United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/029F
Final
9-10-2009
Provisional Peer-Reviewed Toxicity Values for
Methyl phosphonic acid
(CASRN 993-13-5)
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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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
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
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
METHYL PHOSPHONIC ACID (CASRN 993-13-5)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) 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)	U.S. EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. 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 U.S. EPA's 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 U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. 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 5-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 documents 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 Resource Conservation and Recovery Act (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 document and understand the strengths
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and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. 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 U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Methyl phosphonic acid (MP A) is an environmental hydrolysis product of the chemical
warfare nerve agents VX, GB (sarin), and GD (soman) (Munro et al., 1999). MP A has been
detected in VX-contaminated soil, presumably as a hydrolysis product of ethyl methyl
phosphonic acid, which is, itself, a hydrolysis product of VX at low (<6) or high (>10) pH
(Munro et al., 1999). MPA is also formed very slowly in the environment from the hydrolysis of
isopropyl methyl phosphonic acid (IMPA), which is a hydrolysis product of GB
(Munro et al., 1999). In addition, a small number of bacteria species are capable of metabolizing
IMPA to MPA (Zhang et al., 1999; Schowanek and Verstraete, 1990). The chemically related
compound, diisopropyl methyl phosphonate (DIMP) is a by-product of the manufacture of GB
(ATSDR, 1999; Munro et al., 1999). Sega et al. (1998) reported that the abiotic degradation of
DIMP in groundwater resulted in IMPA and MPA, providing another source of MPA in the
environment. The slow hydrolysis of pinacolyl methyl phosphonic acid (the primary product of
GD hydrolysis) results in MPA formation from the environmental release of GD
(Munro et al., 1999). MPA may also be found in the environment as a breakdown product of
methyl phosphonate-containing pesticides and flame retardants (Munro et al., 1999).
In the environment, MPA is fairly stable because it is resistant to hydrolysis, photolysis,
and thermal decomposition (Munro et al., 1999). Its high solubility, low vapor pressure, low Koc,
and low Henry's law constant indicate that MPA will be highly mobile in soils and will exist
primarily in aqueous compartments (Munro et al., 1999). Figure 1 shows the chemical structure
of MPA.
0
II
H3C— P — OH
1
OH
Figure 1. Structure of Methyl Phosphonic Acid
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No chronic RfD, RfC, oral slope factor, or inhalation unit risk for MPA is available on
the U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS)
(U.S. EPA, 2009), Drinking Water Standards and Health Advisories list (U.S. EPA, 2006a), or
Health Effects Assessment Summary Tables (HEAST) (U.S. EPA, 1997). No documents for
MPA are included on the Chemical Assessment and Related Activities (CARA) list (U.S. EPA,
1991, 1994). The U.S. Army (1999) derived an estimated RfD of 5.7 x 10"2 mg/kg-day for MPA
based on a quantitative structure-activity relationship (QSAR) estimate of the chronic rat
LOAEL of 566 mg/kg-day from TOPKAT® (Accelrys, Inc.), a commercial software program.
Munro et al. (1999) mentioned the U.S. Army (1999) QSAR-based RfD but preferred a different
RfD value of 2 x 10"2 mg/kg-day for MPA based on the subchronic rat NOAEL of
279 mg/kg-day for the closely related compound IMPA (Bausum et al., 1999). ATSDR (2007),
NTP (2007), IARC (2007), and the WHO (2007) have not reviewed the toxicity of MPA. MPA
is not included in the National Toxicology Program's (NTP's) 11th Report on Carcinogens (NTP,
2005). The American Conference of Governmental Industrial Hygienist (ACGIH, 2007),
Occupational Safety and Health Administration (OSHA, 2007), and National Institute for
Occupational Safety and Health (NIOSH, 2007) have not established occupational health
standards for MPA. A U.S. Army (1975) review later summarized by Williams et al. (1987) and
a review of chemical warfare agent degradation products (Munro et al., 1999) were consulted for
relevant information.
To identify toxicological information pertinent to the derivation of provisional toxicity
values for MPA, literature searches were initially conducted in January 2007 using the following
databases: MEDLINE, TOXLINE Special, TSCATS/TSCATS 2, CCRIS, DART/ETIC,
GENETOX, HSDB, RTECS (these were not date limited); BIOSIS (from August 2000 to
January 2007); and Current Contents (previous 6 months only). A final search for published
studies was conducted for the period from July 2008 through March 2009.
REVIEW OF PERTINENT DATA
Human Studies
No data regarding human toxicity resulting from oral or inhalation exposure to MPA
were identified in the available reviews or the literature searches.
Animal Studies
Oral Exposure
No chronic, subchronic, developmental, or reproductive toxicity studies conducted by the
oral route of exposure were located for MPA.
Inhalation Exposure
No chronic, subchronic, developmental, or reproductive toxicity studies conducted by the
inhalation route of exposure were located for MPA.
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
TOXICITY VALUES FOR METHYLPHOSPHONIC ACID (RfDs, RfCs)
Due to a lack of data, no chronic or subchronic RfDs or RfCs are developed. However,
the Appendix of this document contains a Screening Value for oral toxicity (RfD) based on an
analog approach, which may be useful in certain instances. Please see the attached Appendix for
details.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
METHYL PHOSPHONIC ACID
Weight-of-Evidence Descriptor
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Inadequate Information to Assess the Carcinogenic Potential' of MP A; there are no human
epidemiology studies, chronic toxicity studies, or carcinogenicity assays.
Quantitative Estimates of Carcinogenic Risk
The lack of data on the carcinogenicity of MP A precludes the derivation of quantitative
estimates of risk for either oral (p-OSF) or inhalation (p-IUR) exposure.
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ACGIH (American Conference of Governmental Industrial Hygienists). 2007. 2007 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Profile for
Diisopropyl Methylphosphonate. Prepared for the Public Health Service. PB/99/102535/AS.
ATSDR (Agency for Toxic Substances and Disease Registry). 2004. Review of the Toxicology
and Health Hazard Considerations for Safe Management of Newport (Indiana) Caustic VX
Hydrolysate. Attachment 2 in: Review of the U.S. Army Proposal for Off-Site Treatment and
Disposal of Caustic VX Hydrolysate from the Newport Chemical Agent Disposal Facility.
Prepared by ATSDR in collaboration with the Centers for Disease Control and Prevention,
Atlanta, GA. November 3, 2004. Online. http://www.cdc.gov/nceh/demil/reports/VX/
VX%20Report.pdf.
ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Online, http://www.atsdr.cdc.eov/toxprofiles/index.asp.
Bausum H.T., G. Reddy, G.J. Lean. 1999. Suggested interim estimates of the reference dose
(RfD) for certain breakdown products of chemical agents. Presented at The Society of
Toxicology Annual Meeting, 14-19 March 1999, New Orleans, LA.
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Blumbach, K., A. Pahler, H.M. Deger et al. 2000. Biotransformation and male rat-specific renal
toxicity of diethyl ethyl-and dimethyl methylphosphonate. Toxicol. Sci. 53:24-32.
Chapin, R.E., S.L. Dutton, M.D. Ross et al. 1984. Development of reproductive tract lesions in
male 344 rats after treatment with dimethyl dimethylphosphonate. Exp. Mol. Pathol.
41:126-140.
Ciba-Geigy. 1977. One month dietary toxicity study in rats with dimethyl methylphosphonate.
Produced 6/28/77 and submitted 7.30/84 to EPA under TSCA section FYI. EPA Doc. No.
FYI-OTS-0784-0242. Fiche No. OTS0000242-2. TSCATS 32684. (Cited in U.S. EPA, 1992).
Ciba-Geigy. 1978. Reproduction study-FAT 80021/B-Rat-Seg. II. Produced 1/16/78 and
submitted 7/30/84 to EPA under TSCA. EPA Doc. No. FYI-OTS-0784-0242. Fiche No.
OTS0000242-2. TSCATS 32683. (Cited in U.S. EPA, 1992).
Dunnick, J.K., B.N. Gupta, M.W. Harris et al. 1984a. Reproductive toxicity of dimethyl
dimethylphosphonate in the male Fischer 344 rat. Toxicol. Appl. Pharmacol. 72:379-387.
Dunnick, J.K., H.A. Solleveld, M.W. Harris et al. 1984b. Dimethyl methylphosphonate
induction of dominant lethal mutations in male mice. Mutat. Res. 138:213-218.
Dunnick, J.K., S.L. Eustis and J.K. Haseman. 1988. Development of kidney tumors in the male
F344/N rat after treatment with dimethyl methylphosphonate. Fund. Appl. Toxicol. 11:91-99.
DuPont. 2004. Toxicology Assessment of Health Hazard Considerations for Safe Management
of Newport Caustic Hydrolysate. DuPont Report 14523, dated March 3, 2004. (Cited in
AT SDR, 2004).
Finlay, C. 2004. Methylphosphonic Acid: Oral Approximate Lethal Dose (ALD) in Rats.
Haskell Laboratories. Dated February 26, 2004. (Cited in AT SDR, 2004).
Hardin, B.D., R.L. Schuler, J.R. Burg et al. 1987. Evaluation of 60 chemicals in a preliminary
developmental toxicity test. Teratog. Carcinog. Mutagen. 7:29-48.
Hoskin, F.C.G. 1956a. Some observations concerning the biochemical inertness of methyl
phosphonic and isopropyl hydrogen methylphosphonic acids. Can. J. Biochem. Physiol.
34:743-746.
Hoskin, F.C.G. 1956b. The enzymatic hydrolysis products of sarin. Can. J. Biochem. Physiol.
34:75-79.
IARC (International Agency for Research on Cancer). 2007. Search IARC Monographs.
Online, http://monoeraphs.iarc.fr/.
Mecler, F.J. 1981. Mammalian toxicological evaluation of DIMP and DCPD (Phase 3- IMP A).
Litton Bionetics, Inc. Contract No. DAMD 17-77-C-7003. U.S. Army Medical Research and
Development Command, Ft. Detrick, Frederick, MD. Final Report.
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Munro, N.B., S.S. Talmage, G.D. Griffin et al. 1999. The sources, fate, and toxicity of chemical
warfare agent degradation products. Environ. Health Perspect. 107(12):933-973.
NIOSH. 2007. Pocket Guide to Chemical Hazards. Index by CASRN. Online.
http: //www, cdc. gov/ni osh/np g/np gdcas. html.
NTP (National Toxicology Program). 1987. Toxicology and carcinogenesis studies of dimethyl
methylphosphonate (CAS No. 756-79-6) in F344/N rats and B6C3F1 mice (gavage studies).
NTP TR-323. November. NMPub.No. 88-2579.
NTP (National Toxicology Program). 2005. 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Online, http://ntp-server.niehs.nih.gov/.
NTP (National Toxicology Program). 2007. Management Status Report.
OSHA (Occupational Safety and Health Administration). 2007. OSHA Regulations. Online.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p id=999
2.
Rosenblatt, D.H., T.A. Miller, J.C. Dacre et al. 1975. Problem definition studies on potential
environmental pollutants. II. Physical, chemical, toxicological, and biological properties of
16 substances. TR-7509. Ft. Detrick, MD: Army Medical Bioengineering Research and
Development Laboratory. Pp. 290.
Schowanek, D. and W. Verstraete. 1990. Phosphonate utilization by bacterial cultures and
enrichments from environmental samples. Appl. Environ. Microbiol. 56:895-903.
Sega, G.A., B.A. Tomkins, W.H. Griest et al. 1998. The hydrolysis of di-isopropyl
methylphosphonate in ground water. J. Environ. Sci. Health. 33:213-236.
Small, M.J. 1984. Compounds formed from the chemical decontamination of HD, GB, and VX
and their environmental fate. AD-A149 515. Ft. Detrick, MD: Army Medical Bioengineering
Research and Development Laboratory.
U.S. Army. 1975. Problem definition studies on potential environmental pollutants. II.
Physical, chemical, toxicological, and biological properties of 16 substances. U.S. Army
Medical Bioengineering Research and Development Laboratory. Fort Detrick, Frederick, MD.
Technical Report 7509. NTIS # AD-D030,428.
U.S. Army. 1999. Derivation of health-based environmental screening levels for chemical
warfare agents. U.S. army Center for Health Promotion and Preventative Medicine. Aberdeen
Proving Ground, MD.
U.S. EPA (U.S. Environmental Protection Agency). 1991. Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April.
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U.S. EPA (U.S. Environmental Protection Agency). 1994. Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
December.
U.S. EPA (U.S. Environmental Protection Agency). 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 (U.S. Environmental Protection Agency). 2005. Guidelines for Carcinogen Risk
Assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register
70(66): 17765-17817. Online, http://www.epa.gov/raf.
U.S. EPA (U.S. Environmental Protection Agency). 2006a. 2006 Edition of the Drinking Water
Standards and Health Advisories. Office of Water, Washington, DC. Summer, 2006.
EPA 822-R-06-013. Online, http://www.epa.eov/waterscience/drinkine/standards/
dwstandards.pdf.
U.S. EPA (U.S. Environmental Protection Agency). 2006b. Provisional Peer Reviewed Toxicity
Values for Dimethyl Methylphosphonate (CASRN 756-79-6). Prepared by the National Center
for Environmental Assessment, Office of Research and Development, Cincinnati, OH.
U.S. EPA (U.S. Environmental Protection Agency). 2009. Integrated Risk Information System
(IRIS). Online. Office of Research and Development, National Center for Environmental
Assessment, Washington, DC. Online, http://www.epa.eov/iris.
WHO (World Health Organization). 2007. Environmental Health Criteria (EHC) Monographs
International Programme on Chemical Safety, Geneva, Switzerland. Online.
http://www.inchem.ore/paees/ehc.html.
Williams, R.T., W.R. Miller and A.R. MacGillivray. 1987. Environmental fate and effects of
tributyl phosphate and methyl phosphonic acid. Govt. Reports Announcements & Index
(GRA & I). NTIS/AD-A184 959/5.
Zhang, Y., R.L. Autenrieth, J.S. Bonner et al. 1999. Biodegradation of neutralized sarin.
Biotechnol. Bioeng. 64:221-231.
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APPENDIX: DERIVATION OF A SCREENING VALUE FOR
METHYL PHOSPHONIC ACID
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for methyl phosphonic acid. However, limited information is available for this
chemical which, although insufficient to support derivation of a provisional toxicity value, under
current guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health
Risk Technical Support Center summarizes available information in an Appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
Past efforts to derive RfDs for MPA employed quantitative structure-activity
relationships (QSAR) to predict the toxicity of MPA (U.S. Army, 1999). The U.S. Army (1999)
used a commercial software program TOPKAT® to predict a rat chronic LOAEL of
566 mg/kg-day, and, from this calculation, derive a chronic RfD of 0.057 mg/kg-day for MPA.
In its review of a DuPont (2004) report, the ATSDR (2004) considered acute toxicity predictions
for MPA based on the TOPKAT program. The ATSDR (2004) concluded that TOPKAT
predictions for MPA were "not reliable because the query structures are poorly represented in
the.. .database." Because the training set in the TOPKAT database is unpublished, it was not
possible to verify ATSDR's concern or to validate this predicted chronic RfD for MPA.
Oral Toxicity Value
Screening Chronic and Subchronic RfD
Based on the consensus of results from the two independent approaches (see
Approaches 1 and 2), the surrogate candidate with the most conservative RfD and highest
similarity score would be recommended as the final surrogate for MPA. Therefore, for MPA, the
provisional chronic and subchronic RfD for DMMP (6 x 10" or 0.06 mg/kg-day), derived by the
U.S. EPA (2006b), and based on male reproductive toxicity in a rat study (Dunnick et al.,
1984a), is recommended as a screening RfD, for MPA, based on the surrogate analyses (most
conservative RfD and highest similarity score) presented here. The peer-reviewed document
uses a LOAEL of 250 mg/kg-day (179 mg/kg-day after TWA adjustment) and includes a
composite UF of 3,000 (10 for interspecies extrapolation, 10 for intraspecies extrapolation, 10
for use of a LOAEL, and 3 for DMMP database uncertainties). These UFs, described in the
PPRTV for DMMP (U.S. EPA, 2006b), have been retained for the MPA assessment.
The screening chronic and subchronic RfD for MPA based on DMMP is derived as follows:
Screening Chronic and Subchronic RfD = LOAEL UF
= 179 mg/kg-day3,000
= 0.06 mg/kg-day or 6 x 10"2 mg/kg-day
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Confidence in the critical reproductive study and database is the same as stated in the
PPRTV for DMMP (see U.S. EPA, 2006b). Confidence in the overall surrogate approach is
medium because the structural similarity is reasonably high between MPA and DMMP and
because the physicochemical properties and the LD50 data among the potential surrogates and
MPA are generally comparable (see Tables 1 and 2). In addition, the screening RfD calculated
for MPA compares favorably with most of the available noncancer toxicity values of the
potential surrogates identified herein (see Table 2). However, due to the high inherent
uncertainty in the overall surrogate approach, confidence in the screening chronic and subchronic
p-RfD is low.
Since the available QSAR predictions of the toxicity of MPA could not be appropriately
validated, two approaches were applied for possible derivation of toxicity values for MPA.
Approach 1 was to identify chemicals from the same chemical class (i.e., phosphonic acid;
phosphonate) as MPA that have U.S. EPA toxicity values (e.g., RfD) and use those as surrogates
for MPA toxicity. Approach 2 was to identify chemicals with U.S. EPA toxicity values that have
sufficient structural similarity to serve as surrogates for MPA toxicity. The structure-activity
relationships (SAR) examined in Approach 2 include both a chemical similarity search and a
comparison of physicochemical properties. Chemical similarity is based on the hypothesis that
similar compounds have similar biological activities or toxicities. Both approaches are presented
and discussed in detail to support the final selection of DMMP as the most appropriate surrogate
for MPA.
Approach 1—Chemical-Class Relationships
Precursor and Biodegradation Products
The search for chemically related analogs of MPA started with an examination of
chemical precursors and degradation products. As mentioned in the Introduction, MPA is an
environmental hydrolysis or abiotic degradation product of chemical warfare nerve agents or
their by-products. Initially, a literature search was conducted for potential analogs that may form
MPA in the environment or in mammalian systems. Given the criterion, isopropyl phosphonic
acid (IMPA), ethyl methylphosphonic acid (EMPA), and diisopropyl methyl phosphonate
(DIMP) were considered as potential analogs. However, no toxicological data were located for
EMPA in the IRIS, ATSDR, NTP, HSDB, ESIS, and TSCATS databases, as well as MedLine
and Toxline, thus ruling out EMPA as a potential surrogate for MPA in this analysis. Only
IMPA and DIMP have available oral toxicity information relevant for provisional oral toxicity
values for MPA and were, therefore, considered further as potential surrogates.
Chemical Class Analogs
Since MPA belongs to the chemical class of phosphonic acid, an initial search was
conducted on the databases for chemicals within this chemical class, which also had available
oral toxicity information. Some unique features within the chemical class have been reported.
Williams et al. (1987) noted that MPA contains a unique structural property in the nonreactive
carbon-phosphorus (C-P) bond. According to Williams et al. (1987), this bond is resistant to
hydrolysis, thermal degradation, and photolysis, and this bond is largely responsible for the
persistence of compounds such as MPA in the environment. Because of its unique properties,
the C-P bond is considered as an essential feature in the selection of potential analogs for the
chemical class. Only chemicals possessing a nonreactive phosphorus-carbon bond, similar to
MPA, are identified as potential analogs.
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In addition to the C-P bond requirement, evaluation of potential analogs was further
conducted in a tiered fashion. The first group (Group 1) of potential analogs included the C-P
bond and short-chain alkyl substitutions for the methyl group of MP A (indicated by -R for
Group 1 in Figure 2). Group 1 was preferred for identifying potential analogs because they were
considered to possess similar biological activity or toxicity with respect to MPA. Search results
identified ethyl phosphonic acid, 1-propyl phosphonic acid, and isopropyl phosphonic acid. To
be considered for further surrogate selection, a literature search was conducted specifically for
the oral route of exposure, but no toxicity values were located for these compounds.
Since no suitable analogs were identified in the first group, a second group with less
stringent criteria (more substitutions) was applied to the same databases. The second group of
potential analogs included short-chain alkyl monoester substitutions for one of the hydroxyl
moieties of MPA and expanded the chemical class to include phosphonates (Group 2 in
Figure 2). Compounds identified as potential analogs in this group included monomethyl
methylphosphonate, as well as EMPA and IMPA (identified in Precursor andBiodegradation
Products). Because toxicological data for monomethyl methylphosphonate were not identified,
no further consideration as a surrogate was possible.
The third group has the least restriction, allowing short-chain alkyl diester substitutions
for both hydroxyl moieties (Group 3 in Figure 2). Compounds identified as potential analogs
included dimethyl methylphosphonate (DMMP), diethyl methylphosphonate, dipropyl
methylphosphonate, and DIMP (identified in Precursor and Biodegradation Products).
Repeated-dose oral toxicity data were located for DMMP, thus identifying DMMP as an
additional potential surrogate.
Group 1	Group 2	Group 3
O	0	0
R — P — OH H3C—P — OH H3C—P — OR
I	I	I
OH	OR	OR
R = Short-Chain Alkyl
Figure 2. Representation of Analogs in Phosphonic Acid or Phosphonate Chemical Class
As a final check on the search for potential analogs, the databases above (IRIS, ATSDR,
NTP, HSDB, ESIS, and TSCATS) were searched for the terms "phosphonate" and "phosphonic
acid" in order to ensure that all potential analogs with repeated-dose toxicity data were
identified. The search of ESIS identified data for phosphonic acid; however, there were no
repeated-dose toxicity data by any route of exposure.
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Overall, based on this tiered evaluation within the chemical class, IMP A, DMMP, and
DIMP were identified as analogs that were further considered as potential surrogates with
available oral toxicity information relevant for deriving a Screening Value of RfD for MPA.
IMP A and DIMP were also identified as potential surrogates based on the biodegradation data in
the previous section. Comparison of these compounds is provided below on the basis of
toxicokinetics, acute lethality, and other available toxicity data.
Comparison of Potential Chemical Class Surrogates
Toxicokinetics
32
MPA is eliminated via the urine. Following intraperitoneal administration of P MPA
(31 mg) to a single adult male Wistar rat, 92% of the dose was excreted unchanged in the urine
within 48 hours (Hoskin, 1956a). No phosphoric acid was observed in chromatographs of the
urine, indicating that MPA is not metabolized to phosphoric acid in the rat.
The available information on the kinetics of DIMP, IMP A, and DMMP suggest that
DIMP has extensive metabolism. ATSDR (1999) reviewed the toxicokinetics of DIMP and
reported that low doses of DIMP are rapidly and completely metabolized to IMP A, which is the
principal urinary metabolite in mice, rats, dogs, mink, and cattle. Male rats have been shown to
convert DIMP to IMPA more rapidly than females; plasma elimination rates of 45 and
250 minutes have been estimated for males and females, respectively (ATSDR, 1999). In
contrast to DIMP, IMPA is not hydrolyzed in the rat, but is excreted largely unchanged.
Hoskin (1956b) administered 285 mg 2P IMPA to 2 rats subcutaneously over a 48-hour span of
time. Analysis of urine collected over 72 hours indicated that most of the radioactivity was
excreted as unchanged IMPA (85.1%, with total recovery of 96.5%). Only trace amounts of
MPA were detected (0.3%) (Hoskin, 1956b).
In rats orally exposed to doses of 50 or 100 mg/kg DMMP, the urine was shown to
contain unchanged DMMP and its main metabolite, methyl methyl phosphonate
(Blumbach et al., 2000). Within 24 hours after dosing, 58-68%) of the administered dose was
recovered in the urine of males, while 88—93%> of the administered dose was recovered in the
urine of females (Blumbach et al., 2000).
Overall, DIMP generally undergoes rapid metabolism and forms major metabolites
including IMPA, while MPA, IMPA, and DMMP stay relatively intact after excretion and have
high recovery in urine after the administered dose.
Acute Lethality
Williams et al. (1987) cited oral lethal doses of 5,000 and >5,000 mg/kg for MPA in rats
and mice, respectively. An ATSDR (2004) review of a DuPont (2004) report entitled
"Toxicology Assessment of Health Hazard Considerations for Safe Management of Newport
Caustic Hydrolysate"1 identified a recent rat study (Finlay, 2004, as cited in ATSDR, 2004) from
which the acute toxicity of MPA was estimated. Efforts to obtain the original report were not
successful. ATSDR (2004) reported that the study estimated an approximate lethal dose of
2,300 mg/kg for MPA administered via gavage to rats (strain not specified). According to the
According to the ATSDR review of the DuPont report, Newport Caustic Hydrolysate, or caustic VX hydrolysate,
contains 80% water with minor amounts of methyl phosphonic acid and other compounds.
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ATSDR summary, MPA was administered to one rat per dose (doses not specified); clinical
signs and body weights were observed for 14 days after exposure. ATSDR (2004) noted that the
report did not give any indication of the clinical endpoints of acute MPA toxicity.
The acute lethality of orally administered MPA does not differ substantially from that of
MPA administered intraperitoneally; Williams et al. (1987) reported intraperitoneal LD50 values
of 2,250 and 3,370 mg/kg-day for rats and mice, respectively. Table 1 contains acute oral
toxicity values (LD50) for DIMP, IMP A, DMMP, and MPA. DIMP is more acutely toxic to both
rats and mice, while IMP A, DMMP, and MPA have comparable acute oral lethality.
Repeated Oral Dose
In rats exposed to IMP A, only trace amounts of MPA were detected, and IMP A was
largely excreted unchanged (Hoskin, 1956b). Furthermore, the only repeated-dose toxicity study
of IMP A, a 90-day rat drinking water study (Mecler, 1981), resulted in the identification of a
freestanding NOAEL (279 mg/kg-day) and, thus, did not identify a critical toxicological
endpoint of IMP A toxicity. The IRIS assessment, as derived in February 1993 for IMP A, cites
studies of DIMP (which is rapidly hydrolyzed to IMP A in mammalian systems) as support for
the IMPA RfD that is based on this freestanding NOAEL. Similarly, the oral studies as cited in
the DIMP IRIS assessment in February 1993 also did not identify a toxicological endpoint for
these compounds.
In contrast, the toxicological database for DMMP is more robust, including both
subchronic and chronic rodent bioassays (NTP, 1987; Dunnick et al., 1988; Ciba-Geigy 1977) as
well as developmental and reproductive toxicity studies (Ciba-Geigy, 1978; Hardin et al., 1987;
Dunnick et al., 1984a,b; and Chapin et al., 1984). The U.S. EPA (2006b) calculated provisional
subchronic and chronic RfDs for DMMP based on a reproductive toxicity study in rats conducted
by Dunnick et al. (1984a). This study identified a LOAEL of 250 mg/kg-day (the lowest dose
tested) for increased resorptions in untreated female rats mated with males treated at this dose
and higher doses. The increase in resorptions was dose related. The U.S. EPA (2006b) adjusted
the LOAEL for continuous exposure (doses were administered by gavage only 5 days per week)
to give an adjusted LOAEL of 179 mg/kg-day. A composite uncertainty factor of 3,000,
including a 10-fold UF for interspecies extrapolation, a 10-fold UF for human variability, a
10-fold UF for use of a LOAEL, and 3-fold UF for DMMP database limitations, was applied in
both the subchronic and chronic RfDs. An uncertainty factor for less-than-chronic duration was
not applied because the 84-day exposure period was considered to be chronic for the critical
effect, reproductive toxicity.
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Table 1. Physical-Chemical Properties of MP A and Potential Analogs

MPA
I MPA
DUMP
DMMP
Structure
0
II
H3C— P — OH
1
OH
h3c
OH \
1 CH=
0= P —0
1
ch3
\\ /H3
H3C— P — O	(
1 \n
0
H3C^^CH3
h3c xp' ch3
0' ch3
CASRN
993-13-5
1832-54-8
1445-75-6
756-79-6
Molecular formula
CH5O3P
C4H„03P
c7h17o3p
c3h9o3p
Molecular weight
96.0
138.1
180.2
124.1
Melting point (°C)
108.5a
NA
<25a
NA
Boiling point (°C)
NA
123-125 at 0.2 torrb
121.05 at 10 mmHga; 134b
181a; 174b
Vapor pressure (mmHg)
2 x 10"6a
0.0119a; 0.0034 at 25 °Cf
0.277b
0.962a
Henry's law constant (atm-m3/mole)
1.22 x 10"lla
6.88 x 10"9a
4.38 x 10"5a
1.25 x 10"6a
Density (g/mL)
ND
1.1091 at 20 °C
0.976b
1.15 at 20 °C
Water solubility (g/L)
>20b
50a; 48f
l-2b
l,000a
Log Kow
-2.28°
-0.54°
1.03a; 0.478f
-0.61a
pKa
2.12a; 2.38°
1.98°
NA
NA
Oral Lethality (LD50)
Rat (mg/kg)
2,300d, 5,000e
7,650 (male), 6,070 (female)f
826f
>3,000s
Mouse (mg/kg)
>5,000e
5,620 (male), 6,550 (female)f
1,04 lf
>6,000s
aPhysProp Database
bRosenblatt et al., 1975
°Small, 1984
dFinlay et al., 2004
"Williams et al., 1987
fMunro et al., 1999
gNTP, 1987
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In summary, IMP A, DIMP, and DMMP were considered potential surrogates for MPA
based on the biodegradation and chemical class specific information and the availability of
repeated-dose oral toxicity data. Ideally, selection of a potential surrogate for MPA would be
based on identifying a compound with target organ toxicity similar to MPA; however, there are
neither toxicity data nor mechanistic information to predict potential target organs or effects of
MPA. In addition, no target organ was identified in toxicological studies of IMP A and DIMP
asreviewed in the IRIS (U.S. EPA, 2009) records for these two compounds. The ATSDR (1999)
identified hematological effects as the critical endpoint for chronic DIMP toxicity; however, this
study was published after the IRIS RfD was posted. U.S. EPA (2006b) identified reproductive
toxicity (increased resorptions in rats) as the critical effect of oral exposure to DMMP.
Considering all relevant toxicity information, selection for final surrogate among DMMP,
IMP A, and DIMP would be based on most conservative toxicity value due to lack of the
mechanistic information. Furthermore, without quantitative assessment of similarity with respect
to MPA, an alternative solution for deriving a provisional RfD for MPA would be a range of
2	1
toxicity values among the three surrogates: 6 x 10" to 1 x 10" mg/kg-day. A separate approach
using structure-activity relationship was applied to facilitate the ranking of identified surrogates
and to search for other potential surrogates; details are presented in the next section.
Approach 2—Structure-Activity Relationships
Structure-activity relationship (SAR) is a means by which the effect of a toxic chemical
on an animal, a human, or the environment can be related to its molecular structure.
Traditionally, this type of relationship may be assessed by considering a series of chemicals,
making gradual changes to them, and noting the effect of each change on their biological
activity. This process is very similar to the search performed earlier (tiered evaluation as
described in Chemical Class Analogs) in identifying potential analogs within a chemical class
(e.g., phosphonic acid). Alternatively, it may be possible to assess similarity by using software
programs or models to try to establish a relationship. One publicly available program,
ChemlDplus flittp: //chero.. si s. nlro.. nih. gov/cherol dplus/). part of National Library of Medicine
Web site, can provide quantitative assessment (similarity score) for identifying and ranking of
potential structural analogs.
A structural analog was considered a potential surrogate if it was structurally related
(>50% similarity in ChemlDplus score) and had toxicity values derived from repeated-dose oral
toxicity data. The threshold of >50% was chosen to identify all relevant structural analogs in
both 2-dimensional and 3-dimensional aspects of a chemical. When combining Similarity
Search under the Structure Search Options on the National Library of Medicine ChemlDplus
with the availability of oral toxicity data of these analogs on the IRIS, ATSDR, NTP, HSDB,
ESIS, and TSCATS databases, three potential surrogates were identified: DMMP, IMP A, and
DIMP. These three potential surrogates are identical to the ones identified in the first approach.
No other potential surrogates were located by the SAR approach.
In addition to ChemlDplus, other programs were also used. DMMP was also identified
as a potential analog using two independent commercial software packages: Leadscope®
(Leadscope, Inc.. http://www.leadscope.com) and TOPKAT® (Accelrys, Inc.,
http://www.accelrvs.com/products/topkat/index.html/.
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http://accelrvs.com/products/discovery-studio/toxicoloev/index.html). The consensus among the
three similarity search programs provides high confidence that the identified structural analog
(DMMP) can be considered as a potential surrogate.
Table 1 shows a comparison between the physicochemical properties and acute oral
lethality data for MP A, IMP A, DIMP, and DMMP. The table indicates that, while
physical-chemical properties of these compounds are generally similar (all have high water
solubility and low log Kow, vapor pressure and Henry's Law constants), DIMP is more toxic to
both rats and mice than the other compounds based on a comparison of acute lethality data. In
contrast, the LD50 data for MP A, IMP A, and DMMP are generally comparable. These similar
physicochemical properties and acute oral lethality data for MPA and three structural analogs
reinforce the appropriateness of IMP A, DIMP, and DMMP as potential surrogates.
Table 2 summarizes all chronic oral noncancer toxicity values for MPA and the three
potential surrogates (DMMP, IMP A, DIMP). Based upon both the most conservative chronic
oral noncancer toxicity values (mg/kg-day) and the highest structural similarity (NLM
ChemlDplus similarity %), the current provisional noncancer oral reference dose (p-RfD) of
6 x 10"2 (U.S. EPA, 2006b) for DMMP may serve as a conservative estimate (surrogate) for oral
toxicity for MPA. Given the high level of uncertainty associated with derivation of chemical
surrogate toxicity values, molecular weight-based adjustment to surrogate values is not
appropriate.
Table 2. Comparison of Chronic Oral Noncancer Toxicity Values for MPA and
Potential Surrogates

U.S. EPA
Provisional RfD
(mg/kg-day)
IRIS RfD
(mg/kg-day)
ATSDR
MRL
(mg/kg-day)
U.S. Army (1999)
QSAR-based RfD
(mg/kg-day)
NLM
ChemlDplus
Similarity (%)
MPA
ND
ND
ND
6 x 10-2
100
DMMP
6 x 10 2
ND
ND
ND
72
IMPA
ND
1 x 10"1
ND
ND
68
DIMP
ND
8 x 10"2
6 x 10"1
ND
56
ND = No Data
Using information from Approaches 1 and 2, the three top candidates with available RfDs
were selected: DMMP, IMP A, and DIMP.
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