United States
Environmental Protection
1=1 m m Agency
EPA/690/R-07/038F
Final
5-15-2007
Provisional Peer Reviewed Toxicity Values for
Triphenylphosphine oxide
(CASRN 791-28-6)
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 and Abbreviations
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
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-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-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
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p-RfD
provisional oral reference dose
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
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
l^g
microgram
[j,mol
micromoles
voc
volatile organic compound
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5-15-2007
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
TRIPHENYLPHOSPHINE OXIDE (CASRN 791-28-6)
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 new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. 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.
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
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5-15-2007
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
RfD, RfC, and, cancer assessments are not available on IRIS (U.S. EPA, 2007) or in
HEAST (U.S. EPA, 1997) for triphenylphosphine oxide (TPPO). ACGM (1996), OSHA (2001),
and NIOSH (1997) have not established occupational exposure limits to protect workers exposed
to TPPO. No documents on TPPO were listed in the CARA database (U.S. EPA, 1994).
TPPO has not been the subject of toxicological reviews by ATSDR (2001), NTP (2001)
or WHO (2001). Literature searches of HSDB, RTECS, TSCATS, MEDLINE, and TOXLINE
(and its subfiles) databases were conducted and screened in January 1998. Updated literature
searches of TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB,
EMIC/EMICBACK, DART/ETICBACK, RTECS and TSCATS were conducted in September
2001 for literature from 1998-2001 and again in January 2007. Additional toxicology data were
not found in any of these searches. This document has passed the STSC quality review and peer
review evaluation indicating that the quality is consistent with the SOPs and standards of the
STSC and is suitable for use by registered users of the PPRTV system.
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REVIEW OF PERTINENT LITERATURE
Human Data
No studies of the effects of TPPO on humans were found.
Animal Data
A small number of unpublished reports of the toxic effects of TPPO on laboratory
animals were found in the TSCATS subfile of TOXLINE. These studies are characterized by a
low number of experimental animals, an acute exposure regimen (maximum of 21 days), and a
limited range of doses.
Beagle dogs (2/sex/group) were administered a single oral dose of either 300 or 500
mg/kg in corn oil (Atochem, 1992). All dogs died, preceded by violent convulsions, tremors,
uncoordinated body movements, "paddling" and "swimming" movements, aggressive behavior,
vocalization, excessive salivation, dyspnea, and emesis. Neurological examination of four dogs
that were still alive on the day of dosing showed evidence of impaired visual placing,
locomotion, standing, and righting reflexes. However, flexor and extensor reflexes were
unaffected in three of the four dogs.
Because of the deaths of the dogs receiving doses of 300 or 500 mg/kg, a subsequent
groups with two dogs each received single doses of either 50 mg/kg (2 females; 2 week
observation period) or 100 mg/kg (1 male and 1 female; 1 week observation period) TPPO
(Atochem, 1992). Plasma cholinesterase activity was measured pretest and 3 hours after the last
dose. Brain cholinesterase was measured after sacrifice. The two dogs receiving 50 mg/kg
TPPO showed no unusual signs after dosing or during the 2-week observation period. The two
dogs receiving 100 mg/kg showed similar symptoms to those that had received 300 or 500
mg/kg, but recovered by the next day and showed no unusual signs during the 1-week
observation period. No impairment of reflexes was noted during the observation period for dogs
receiving either 50 or 100 mg/kg. Slight body weight losses occurred only in dogs receiving 50
mg/kg. Cholinesterase activity measurements showed no clear evidence of inhibition in either
dose group. Neurological examination of the dogs receiving single doses of either 50 or 100
mg/kg showed no evidence of impaired reflexes during the observation period.
A subsequent 7-week neurotoxicity study was conducted with exposure of six beagle
dogs (3/sex) receiving either 0 or 50 mg/kg-day TPPO in corn oil for 21 days. Persistence and
reversibility of effects were evaluated in a subsequent 4-week observation period (Atochem,
1992; Biodynamics, Inc., 1979). The TPPO was administered orally in corn oil. Neurological
examinations were performed on days 0, 1, 4, 7, 10, 21, 28, 35, 42, and 49. Five of the six dogs
receiving TPPO (2 male and 3 female) exhibited violent convulsions, tremors, uncoordinated
body movements, "paddling" and "swimming" movements, excessive salivation, vocalization,
and dyspnea following the first dose. Signs appeared approximately 1-2 hours after dosing and
subsided within 4 hours after dosing. Three female dogs exhibited slight intermittent head
tremors following the second dose. No further signs indicative of neurologic effects were seen
for the duration of the experiment, with one exception. One male dog choked immediately after
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dosing on two occasions (days 4 and 17). The dog became rigid and exhibited convulsions,
tremors, dyspnea, excessive salivation, and inability to stand. This was followed by rapid
recovery, and the dog appeared normal within 30 minutes. This effect seemed to be associated
with partial aspiration of the dosing mixture. There were no signs of neurologic effects during
any of the examinations throughout the experiment. Weight gains of males receiving TPPO
were equal to or greater than the controls. Two females receiving TPPO showed slight weight
losses during the first weeks of the study; however, weight gains during the recovery period were
considered comparable to controls. There was no evidence of cholinesterase inhibition in plasma
or brain tissue from dogs treated with TPPO. Gross pathology examinations did not indicate any
findings related to TPPO exposure. The results indicated 50 mg/kg-day as the minimal effective
dose without changes in cholinesterase activity levels in the brain or plasma.
Four dogs (2/sex/group) were exposed to mean concentrations of 10.5 or 78.5 mg/m3 for
6 hours/day, 5 days/week, for 4 weeks (Rohm & Haas Company, 1992). A control group was
exposed to isopropanol for the same period. After the exposure period, the animals were
observed for 4 weeks and then sacrificed. There were no signs of neurological or other effects
during or after the exposure. No gross lesions or abnormalities were observed during the
experiment.
In an acute lethality experiment in hens, the oral LD50 was found to be greater than 5.0
g/kg TPPO (Rohm & Haas Company, 1992). No indication of permanent locomotor impairment
was noted after doses of 3.5 or 5.0 g/kg. At 7.2 g/kg, moderate locomotor impairment was noted
on day 14 in 5 of 9 subjects, though this may represent a general toxic response rather than a
specific neurotoxic effect.
Non-availability of Relevant Studies To fulfill the reporting requirements of TSCA,
BASF Corporation (1992) reported that acute and subchronic tests for TPPO had been conducted
for durations ranging from single doses up to 3 months. The details of these studies, however,
were not included in the submission letter, and no attached reports were included in the TSCATS
file. The letter states that an English translation of a summary of the studies indicates that
neurotoxicity was observed in several species following administration of TPPO by several
routes of exposure. Liver effects were also mentioned for rats and dogs in the subchronic
feeding studies. The full text of these studies was not obtained from BASF Corporation.
Immunotoxicity TPPO has been shown to suppress immune responses in vitro (Esa et
al., 1988; Fautz and Miltenburger, 1994). Esa et al. (1988) evaluated several organophosphorous
compounds for their effects on human in vitro cell-mediated responses. At a non-cytotoxic
concentration of 5 |iM TPPO caused significant suppression of antigen-specific lymphocyte
proliferation (p<0.01). Also, TPPO caused a significant inhibition of monocyte antigen
presentation at concentrations as low as 1 |iM (p<0.001).
Fautz and Miltenburger (1994) investigated the effects of TPPO on different immune
functions in vitro using peritoneal cells and splenocytes isolated from female C57B1 mice. A
concentration-related suppression of spleen cell natural killer cell activity was observed after
treatment with 33.3 |iM TPPO for 1 hour. TPPO, however, had no significant effect on
macrophage phagocytotic activity, blastogenesis (T and B lymphocytes), and antibody synthesis
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5-15-2007
(B lymphocytes). In summary, TPPO was found to be an immunomodulating agent that elicited
adverse effects on the cells of the innate immunity system, but was inactive against adaptive
immunity functions of the T- and B-lymphocytes.
Related Compounds The compound triphenylphospine (TPP) was also studied in
parallel experimental protocols to those for TPPO in several of the reports examined. For
example, four beagle dogs (2/sex) receiving a single oral dose of 500 mg/day exhibited
convulsions, tremors, and other signs as described for TPPO (Atochem, 1992). The dogs were
lethargic on the following day, but all survived and had recovered by day 4. Minimal signs of
neurological damage were noted by the end of a 4-week observation period. Another group of
six beagle dogs (3/sex) received a single dose of 300 mg/kg of TPP, followed by doses of 50
mg/kg-day for the following 13 days. The dogs exhibited convulsions, tremors, and other signs
as described for TPPO. One of the six dogs was found dead the day after initial dosing, and the
other dogs were lethargic or recumbent. The dogs initially recovered after the single 300 mg/kg
dose; however, on days 13 and 14 these dogs exhibited front and hind leg weakness with
inability to stand for normal periods. These signs persisted during the 2-week observation
period. Impairment of the flexor, extensor, and visual placing reflexes was observed on days 14,
21, and/or 28. There was no indication of inhibition of cholinesterase activity in blood or brain
samples in either group.
In a subsequent 7-week oral exposure study, groups of 6 beagle dogs (3/sex) were
administered TPP doses of 25 mg/kg-day for 21 consecutive days, followed by a 4-week
observation period (Atochem, 1992). Controls received only the corn oil vehicle. All animals
survived for the duration of the experiment. Signs of neurological impairment, ataxia and
hindlimb weakness, were first noted after 14 days in 3 of 6 dogs. There was an initial slight
improvement immediately after the end of the exposure period; however, there was no further
improvement. Histopathological examination showed myelin degeneration in the spinal cord of
dosed animals. Similar lesions were noted to a lesser extent in the cerebrum. Peripheral nerves
were not affected.
In an inhalation study, groups of four beagle dogs were exposed to concentrations of
either 18.0 or 94.8 mg/m3 of TPP for 6 hours/day, 5 days/week for 5 weeks (Atochem, 1992).
Control groups received 150 mg/m3 of the xylene vehicle. Following the end of the exposure,
the dogs were observed during a 4-week recovery period. Visual evidence of locomotor
dysfunctions was seen in the high-dose group in the second week of exposure. These signs
persisted for the remainder of the exposure period and throughout the recovery period; however,
the signs did not increase in severity. Levels of serum alkaline phosphatase and cholesterol were
elevated in both exposure groups during the exposure period, but there was some evidence of
recovery during the observation period. Patchy to segmental degeneration of the myelin in the
white tracts of the brain and spinal cord were seen in both exposure groups.
In a subsequent inhalation study, groups of two beagle dogs (1/sex/group) were exposed
to concentrations of 0.5, 3.2, 9.7, or 28 mg/m3 TPP as a respirable aerosol in a xylene vehicle for
6 hours/day, 5 days/week, for 4 weeks (Atochem, 1992). Controls received the xylene vehicle
only at 150 ppm. Another set of beagle dogs (1/sex /group) were exposed to concentrations of
0.3, 3.6, or 24 mg/m3 TPP for 6 hours for 2 days, and then observed during a 4-week recovery
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period. All animals survived for the duration of the experiments. Signs of neurological
impairment were noted in male dogs exposed to 24 mg/m3 for 2 days and in males and females
exposed to 28 mg/m3 for 4 weeks. Histopathological examinations showed moderate generalized
vacuolative degeneration of the spinal cord in dogs exposed to 28 mg/m3 for 4 weeks. Similar
spinal cord lesions, although minimal and focal in nature, were also observed in dogs in the 0.5
and 3.2 mg/m3 dose groups exposed for 4 weeks. These lesions were not observed in control
dogs.
DERIVATION OF A PROVISIONAL SUBCHRONIC AND CHRONIC RfD FOR
TRIPHENYLPHO SPHINE OXIDE (TPPO)
The studies reported in the initial submission from Atochem (1992) indicate that TPPO
administered as a single dose over a long duration can induce dramatic neurological effects.
Considering the clinical symptoms, brain/plasma cholinesterase activity levels and neurological
examinations, the 7-week dog study (Atochem, 1992; Biodynamics, Inc., 1979) is adequate to
develop a subchronic p-RfD.
The Atochem (1992); Biodynamics, Inc. (1979) study reported clinical symptoms of
cholinesterase inhibition without any histopathological changes or plasma/brain cholinesterase
activity levels in dogs. Thus, the 50 mg/kg-day dose of TPPO is considered a minimum effect
level.
LOAEL (minimal)
Uncertainty Factor
subchronic p-RfD	=
subchronic p-RfD =
* Half-log of 10 rounded to 3
50 mg/kg-day
3000 (3* for use of a minimal LOAEL in place of a
NOAEL, 10 for use of animal studies rather than
human studies, 10 for sensitive human subgroups, 3
for lack of developmental and reproductive studies,
and 3 for lack of additional supporting studies)
LOAEL / Uncertainty Factor
50 mg/kg-day / 3000
0.02 mg/kg-day or 2E-2 mg/kg-day
Although there is a lack of chronic animal or human studies, the studies used for
derivation of the provisional subchronic RfD (Atochem, 1992; Biodynamics, 1979) are
considered appropriate for use in deriving the chronic provisional RfD. No additional
Uncertainty Factor for subchronic-to-chronic extrapolation is applied because the adverse effects
mediated by inhibition of cholinesterase are considered to be short lived and reversible at low
doses. Thus, doses producing effects following a repeated daily exposure regimen are
comparable to those following a single dose. Also, comparable degrees of cholinesterase
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5-15-2007
inhibition are seen from the same dose, whether delivered in one acute dose or following
subchronic or chronic dosing. Additional justification is provided in the IRIS file on Aldicarb,
Section I.A.3. (U.S. EPA, 2007) and Rhone-Poulenc (1992).
p-RfD	= 0.02 mg/kg-day or 2E-2 mg/kg-day
Due to lack of complete published information and additional studies, low confidence in
the provisional subchronic and chronic RfDs and data base is recommended.
DERIVATION OF A PROVISIONAL CHRONIC RfC FOR
TRIPHENYLPHO SPHINE OXIDE (TPPO)
There is insufficient information available to derive a p-RfC for TPPO. The single
inhalation study reviewed for this risk issue paper was inadequate for a p-RfC derivation. The
study included 2 dogs/sex/group with no neurological or other effects noted during or after the
exposure.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
TRIPHEN YLPHO SPHINE OXIDE (TPPO)
The potential human carcinogenicity hazard for TPPO cannot be determined due to an
inadequate database (U.S. EPA, 2005). With one exception, the toxicity studies reviewed for
this risk issue paper were acute studies with a maximum exposure duration of 21 days. The
TSCA initial submission from BASF (1992) briefly indicated that liver effects in rats and dogs
had been observed in a subchronic feeding study, however, the nature of the effects and details
of the experimental protocol were not provided. The available database is inadequate to
determine the potential human carcinogenicity hazard for TPPO. Under the final guidelines
(U.S. EPA, 2005) the data are inadequate for assessment of human carcinogenic potential.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 1996. 1996 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
ACGIH, Cincinnati, OH.
Atochem. 1992. Letter from Atochem North America Inc. to U.S. EPA regarding toxicity
studies of triphenylphosphine and triphenylphosphine oxide w/attachments & cover letter dated
102292 Bio/Dynamics Inc. NTIS/OTS0571918.
ATSDR (Agency for Toxic Substances and Disease Registry). 2001. Internet HazDat -
Toxicological Profile Query. Examined September 2001. Online.
http ://www. atsdr. cdc. gov/ gsql/toxprof. script
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BASF Corporation. 1992. Initial submission: Letter from BASF Corp. submitting results of
industrial toxicology tests with triphenylphosphine oxide in mice, rats, rabbits, cats, and dogs.
NTIS/OTS0539646.
Biodynamics, Inc. 1979. A seven week neurotoxicity study in dogs with triphenylphosphine
oxide. Project no. 79-2379.
Esa, A.H., G.A. Warr and D.S. Newcombe. 1988. Immunotoxicity of organophosphorus
compounds: Modulation of cell-mediated immune response by inhibition of monocyte accessory
functions. Clin. Immunol. Immunopath. 49: 41-52.
Fautz, R. and H.G. Miltenburger. 1994. Influence of organophosphorus compounds on different
cellular immune functions in vitro. Toxicol, in Vitro. 8: 1027-1031.
NIOSH (National Institute for Occupational Safety and Health). 1997. Pocket Guide to
Chemical Hazards. U.S. Department of Health and Human Services, Washington, DC. Online.
http://www.cdc.gov/niosh/npg/pgdstart.html
NTP (National Toxicology Program). 2001. Online. National Institute of Environmental Health
Services, Research Triangle Park, NC. Examined September 2001. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html
OSHA (Occupational Safety and Health Administration). 2001. 29 CFR 1910.1000. Online.
Office of Federal Register, National Archives and Records Administration. Washington, DC.
Online. http://www.osha-slc.gov/Preamble/AirCont toc/AirCont toe by sect.html
Rhone-Poulenc Ag Company. 1992. MRID No. 423730-01; HED Doc. No. 0010459.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Rohm & Haas Company. 1992. Initial submission: Letter from Rohm & Haas Co. to U.S. EPA
regarding toxicity studies of triphenylphosphine with attachments and cover letter dated 09-22-
02 Bio/Dynamics Inc.
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 (HEAST). 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 PB 97-921199.
U.S. EPA. 2005. Guidelines for carcinogen risk assessment. Risk Assessment Forum,
Washington, DC; EPA/630/P-03/001F. Federal Register 70(66): 17765-17817. Available
online at http://www.epa.gov/raf
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U.S. EPA. 2007. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Examined
August 2001. Online, http://www.epa.gov/iris
WHO (World Health Organization). 2001. Online catalogs for the Environmental Health
Criteria series. Examined August 2001. Online, http://www.who.int/dsa/cat97/zehc.htm
and http://vvvvvv.vvho.int/dsa/iustpub/add.htm
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