeters
TSCA - Toxic Substances Control Act
UF - uncertainty factor
ug - microgram
umol - micromoles
VOC - volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
DIMETHYLPHENETHYLAMINE (CASRN 122-09-8; Phentermine)
Derivation of Subchronic and Chronic Oral RfDs
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions or the EPA Headquarters Superfund Program
sometimes request that a frequently used PPRTV be reassessed. Once an IRIS value for a
specific chemical becomes available for Agency review, the analogous PPRTV for that same
chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a
PPRTV cannot be derived based on inadequate data.
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Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Dimethylphenethylamine (l,l-dimethyl-2-phenylethylamine), commonly known as
phentermine, is used as an appetite suppressant (anorectic) drug. Neither a subchronic nor
chronic RfD for phentermine is listed on IRIS (U.S. EPA, 2003) or in the HEAST (U.S. EPA,
1997) or Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). The CARA list
(U.S. EPA, 1991, 1994) does not report any relevant documents for phentermine. ATSDR
(2002), I ARC (2002) and WHO (2002) have not published review documents for phentermine.
The initial literature searches of TOXLINE (1965-1995), MEDLINE (1980-1995),
CANCERLINE (1986-1995), CCRIS, TSCATS, RTECS, GENETOX, DART/ETICBACK, and
EMIC/EMICBACK were conducted and screened in September 1995 to identify relevant data on
phentermine. Update literature searches from 1995 to 2003 were performed in January, 2003
using the same databases, except for replacement of CANCERLIT with CANCERLINE and the
addition of HSDB. The MEDLINE search strategy was unusually broad to facilitate identifying
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pertinent clinical studies. The NTP (2002) status report was also searched for relevant
information. Additional literature searches from January 2003 through September 2004 were
conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological
Abstracts databases.
Phentermine acts on the nervous system by the same general mechanism as amphetamine
(l-methyl-2-phenylethylamine) by stimulating sympathetic nerves via mimicking the action of
catecholamine neurotransmitters (norepinephrine) and by stimulating the release of dopamine
(Balcioglu and Wurtman, 1998; Baumann et al., 2000; Glazer, 2001; Hoffman and Lefkowitz,
1990; Silverstone, 1992; Sullivan and Comai, 1978). Stimulation of the sympathetic nervous
system elicits various types of physiological and metabolic responses, although not all
sympathomimetic amines produce each response and many differences in effects of these
compounds are only quantitative. Effects of phentermine are mainly associated with the CNS,
particularly appetite reduction and excitatory changes, and appetite suppression seems to be the
main basis for phentermine-related weight loss.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
Phentermine is usually administered by capsule in a single daily dose of 30 mg, often as
the hydrochloride salt (equivalent to 24 mg phentermine base) complexed in a sustained release
ion-exchange resin (Table 1). Assuming an average body weight of 90 kg for obese people
based on typical values from clinical studies of phentermine (Table 1), the usual therapeutic
dosage of 24-30 mg/day corresponds to approximately 0.3 mg/kg-day. Phentermine seems to be
preferred for short-term therapeutic use (up to 6 months) in selected patients with significant
obesity and medical risk, and there is currently limited information on efficacy or safety of
prolonged use and possible development of tolerance, particularly in healthy individuals
(Silverstone, 1992).
Numerous clinical trials of phentermine have been conducted to assess its efficacy as an
appetite suppressant (i.e., an anorectic drug) and (in some studies) potential for adverse side
effects (Table 1). The people tested in these trials are not representative of the general
population in that they were markedly overweight (generally averaged 43-55% over ideal
weight) and, in many of the studies, had calorie restricted diets (generally 1000-1500 cal/day).
The preponderance of phentermine studies were double-blind and 3-6 months in duration and,
when considered together, demonstrate that 0.3 mg/kg-day dosages of phentermine are effective
in promoting weight loss. Body weight losses were quite variable but averaged 6-13% lower
than placebo or pretreatment weights at the end of most of the studies, reflecting average weekly
losses in the 0.2-0.4 kg range. Weekly losses tended to decrease after several weeks of
treatment, but it is unclear if this was due to development of tolerance or a plateau effect
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(maintenance weight). The anorectic effectiveness of phentermine appears to be similar
following intermittent (alternate 4-week) or continuous exposure (Munro et al., 1968; Truant et
al., 1972; Steel et al., 1973). There is a dearth of information on objective effects of phentermine
other than weight loss; blood pressure and heart rate were reduced approximately 3% in one trial
(Valle-Jones et al, 1983), but these cardiovascular effects were attributed to weight loss rather
than directly to the chemical. Subjective side effects were reported in many of the clinical
studies, with dry mouth and symptoms of CNS stimulation (e.g., insomnia, nervousness,
irritability, mild hyperactivity) occurring most frequently (Table 1). Prevalences and incidences
of subjective effects were often in the range of 20-30%; however, they were not reported by
subjects in all studies (Langlois et al., 1974; Jackson and Vanik, 1976), and some of the studies
were limited by lack of placebo comparisons and other data insufficiencies.
In a case-control analysis of a cohort of more than 8000 U.K. patients who received
prescriptions for anorectic drugs (887 exposed to phentermine, 6091 exposed to
dexfenfluramine, and 2355 exposed to fenfluramine) and 17,225 obese subjects without exposure
to these drugs, no cases of stroke associated with phentermine use were identified (Derby et al.,
1999).
The only information located regarding possible adverse human birth outcomes following
exposure to phentermine during pregnancies was an abstract report that no pattern of offspring
malformation or increase in spontaneous abortion rate was found among 86 women who used
anorectic drugs (77 used phentermine) during the first trimester of pregnancy (McElhatton et al.,
2000).
In weight-control therapy programs, phentermine has been used in combination with
fenfluramine, an appetite suppressant which is thought to act via activation of serotonergic
pathways (not via noradrenergic pathways as with phentermine). In September, 1997, however,
fenfluramine was voluntarily withdrawn from the market as a result of a Food and Drug
Administration (FDA) survey of reports that 32% of 271 users of the combination ("phen-fen")
showed asymptomatic heart valve abnormalities (valvular regurgitation) and a report of 24 cases
of symptomatic valvular heart disease associated with phen-fen use (Connolly et al., 1997;
Glazer, 2001). The combined use of these drugs for weight control (each individually approved
for weight control by the FDA) was based on placebo-controlled clinical trials and showed that a
combination treatment with fenfluramine (30 mg once daily) and phentermine (15 mg once
daily) was equally effective in inducing weight loss with fewer adverse effects (dry mouth,
palpitations, or CNS symptoms including sleep difficulties, nervousness, depression, fatigue, or
increased dreaming) compared with phentermine (30 mg once daily) alone or fenfluramine (20
mg, three times per day) alone (Weintraub et al., 1984, 1992). Since the withdrawal of
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Table 1. DOUBLE-BLIND CLINICAL STUDIES OF PHENTERMINE
Population
Experimental Design
Results and Comments
Reference
23 women. Mean age 56
years, mean weight 202 lb
(92 kg).
Capsules containing 30 mg phentermine
as resin were ingested once daily for 12
weeks. Body weight was measured
biweekly.
No placebo was used. Subjects initially averaged 43% over
ideal weight and had 3% mean weight loss after 12 weeks.
Most of the effect occurred during the first 4-8 weeks;
cumulative mean weight loss was 2.0, 2.5 and 2.7 kg at
week 4, 8 and 12, respectively. Mean rate of weight loss
was 0.2 kg/week. Spontaneously reported subjective side
effects included thirst (8/23), dry mouth (4/23), reduced
appetite (4/23), nausea (3/23), increased energy (3/23) and
constipation (2/23). Some of the phentermine subjects may
have had mild diabetes mellitus controlled by diet alone
(reported by 7 of 56 exposed to phentermine or
dexamphetamine).
Seaton et al., 1964
108 women in 3 groups of
36. In Groups 1, 2 and 3,
mean age was 42, 35 and
38 years, and mean body
weight was 203, 207 and
214 lb (92, 94 and 97 kg),
respectively.
Capsules containing phentermine as
resin were ingested once daily in
dosages of 0 mg (placebo) continuously
(Group 1), 30 mg continuously (Group
2) or 30 mg intermittently (Group 3) for
36 weeks. The intermittent schedule
involved alternate 4-week exposures to
phentermine (5 periods) and placebo (4
periods). Body weight and symptoms
were evaluated every 4 weeks.
Subjects in Groups 1, 2 and 3 had recommended diets
providing =1000 calories/day (restricted carbohydrates),
initially averaged 48, 58 and 55% higher body weight over
ideal weight, and had 5, 13 and 13% mean total weight loss
after 36 weeks. The rate of weight loss also was similar in
Groups 2 and 3 and was greatest during the first 20 weeks.
25, 17 and 22 of the subjects in Groups 1, 2 and 3
respectively, completed the trial; of those that failed
completion, 0, 8 and 11% were due to subjective side
effects attributed to CNS stimulation. Effects in Groups 1,
2 and 3 included reduced appetite (20, 71, 82%),
"troublesome" symptoms suggesting CNS stimulation (8,
24, 27%), and drv mouth (0, 0, 18%).
Munro et al., 1968
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Table 1. (cont.) DOUBLE-BLIND CLINICAL STUDIES OF PHENTERMINE
Population
Experimental Design
Results and Comments
Reference
104 subjects in groups of
36 (Group 1; 26F, 10M),
34 (Group 2; 25F, 9M) and
34 (Group 3; 23F, 11M).
Group mean ages were 37-
38 years, and group mean
baseline body weights
were 175-179 lb (80-81
kg).
Capsules containing phentermine resin
were ingested once daily in doses of 0
mg (placebo) continuously (Group 1), 30
mg continuously (Group 2) or 30 mg
intermittently (Group 3) for 16 weeks.
The intermittent schedule involved
exposure to phentermine alternated with
placebo during weeks 4, 8, 12 and 16.
All groups were followed for 4 weeks
post-treatment. Body weight, side
effects, temperature, blood pressure, and
pulse and respiration rates were
evaluated weekly. Complete physical
exams and laboratory tests were
performed at beginning and end of
study.
Diets had a fixed caloric content (provided 60% of the
calories required to maintain ideal weight of each subject).
Group body weights initially averaged 43-45% higher than
ideal weight. Mean weight losses in Groups 2 and 3 were
similar to each other and higher than in Group 1 during all
treatment periods. Mean weight loss at the end of week 16
was 11.5, 20.3 and 18.4 lb ( = 6.5, 10.3 and 11.6%) in
Groups 1, 2 and 3, respectively. No clear indications of
tolerance were found. Evaluation at the end of the 4-week
observation period showed that = 22% (5/23) and 48%
(26/53) of the placebo and combined treated groups,
respectively, had gained more than 1 pound. Success in
attaining 16-week target weights and rate of weight loss
also were more frequent in the treated groups than in
controls. The most frequently reported complaints in
Groups 1, 2 and 3 were dry mouth (=19, 53 and 38%),
constipation (=17, 41 and 21%), insomnia ( = 8, 32 and
27%) and nervousness ( = 8, 29 and 15%).
Truant et al., 1972
32 women. Mean age 39
years, mean weight 206 lb
(94 kg).
36-week intermittent schedule in which
five 4-week exposure periods (one
capsule containing 30 mg phentermine
daily) were alternated with four 4-week
non-exposure periods (placebo daily).
Body weight and symptoms were
evaluated every 4 weeks.
Diets providing approximately 1000 calories/day (restricted
carbohydrates) were recommended. Subjects initially
averaged 43.7% over ideal weight. Mean weight loss at the
end of 36 weeks was 12.8% and mean rate of weight loss
was 0.3 kg/week. Weight loss was greatest during the first
half of the study, particularly during the treatment weeks.
A side effect (dizziness) during the first 4 weeks excluded
2 subjects from the trial. Many (not quantified) subjects
noted dry mouth, constipation or increased urinary
frequency at beginning of the test but these effects were
well tolerated. Other side effects included sleeplessness
(20%), nausea and vomiting (14%), dizziness (9%) and
drowsiness (8%). The side effects were attributed to CNS
stimulation but not regarded as "clinically appreciable".
Steel et al., 1973
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Table 1. (cont.) DOUBLE-BLIND CLINICAL STUDIES OF PHENTERMINE
Population
Experimental Design
Results and Comments
Reference
Groups of 30 (5M, 25F)
control and 29 (24F, 5M)
treated subjects. Mean age
35.1 years (control) and
39.7 years (treated). Mean
weight 187 lb (85 kg)
(same for both groups).
Phentermine was administered as the
hydrochloride in capsule once daily in
dosages of 0 mg (placebo) during weeks
1-2 (all subjects, pretreatment), 0 or 30
mg during weeks 3-16, and 0 mg during
weeks 17-18 (all subjects, post-
treatment). Patient history was
evaluated pretreatment and at week 16.
Clinical evaluations (body weight, vital
signs, clinical symptoms) were
performed pretreatment and at 2-week
intervals for 18 weeks. Body weights
were also determined at week 22 (27
controls, 25 treated, sex distribution not
reported). Laboratory evaluations
(hematology, clinical chemistry,
urinalysis) were performed pretreatment
and at weeks 4, 8, 12, 16 and 18.
Physical examinations (systems
evaluation, ophthalmologic examination,
chest X-ray, EKG) were performed
pretreatment and at week 16.
Subjects initially averaged 42.2% (controls) and 42.8%
(treated) over ideal weight. 84% of the subjects (23
controls, 26 treated, sex distribution not reported)
completed 18 weeks of evaluation. A 1000 calories/day
diet was encouraged but not enforced. Mean body weight
and mean weight loss after week 2 baseline were
significantly (p<0.05-0.001) lower and higher, respectively,
than the placebo group at each evaluation period. At week
16, body weight was -1% lower and weight loss was
= 313% higher than in the control group. Average weight
loss per week was 1.2 and 0.3 lbs. in the treated and control
groups, respectively. Both body weight and weight gain
were increased in control and treated groups during post-
treatment weeks 16-18, but the increases in the treated
group were significantly greater than in the controls. Mean
body weight increased in both groups during weeks 18-22,
but was lower in the treated group than in controls (6.3%,
p<0.001 at week 22). Mean body weight of the treated
group, but not controls, was lower at week 22 than at the
week 2 baseline (6.5%, p<0.001). No treatment-related
differences in incidences of side effects (headaches,
nervous, insomnia, dizzy, sweating, irritability) or other
clinically significant inter- or intra-group changes were
found.
Langlois et al.,
1974
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Table 1. (cont.) DOUBLE-BLIND CLINICAL STUDIES OF PHENTERMINE
Population
Experimental Design
Results and Comments
Reference
26 obese diabetics. Sex,
age and weight not
reported.
Phentermine in capsule was ingested
once daily in dosages of 0 (placebo) or
30 mg on alternating months for 6
months. No continuous exposure to
phentermine or placebo. Body weight,
pulse rate, blood pressure, urine and
blood glucose, plasma insulin,
triglycerides and cholesterol were
evaluated monthly.
Subjects lost a group total of 63.4 kg while taking
phentermine and gained 21 kg while taking placebo. Mean
weight loss per subject was 0.81 kg/month. Weight loss
and weight gain occurred in 23 and 3 patients on
phentermine, respectively, and in 8 and 18 patients on
placebo, respectively; the difference between the median
weights of the drug and placebo groups was significant
(p<0.01). The 10 patients who left the study did so for
reasons other than side effects, and no adverse or other side
effects were reported by the subjects.
Jackson and
Vanik, 1976.
66 obese diabetics (32
controls, 34 treated). The
diabetes was controlled
with insulin (Subgroup 1; 3
controls, 5 treated), diet
alone (Subgroup 2; 14
controls, 15 treated) or an
oral hypoglycemic agent
(Subgroup 3; 15 controls,
14 treated). Sex, age and
body weight not reported.
Capsules containing 0 (placebo) or 30
mg phentermine as resin were ingested
once daily for 6 months. 14 subjects
from the placebo group were then
switched to 30 mg/day phentermine for 6
months; this new treated group was
uncontrolled. Body weight, side effects,
diabetic symptoms, urinary glucose
(home tests), blood pressure, blood
glucose and serum cholesterol were
recorded or measured at 28-day intervals
throughout the study.
Analysis of complete groups (i.e., not by diabetic therapy
subgroup) showed that the subjects treated with
phentermine lost significantly (p<0.001, test not reported)
more weight than those on placebo [mean weight loss 11.6
lb. (obese group) compared to 3.2 lb (placebo group)].
Percent weight loss in the overweight subjects cannot be
calculated due to lack of initial body weight data. The
increased weight loss was not accompanied by appreciable
reduction in insulin or oral hypoglycemic drug dosage or
change in glycemia or glycosuria, and appears to be mainly
due to responses in Subgroups 1 and 2. Mean weight loss
also was significantly (p<0.01) greater during phentermine
treatment (14.4 lb) than during placebo treatment (2.6 lb) in
the group exposed to phentermine following exposure to
placebo. Evaluation of the anorectic effect is complicated
by lack of baseline body weight data (precluding
calculating percent body weight loss) and information on
matching of the exposed and placebo groups, although the
14 subjects given placebo followed by phentermine can be
viewed as serving as their own controls. Slight mouth
dryness and initial minor sleep disturbance were the only
side effects noted.
Campbell et al.,
1977
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Table 1. (cont.) DOUBLE-BLIND CLINICAL STUDIES OF PHENTERMINE
Population
Experimental Design
Results and Comments
Reference
32 women and 18 men
(mean age for all subjects,
49.9 years). Mean weight
181.9 lbs (82.7 kg) [170.5
lbs (77.5 kg) for women,
202.4 lbs (92.0 kg) for
men].
Capsules containing 30 mg phentermine
as resin were ingested once daily for 12
weeks. Body weight, blood pressure and
heart rate were evaluated pretreatment.
Subsequently, these endpoints and
subjective side effects were evaluated
every 4 weeks.
Study not double-blind or placebo controlled. Subjects
initially averaged 33% over ideal weight. All subjects
completed the study. A 1500 calories/day diet was
encouraged but not enforced. Cumulative mean weight
loss at week 12 was 18.2 lbs [16.8 lbs in males and 19.0 lbs
in females (8.3% and 11.1% of initial weight, respectively].
Total weight loss as a percentage of initial overweight was
44.5% (43.4% in males and 48.1% in females). Other
effects after 12 weeks treatment included reduced systolic
blood pressure (2.8% lower than initial value, p<0.05),
diastolic blood pressure (3.0%, p<0.001) and heart rate
(3.3%, p<0.01); these were concluded to be almost
certainly related to weight loss rather than directly to drug
treatment. The reductions in blood pressure occurred
mainly in subjects whose initial systolic values were >150
mm Hg. 20 subjective side effects were reported by 15
subjects; drowsiness/tiredness (6), dry mouth (4),
constipation (4) and dizziness/giddiness (3) were most
prevalent.
Valle-Jones et al.,
1983.
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Table 1. (cont.) DOUBLE-BLIND CLINICAL STUDIES OF PHENTERMINE
Population
Experimental Design
Results and Comments
Reference
50 women. Mean age 40.0
years, mean weight 228.1
lb (103.7 kg).
Phentermine as resin was ingested in a
single mean daily dose of 36 mg (range
15-60 mg) for 20 weeks. The initial
dose was 15 mg/day; this was increased
in 5 mg increments (duration not
specified) to 30 mg and subsequently, if
weight loss was not produced, to a
maximum of 60 mg unless precluded by
side effects. Body weight, blood
pressure, degree of appetite suppression
and subjective side effects were recorded
every two weeks. Plasma phentermine
concentrations were assayed blind at
weeks 6, 8, 16 and 18.
No placebo or other control group. Initially, an average of
68.4% excess body weight was reported as contrasted to
normal body weight A 1000 kcal/day diet was
recommended. 34 subjects completed the study with a
6.5% mean weight loss (6.7 kg) and wide individual
variation (2.2 kg gain to 28.6 kg loss). Seven subjects
withdrew from the study because of side effects after 4-8
weeks, including incapacitating headaches (3) and
increased irritability with increased palpitations or
increased blood pressure (2). Side effects in the 34
subjects that completed the study were mild and usually
transient, including increased irritability (9), sleeplessness
(8), occasional disturbing nightmares (5), increased energy
(3) and palpitations on exertion (2). There was no
correlation between plasma phentermine concentrations
and daily dosage or weight loss; degree of obesity and
plasma phentermine concentration, weight loss or daily
dose; or plasma phentermine concentration and irritability,
increased energy, sleeplessness or dreaming. The degree of
subjective appetite suppression was related to weight loss
but not to phentermine dosage or plasma phentermine
concentration.
Douglas et al.,
1983
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Table 1. (cont.) DOUBLE-BLIND CLINICAL STUDIES OF PHENTERMINE
Population
Experimental Design
Results and Comments
Reference
Groups of 20 control
(17F, 3M) and 20 treated
(17F, 3M) subjects. Mean
age 35.1 years (control)
and 34.5 years (treated).
Mean weight 35.1 years
(control) and 34.5 years
(treated).
Capsules containing 0 (placebo) or 30
mg phentermine as resin were ingested
once daily for 16 weeks. This was
followed by 4 weeks of dose tapering
(week 17, 15 mg/day; week 18, 7.5
mg/day; week 19, 7.5 mg every other
day; week 20, 7.5 mg every third day)
and subsequently 4 weeks of follow-up
with no treatment. Body weight was
measured at weeks 4, 6 and 8 and
thereafter every 4 weeks, and subjective
complaints were used to assess adverse
effects.
Subjects initially averaged 55% over their ideal body
weight. Diets of 20 kcal/kg ideal body weight/day (range,
900-1800 kcal/day) were recommended. The treated group
lost significantly (p<0.01) more weight than controls at all
time points beginning at week 6. Weight loss at the end of
week 16 (end of full dose treatment) was 4.9% and 11.0%
of baseline in the control and treated groups, respectively.
Compared to controls, treated subjects had significantly
(p<0.05) more total complaints (241 vs. 79) and
cardiovascular and CNS complaints (212 vs. 56). At the
end of week 8 a total of 17 treated and 4 control subjects
had complaints; these included dry mouth, CNS effects
(sleep difficulties, nervousness, depression, fatigue and/or
increasing dreaming) and palpitations in 12, 14 and 1
treated and 1, 4 and 0 control subjects, respectively. Of 10
treated and 2 control subjects with complaints at the end of
week 16, dry mouth, CNS effects and palpitations were
reported by 7, 7 and 1 treated and 0, 1 and 0 control
subjects, respectively.
Weintraub et al.,
1984
6 women. Age 24-28
years, moderately
overweight (not
quantified).
Each subject ingested one capsule
containing 0 (placebo), 15 mg and 30 mg
phentermine resin following overnight
fast in three separate sessions. Order of
dosing was randomized, but interval
between doses was not reported.
Anorectic effect was evaluated using a
visual hunger rating scale before, 5
hours after and 10 hours after each dose.
Calorie consumption was determined
from amount of a standard sandwich
meal ingested 5 and 10 hours post-dose.
Mean hunger ratings were significantly reduced at 15 mg
and 30 mg when 5- and 10-hr values were combined (both
p<0.01) and at 30 mg after 10 hours (p<0.05). Mean total
calorie intake in the 5-hr, 10-hour and combined post-dose
groups was 31,18 and 25% lower than placebo at 15 mg,
and 30, 38 and 33% lower than placebo at 30 mg. The
decreases were significant at 15 and 30 mg when 5 and 10
hour values were combined (both p<0.01) and at 30 mg
(p<0.01) after 10 hours. A significant correlation (r=+0.68,
p<0.01) was found between pre-meal hunger ratings and
calories consumed during the meal. Side effects were not
discussed.
Silverstone, 1972
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SRC TR-03-045/ 12-21-04
fenfluramine from the market, several other reports and studies (e.g., Burger et al., 1999; Gardin
et al., 2000; Graham and Greene, 1997; Hensrud et al., 1999; Khan et al., 1998; Jick et al., 1998;
Wee et al., 1998) have reported data on the prevalence of valvular regurgitation in patients who
received phen-fen therapy. Each prevalence study found an association between phen-fen therapy
and increased prevalence of valvular regurgitation. Among the studies, reported prevalences
ranged from approximately 2% to 30% (see Gardin et al., 2000 and Glazer, 2001 for review). In
addition, there are several case reports of pulmonary hypertension associated with phen-fen
therapy (e.g., Dillon et al., 1999; Mark et al., 1997). A proposed mechanistic hypothesis
involving serotonin agonistic effects of fenfluramine is supported by reports that endocardial
fibroplasia seen in heart valves from phen-fen patients with valvular regurgitation was similar to
changes associated with serotonin excess ("carcinoid syndrome") or exposure to ergotamine, a
serotonin agonist, and the lack of reports of valvular abnormalities or other cardiovascular
problems associated with phentermine monotherapy (Glazer, 2001).
Information regarding the possible developmental toxicity of phen-fen therapy is restricted
to an abstract report of pregnancy outcome data for 100 women who used phen-fen, but
discontinued use of the combined drug by the end of the first trimester of pregnancy (Johnson et
al., 1998). Among 46 infants examined for gross abnormalities, one had a penile chordee and a
second had a unilateral preauricular pit. The family of the second infant had a history of
unilateral preauricular pits.
Animal Studies
Studies of phentermine in animals generally investigated anorectic and CNS behavioral
effects. Most of these studies involved acute or short-term exposures by intravenous or parenteral
injection, and all used dosages similar to or greater (most were substantially higher) than the 0.3
mg/kg-day therapeutic level. A few less-than-subchronic oral studies in animals were located,
consisting of a 7-day study in rats showing anorectic effects at 4 and 8 mg/kg-day (Lawlor et al.,
1969); a 35-day study in rats showing an anorectic effect, but no lung or heart histopathology at
27 mg/kg-day (Hasleton et al., 1977); and a 28-day study in mice showing an anorectic effect and
associated increased metabolic energy expenditure at 25 mg/kg-day (Arch, 1981).
Developmental toxicity of phentermine was assessed in one study in rats which found that
subcutaneous injection of 30 mg/kg-day on gestation days 16-20 did not cause any external
abnormalities or effects on behavior, physical condition, body weight, crown-rump length, liver
and lung weights, or lung histology and phospholipid content in neonates (Thoma-Laurie et al.,
1982). Other developmental toxicity data are restricted to a study in which pregnant rats were
infused with phentermine (10 mg/kg-day) plus dexfenfluramine (3 mg/kg-day) on gestation days
3 through 17; drug treatment did not affect the number of offspring, their birth weights, or their
motor coordination assessed at 11 days of age (Bratter et al., 1999). Examination of 24 offspring
hearts by light microscopy showed thickened mitral valves in 6 hearts, in contrast with no mitral
valve thickening in an unspecified number of examined control offspring hearts (Bratter et al.,
1999).
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The effects of acute (single doses up to 2 weeks of exposure) parenteral administration of
phentermine in combination with fenfluramine or dexfenfluramine have been examined on
dopamine and/or serotonin release in rat striatum (Balcioglu and Wurtman, 1998), rat nucleus
accumbens (Baumann et al., 2000; Rada and Hoebel, 2000), and rat anterior hypothalamus (Prow
et al., 2001); brain serotonin levels in mice (Baumann et al., 1996) and rats (Lew et al., 1997;
McCann et al., 1998); cocaine self-administration in rhesus monkeys (Glowa et al., 1997);
conditioned reinforcement response in rats (Rea et al., 1998); and daily food intake in rats (Roth
and Rowland, 1998). The doses of phentermine in these experiments were predominantly well
above the therapeutic human dose of 0.3 mg/kg-day (>3 mg/kg-day). Fluoxetine, a replacement
drug for fenfluramine, increases the anorectic and long-term dopamine-depleting effects of
phentermine. When administered i.p. in combination with phentermine (10 mg/kg, each), no
effects on weight loss were reported despite reductions in brain monoamine. Phentermine
administered i.p. alone did not cause any effect on weight loss or brain monoamines (Callahan et
al., 2000). The results from these experiments are not directly related to the derivation of
subchronic and chronic RfDs for phentermine, and are thus not further discussed in this issue
paper.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC RfDs
FOR PHENTERMINE
No data were located regarding adverse effects in overweight humans or laboratory
animals following chronic oral exposure to phentermine. The human clinical data clearly indicate
that subchronic exposure to 0.3 mg/kg-day dosages of phentermine is associated with 6-13%
reductions in body weight and 0-30% prevalences of subjectively reported symptoms of mild
CNS excitation and dry mouth. Effects such as these have been reported in obese patients and
may be considered adverse when occurring in the general population (although they are not
regarded as appreciable side effects of phentermine therapy), but the small magnitude of the body
weight effect and the variable and generally low prevalences of side effects suggest that effects
were only minimal in the phentermine studies.
The relevance of phentermine clinical trials to typical environmental exposures is
somewhat unclear due to dissimilarities between the exposed subjects and the general population,
specifically the significant obesity (and consequent medical risk) and low calorie diets of the
subjects. The relevance of these potentially complicating factors to RfD derivation is not as
problematic, however, as the limited ability of the available human data to describe subchronic
dosage levels that produce no effects. Similarly, data from the available oral animal studies do
not describe no-effect dosages.
Amphetamine (l-methyl-2-phenylethylamine) and chlorphentermine [l-methyl-2-(4-
chlorophenyl)ethylamine] are structurally similar to phentermine, but appear to be unsuitable
bases for derivation of an RfD for phentermine by analogy. The pharmacological properties of
these potential surrogates markedly differ from those of phentermine in that chlorphentermine
produces qualitatively different effects, particularly lipidosis of lung and other tissues (Lullmann
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SRC TR-03-045/ 12-21-04
et al., 1973; Thoma-Laurie et al., 1982; Reasor, 1989; Elmaleh et al., 1993), and amphetamine has
much more pronounced CNS activity, producing marked stimulant and euphoric effects (Sullivan
and Comai, 1978; Silverstone, 1992). Amphetamine has been the most intensively studied
anorectic sympathomimetic amine; however, it is unclear if its dose-effect relationships are well
characterized (Silverstone, 1972).
The patient base for which weight loss was assessed was almost entirely overweight
individuals, and the weight loss was nominal and occurred over a considerable length of time in
most cases. The weight loss generally occurred during concomitant dieting, which is potentially
confounding. Therefore, the weight loss, per se, in obese subjects should be considered a desired
effect, not a toxic adverse effect.
Available human and animal data are considered inappropriate for development of either a
subchronic or chronic p-RfD for dime thy lphenethylamine.
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Callahan, B.T., J. Yuan and G.A. Ricaurte. 2000. Fluoxetine increases phentermine-fluoxetine
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Campbell, C.J., I.P. Bhalla, J.M. Steel and L.J.P. Duncan. 1977. A controlled trial of
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Gardin, J.M., D. Schumacher, G. Constantine et al. 2000. Valvular abnormalities and
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JAMA. 283: 1703-1709.
Glazer, G. 2001. Long-term pharmacotherapy of obesity 2000: A review of efficacy and safety.
Arch. Intern. Med. 161:1814-1824.
Glowa, J.R., K.C. Rice, D. Matecka and R.B. Rothman. 1997. Phentermine/fenfluramine
decreases cocaine self-administration in rhesus monkeys. Neuro Report. 8: 1347-1351.
Graham, D.J. and L. Green. 1997. Further cases of valvular heart disease associated with
fenfluramine-phentermine. N. Eng. J. Med. 337: 635.
Hasleton, P.S., J.M. Kay and D. Heath. 1977. Phentermine resinate and the pulmonary
vasculature of the rat. Arzneimittelforschung. 27(11): 2112-2113.
Hensrud, D.D., H.M. Connolly, M. Grogan et al. 1999. Echocardiographic improvement over
time after cessation of use of fenfluramine and phentermine. Mayo Clin. Proc. 74: 1191-1197.
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Hoffman, B.B. and R.J. Lefkowitz. 1990. Catecholamines and sympathomimetic drugs. In:
Goodman and Gilman's. The pharmacological basis of therapeutics, 8th ed. A.G. Gilman, T.W.
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IARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary
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Jackson, W.P.U. and A.I. Vanik. 1976. Phentermine (duromine) for obese diabetics. S. Afr.
Med. J. 50: 1351.
Jick, H., C. Vasilakis, L.A. Weinrauch et al. 1998. A population-based study of appetite-
suppressant drugs and the risk of cardiac-valve regurgitation. N. Engl. J. Med. 339: 719-724.
Johnson, K.A., C.D. Chambers, L.M. Dick et al. 1998. Pregnancy outcome of women exposed to
fen/phen. Teratology. 57: 188-189.
Khan, M.A., C.A. Herzog, J.V. St. Peter et al. 1998. The prevalence of cardiac valvular
insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite
suppressant drugs. N. Eng. J. Med. 339: 713-718.
Langlois, K.J., J.A. Forbes, G.W. Bell and G.F. Grant, Jr. 1974. A double-blind clinical
evaluation of the safety and efficacy of phentermine hydrochloride (fasting) in the treatment of
exogenous obesity. Curr. Ther. Res. Clin. Exp. 16(4)289-296.
Lawlor, R.B., M.C. Trivedi and J. Yelnosky. 1969. A determination of the anorexigenic
potential of dl-amphetamine, d-amphetamine, 1-amphetamine and phentermine. Arch. Int.
Pharmacodyn. 179(2): 401-407.
Lew, R., B. Weisenberg, G. Vosmer and L.S. Seiden. 1997. Combined
phentermine/fenfluramine administration enhances depletion of serotonin from central terminal
fields. Synapse. 26: 36-45.
Lullmann, H., E. Rossen and K. U. Seiler. 1973. The pharmacokinetics of phentermine and
chlorphentermine in chronically treated rats. J. Pharm. Pharmacol. 25: 239-243.
Mark, E.J., E.D. Patalas, H.T. Chang et al. 1997. Fatal pulmonary hypertension associated with
short-term use of fenfluramine and phentermine. N. Eng. J. Med. 337: 602-606.
McCann, U.D., J. Yuan and G.A. Ricaurte. 1998. Neurotoxic effects of () fenfluramine and
phentermine, alone and in combination, on monoamine neurons in the mouse brain. Synapse. 30:
239-246.
McElhatton, P.R., K.R. Pughe, C. Evans et al. 2000. Is exposure to amphetamine-like drugs in
pregnancy associated with malformations? J.Toxicol. 38:195-196.
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Munro, J.F., A.C. MacCuish, E.M. Wilson and L.J.P. Duncan. 1968. Comparison of continuous
and intermittent anorectic therapy in obesity. Br. Med. J. 1: 352-354.
NTP (National Toxicology Program). 2002. Management Status Report. Online.
http://ntp-server.niehs.nili.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
Prow, M.R., B. Lancashire, S. Aspley et al. 2001. Additive effects on rat brain 5HT release of
combining phentermine with dexfenfluramine. Int. J. Obes. 25: 1450-1453.
Rada, P.V. and B.G. Hoebel. 2000. Supraadditive effect of t/-fenfluramine plus phentermine on
extracellular acetylcholine in the nucleus accumbens: possible mechanism for inhibition of
excessive feeding and drug abuse. Pharmacol. Biochem. Behav. 65: 369-373.
Rea, W.P., R.B. Rothman and T.S. Shippenberg. 1998. Evaluation of the conditioned reinforcing
effects of phentermine and fenfluramine in the rat: concordance with clinical studies. Synapse.
30: 107-111.
Reasor, M.J. 1989. A review of the biology and toxicologic implications of the induction of
lysosomal lamellar bodies by drugs. Toxicol. Appl. Pharmacol. 97: 47-56.
Roth, J.D. and N.E. Rowland. 1998. Efficacy of administration of dexfenfluramine and
phentermine, alone and in combination, on ingestive behavior and body weight in rats.
Psychopharmacology. 137: 99-106.
Seaton, D.A., K. Rose and L.J.P. Duncan. 1964. A comparison of the appetite suppressing
properties of dexamphetamine and phentermine. Scott. Med. J. 9: 482-484.
Silverstone, T. 1972. The anoretic effect of a long-acting preparation of phentermine
(duromine). Psychopharmacologia (Berl.). 25:315-320.
Silverstone, T. 1992. Appetite Suppressants. A Review. Drugs. 43:820-836.
Steel, J.A., J.F. Munro and L.J.P. Duncan. 1973. A comparative trial of different regimens of
fenfluramine and phentermine in obesity. Practioner. 211: 232-236.
Sullivan, A.C. and K. Comai. 1978. Pharmacological treatment of obesity. Int. J. Obes. 2:
167-189.
Thoma-Laurie, D., E.R. Walker and M.J. Reasor. 1982. Neonatal toxicity in rats following in
utero exposure to chlorphentermine or phentermine. Toxicology. 24: 85-94.
Truant, A.P., L.P. Olon and S. Cobb. 1972. Phentermine resin as an adjunct in medical weight
reduction: a controlled, randomized, double-blind prospective study. Curr. Ther. Res.
14: 726-738.
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U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
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Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA-540-R-97-036. NTIS PB97-921199.
U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
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http://www.epa. gov/waterscience/drinking/standards/dwstandards.pdf
U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and
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http://www.epa.gov/iris
Valle-Jones, J.C., N.H. Brodie, H.O. O'Hara et al. 1983. A comparative study of phentermine
and diethylpropion in the treatment of obese patients and general practice. Pharmatherapeutica.
3: 300-304.
Wee, C.C., R.S. Phillips, G. Aurigemma et al. 1998. Risk for valvular heart disease among users
of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication.
Ann. Intern. Med. 129: 870-874.
Weintraub, M., J.D. Hasday, A.I. Mushlin and D.H. Lockwood. 1984. A double-blind clinical
trial in weight control. Arch. Intern. Med. 144: 143-1148.
Weintraub, M., P.R. Sundaresan, M. Madan et al. 1992. Long-term weight control study. I
(weeks 0 to 34): the enhancement of behavior modification, caloric restriction, and exercise by
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Glazer, 2001)
WHO (World Health Organization). 2002. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/dsa/cat98/zehc.htm
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Provisional Peer Reviewed Toxicity Values for
Dimethylphenethylamine (Phentermine)
(CASRN 122-09-8)
Derivation of Subchronic and Chronic Inhalation RfCs
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms
bw - body weight
cc - cubic centimeters
CD - Caesarean Delivered
CERCLA - Comprehensive Environmental Response, Compensation, and Liability Act of 1980
CNS - central nervous system
cu.m - cubic meter
DWEL - Drinking Water Equivalent Level
FEL - frank-effect level
FIFRA - Federal Insecticide, Fungicide, and Rodenticide Act
g - grams
GI - gastrointestinal
HEC - human equivalent concentration
Hgb - hemoglobin
i.m. - intramuscular
i.p. - intraperitoneal
i.v. - intravenous
IRIS - Integrated Risk Information System
IUR - Inhalation Unit Risk
kg - kilogram
L - liter
LEL - lowest-effect level
LOAEL - lowest-observed-adverse-effect level
LOAEL(ADJ) - LOAEL adjusted to continuous exposure duration
LOAEL(HEC) - LOAEL adjusted for dosimetric differences across species to a human
m - meter
MCL - maximum contaminant level
MCLG - maximum contaminant level goal
MF - modifying factor
mg - milligram
mg/kg - milligrams per kilogram
mg/L - milligrams per liter
MRL - minimal risk level
MTD - maximum tolerated dose
MTL - median threshold limit
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NAAQS - National Ambient Air Quality Standards
NOAEL - no-observed-adverse-effect level
NOAEL(ADJ) - NOAEL adjusted to continuous exposure duration
NOAEL(HEC) - NOAEL adjusted for dosimetric differences across species to a human
NOEL - no-observed-effect level
OSF - Oral Slope Factor
p-RfD - provisional Oral Reference Dose
p-RfC - provisional Inhalation Reference Concentration
p-OSF - provisional Oral Slope Factor
p-IUR - provisional Inhalation Unit Risk
PBPK - physiologically based pharmacokinetic
ppb - parts per billion
ppm - parts per million
PPRTV - Provisional Peer Reviewed Toxicity Value
RBC - red blood cell(s)
RCRA - Resource Conservation and Recovery Act
RGDR - Regional deposited dose ratio (for the indicated lung region)
REL - relative exposure level
RGDR - Regional gas dose ratio (for the indicated lung region)
RfD - Oral Reference Dose
RfC - Inhalation Reference Concentration
s.c. - subcutaneous
SCE - sister chromatid exchange
SDWA - Safe Drinking Water Act
sq.cm. - square centimeters
TSCA - Toxic Substances Control Act
UF - uncertainty factor
ug - microgram
umol - micromoles
VOC - volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
DIMETHYLPHENETHYLAMINE (CASRN 122-09-8; Phentermine)
Derivation of Subchronic and Chronic Inhalation RfCs
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. Once an IRIS value for a specific chemical
becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It
should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived
based on inadequate data.
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Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Dimethylphenethylamine (l,l-dimethyl-2-phenylethylamine), commonly known as
phentermine, is used as an appetite suppressant (anorectic) drug that is orally administered.
Neither a subchronic nor chronic RfC for phentermine is listed on IRIS (U.S. EPA, 2003) or in
the HEAST (U.S. EPA, 1997). The CARA list (U.S. EPA, 1991, 1994) does not report any
relevant documents for phentermine. ATSDR (2002), IARC (2002) and WHO (2002) have not
published review documents for phentermine. Occupational exposure limits for phentermine
have not been established by ACGIH (2002), NIOSH (2002), or OSHA (2002a,b). The initial
literature searches of TOXLINE (1965-1995), MEDLINE (1980-1995), CANCERLINE (1986-
1995), CCRIS, TSCATS, RTECS, GENETOX, DART/ETICBACK, and EMIC/EMICBACK
were conducted and screened in September 1995 to identify relevant data on phentermine.
Update literature searches from 1995 to 2003 were performed in January, 2003 using the same
databases, except for replacement of CANCERLIT with CANCERLINE and the addition of
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HSDB. The MEDLINE search strategy was unusually broad to facilitate identifying pertinent
clinical studies. The NTP (2002) status report was also searched for relevant information.
Additional literature searches from January 2003 through September 2004 were conducted by
NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No studies were located regarding inhalation exposure of humans to phentermine.
Animal Studies
No studies were located regarding inhalation exposure of animals to phentermine.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
RfCs FOR PHENTERMINE
In the absence of subchronic or chronic inhalation data on the toxicity of phentermine,
derivation of a provisional subchronic or chronic RfC is precluded.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2002. 2002 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Internet HazDat
Toxicological Profile Query. U.S. Department of Health and Human Services, Public Health
Service. Atlanta, GA. Online. http://www.atsdr.cdc.gOv//qsql/toxprof.script
IARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary
Evaluations. Online. http://193.51.164.il/cgi/iHound/Chem/iH Chem Frames.html
NIOSH (National Institute for Occupational Safety and Health). 2002. Online NIOSH Pocket
Guide to Chemical Hazards. Index of Chemical Abstract Numbers (CAS No.). Online.
http://www.cdc.gov/niosh/npg/npgdcas.html
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NTP (National Toxicology Program). 2002. Management Status Report. Online.
http://ntp-server.niehs.nili.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
OSHA (Occupational Safety and Health Administration). 2002a. OSHA Standard 1910.1000
Table Z-2. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-2.html
OSHA (Occupational Safety and Health Administration). 2002b. OSHA Standard 1915.1000
for Air Contaminants. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1915 1000.html
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA-540-R-97-036. NTIS PB97-921199.
U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa.gov/iris
WHO (World Health Organization). 2002. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/dsa/cat98/zehc.htm
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Provisional Peer Reviewed Toxicity Values for
Dimethylphenethylamine (Phentermine)
(CASRN 122-09-8)
Derivation of a Carcinogenicity Assessment
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms
bw - body weight
cc - cubic centimeters
CD - Caesarean Delivered
CERCLA - Comprehensive Environmental Response, Compensation, and Liability Act of 1980
CNS - central nervous system
cu.m - cubic meter
DWEL - Drinking Water Equivalent Level
FEL - frank-effect level
FIFRA - Federal Insecticide, Fungicide, and Rodenticide Act
g - grams
GI - gastrointestinal
HEC - human equivalent concentration
Hgb - hemoglobin
i.m. - intramuscular
i.p. - intraperitoneal
i.v. - intravenous
IRIS - Integrated Risk Information System
IUR - Inhalation Unit Risk
kg - kilogram
L - liter
LEL - lowest-effect level
LOAEL - lowest-observed-adverse-effect level
LOAEL(ADJ) - LOAEL adjusted to continuous exposure duration
LOAEL(HEC) - LOAEL adjusted for dosimetric differences across species to a human
m - meter
MCL - maximum contaminant level
MCLG - maximum contaminant level goal
MF - modifying factor
mg - milligram
mg/kg - milligrams per kilogram
mg/L - milligrams per liter
MRL - minimal risk level
MTD - maximum tolerated dose
MTL - median threshold limit
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NAAQS - National Ambient Air Quality Standards
NOAEL - no-observed-adverse-effect level
NOAEL(ADJ) - NOAEL adjusted to continuous exposure duration
NOAEL(HEC) - NOAEL adjusted for dosimetric differences across species to a human
NOEL - no-observed-effect level
OSF - Oral Slope Factor
p-RfD - provisional Oral Reference Dose
p-RfC - provisional Inhalation Reference Concentration
p-OSF - provisional Oral Slope Factor
p-IUR - provisional Inhalation Unit Risk
PBPK - physiologically based pharmacokinetic
ppb - parts per billion
ppm - parts per million
PPRTV - Provisional Peer Reviewed Toxicity Value
RBC - red blood cell(s)
RCRA - Resource Conservation and Recovery Act
RGDR - Regional deposited dose ratio (for the indicated lung region)
REL - relative exposure level
RGDR - Regional gas dose ratio (for the indicated lung region)
RfD - Oral Reference Dose
RfC - Inhalation Reference Concentration
s.c. - subcutaneous
SCE - sister chromatid exchange
SDWA - Safe Drinking Water Act
sq.cm. - square centimeters
TSCA - Toxic Substances Control Act
UF - uncertainty factor
ug - microgram
umol - micromoles
VOC - volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUE FOR
DIMETHYLPHENETHYLAMINE (CASRN 122-09-8; Phentermine)
Derivation of a Carcinogenicity Assessment
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. Once an IRIS value for a specific chemical
becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It
should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived
based on inadequate data.
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Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Dimethylphenethylamine (l,l-dimethyl-2-phenylethylamine), commonly known as
phentermine, is used as an appetite suppressant (anorectic) drug that is orally administered. A
carcinogenicity assessment for phentermine is not available on IRIS (U.S. EPA, 2003), in the
HE AST (U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories List (U.S.
EPA, 2002). The CARA list (U.S. EPA, 1991, 1994) does not report any relevant documents for
phentermine. IARC (2002), ACGIH (2002), and NTP (2002) have not assessed the
carcinogenicity of phentermine. ATSDR (2002) and WHO (2002) have not published review
documents for phentermine. The initial literature searches of TOXLINE (1965-1995),
MEDLINE (1980-1995), CANCERLINE (1986-1995), CCRIS, TSCATS, RTECS, GENETOX,
DART/ETICBACK, and EMIC/EMICBACK were conducted and screened in September 1995
to identify relevant data on phentermine. Update literature searches from 1995 to 2003 were
performed in January, 2003 using the same databases, except for replacement of CANCERLIT
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with CANCERLINE and the addition of HSDB. The MEDLINE search strategy was unusually
broad to facilitate identifying pertinent clinical studies. Additional literature searches from
January 2003 through September 2004 were conducted by NCEA-Cincinnati using MEDLINE,
TOXLINE, Chemical and Biological Abstracts databases.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No information was located regarding the carcinogenicity of phentermine in humans by
any route of exposure.
Animal Studies
No information was located regarding the carcinogenicity of phentermine in animals by
any route of exposure.
Supporting Studies
The genotoxicity of phentermine was evaluated in three in vitro assay systems that
surveyed activity of various pharmaceutical drugs. These assays showed that phentermine
induced reverse mutations in Salmonella typhimurium and Streptomyces coelicolor (Carere et al.,
1975, reported as an abstract), and mitotic segregation (mainly non-disjunction) in diploid strains
of Aspergillus nidulans (Bignami et al., 1974).
PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION
As the available data are insufficient to assess carcinogenic potential in animals or
humans, they are consistent with the hazard descriptor, "inadequate information to assess
carcinogenic potential," as specified by the proposed U.S. EPA (1999) Guidelines for Cancer
Risk Assessment.
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Lack of human or animal cancer data precludes derivation of quantitative estimates of
cancer risk for phentermine.
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REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2002. 2002 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Internet HazDat
Toxicological Profile Query. U.S. Department of Health and Human Services, Public Health
Service. Atlanta, GA. Online. http://www.atsdr.cdc.gOv//qsql/toxprof.script
Bignami, M., G. Morpurgo, R. Pagliani et al. 1974. Non-disjunction and crossing-over induced
by pharmaceutical drugs in Aspergillus nidulans. Mutat. Res. 26: 159-170.
Carere, A., G. Morpurgo, G. Cardamone et al. 1975. Point mutations induced by
pharmaceutical drugs. Mutat. Res. 29: 235 (abstract).
IARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary
Evaluations. Online. http://193.51.164.il/cgi/iHound/Chem/iH Chem Frames.html
NTP (National Toxicology Program). 2002. Management Status Report. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA-540-R-97-036. NTIS PB97-921199.
U.S. EPA. 1999. Proposed Guidelines for Cancer Risk Assessment. July. Office of Research
and Development, National Center for Environmental Assessment, Washington, DC.
U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-02-038. Online.
http://www.epa. gov/waterscience/drinking/standards/dwstandards.pdf
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U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa.gov/iris
WHO (World Health Organization). 2002. Online Catalogs for the Environmental Criteria
Series. Online, http://www.who.int/dsa/cat98/zehc.htm
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