SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
Category name: Phosphoric Acid Derivatives
SUB-CATEGORY I
SPONSORED CHEMICAL
Tris(2-ethylhexyl) phosphate CAS No. 78-42-2
[9th CI Name: Phosphoric acid, /m(2-ethylhexyl) ester]
SUB-CATEGORY II
SPONSORED CHEMICALS
Bis(2-ethylhexyl) phosphate CAS No. 298-07-7
[9th CI Name: Phosphoric acid, />/.s(2-ethylhexyl) ester]
Phosphoric acid, 2-ethylhexyl ester CAS No. 12645-31-7
(Mixture of CAS No. 298-07-7 and CAS No. 1070-03-7)
[9th CI Name: Phosphoric acid, 2-ethylhexyl ester]
SUPPORTING CHEMICAL
Mono(2-ethylhexyl) phosphate CAS No. 1070-03-7
[9th CI Name: Phosphoric acid, mono(2-ethylhexyl) ester]
SUB-CATEGORY III
SPONSORED CHEMICAL
Triisobutyl phosphate CAS No. 126-71-6
[9th CI Name: Phosphoric acid, fns(2-methylpropyl) ester]
SUPPORTING CHEMICAL
Tributyl phosphate CAS No. 126-73-8
[9th CI Name: Phosphoric acid tributyl ester]
June 2008
INTERIM
Prepared by
High Production Volume Chemicals Branch
Risk Assessment Division
Office of Pollution Prevention and Toxics
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460-0001
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SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
The High Production Volume (HPV) Challenge Program1 is a voluntary initiative aimed at developing and making
publicly available screening-level health and environmental effects information on chemicals manufactured in or
imported into the United States in quantities greater than one million pounds per year. In the Challenge Program,
producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and
initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do
not exist, and making both new and existing data and information available to the public. Each complete data
submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2) endpoints that
are screening-level indicators of potential hazards (toxicity) for humans or the environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data
submitted in the HPV Challenge Program on approximately 1400 sponsored chemicals. OPPT is using a hazard-
based screening process to prioritize review of the submissions. The hazard-based screening process consists of two
tiers described below briefly and in more detail on the Hazard Characterization website3.
Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established
criteria to "bin" chemicals/categories for OPPT review. This is an automated process performed on the data as
submitted by the sponsor. It does not include evaluation of the quality or completeness of the data.
In Tier 2, a screening-level hazard characterization is developed by EPA that consists of an objective evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions. The evaluation is
performed according to established EPA guidance2'4 and is based primarily on hazard data provided by sponsors.
EPA may also include additional or updated hazard information of which EPA, sponsors or other parties have
become aware. The hazard characterization may also identify data gaps that will become the basis for a subsequent
data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar
chemical structures, properties and biological activities may be grouped together and their data shared across the
resulting category. This approach often significantly reduces the need for conducting tests for all endpoints for all
category members. As part of Tier 2, evaluation of chemical category rationale and composition and data
extrapolation(s) among category members is performed in accord with established EPA2 and OECD5 guidance.
The screening-level hazard characterizations that emerge from Tier 2 are important contributors to OPPT's existing
chemicals review process. These hazard characterizations are technical documents intended to support subsequent
decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general
public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on
HPV chemicals and provide information previously not readily available to the public. The public, including
sponsors, may offer comments on the hazard characterization documents.
The screening-level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical
or a chemical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of
and exposures to high-volume TSCA existing chemicals, submitted in accordance with the requirements of the
Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the
IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the
screening-level hazard characterizations to develop screening-level risk characterizations4'6. The screening-level
risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts
are currently underway to consider how best to utilize these screening-level risk characterizations as part of a risk-
based decision-making process on HPV chemicals which applies the results of the successful U.S. High Production
Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action.
1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3 U.S. EPA. HPV Chemicals Hazard Characterization website (http://www.epa.gov/hpvis/abouthc.html).
4 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
5 OECD. Guidance on the Development and Use of Chemical Categories; http://www.oecd.org/dataoecd/60/47/1947509.pdf.
6 U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm.
2
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SCREENING-LEVEL HAZARD CHARACTERIZATION
Phosphoric Acid Derivatives
Introduction
The sponsor, American Chemistry Council (ACC) Phosphoric Acid Derivatives Panel, submitted a Test Plan and
Robust Summaries to EPA for phosphoric acid derivatives on December 13, 2001. EPA posted the submission on
the ChemRTK HPV Challenge website on January 15, 2002
(http://www.epa.gov/chemrtk/pubs/summaries/phsacdde/cl3356tc.htm'). EPA comments on the original submission
were posted to the website on November 19, 2002. Public comments were also received and posted to the website.
The sponsor submitted updated/revised documents on December 22, 2005, which were posted to the ChemRTK
website on March 21, 2006. For reasons discussed in the Category Definitions and Category/Supporting Chemical
Justification sections below, EPA has divided the sponsored chemicals and proposed supporting chemicals into three
sub-groups for assessment of data adequacy for endpoints under the HPV Challenge Program:
SUB-CATEGORY I
SPONSORED CHEMICAL
7r/5(2-ethylhexyl) phosphate CAS No. 78-42-2
[9th CI Name: Phosphoric acid, tris(2-ethylhexyl) ester]
SUB-CATEGORY II
SPONSORED CHEMICALS
Bis(2-ethylhexyl) phosphate CAS No. 298-07-7
[9th CI Name: Phosphoric acid, />/.v(2-cthvlhc\yl) ester]
Phosphoric acid, 2-ethylhexyl ester CAS No. 12645-31-7
(Mixture of CAS No. 298-07-7 and CAS No. 1070-03-7)
[9th CI Name: Phosphoric acid, 2-ethylhexyl ester]
SUPPORTING CHEMICAL
Mono(2-ethylhexyl) phosphate CAS No. 1070-03-7
[9th CI Name: Phosphoric acid, mono(2-ethylhexyl) ester]
SUB-CATEGORY III
SPONSORED CHEMICAL
Triisobutyl phosphate CAS No. 126-71-6
[9th CI Name: Phosphoric acid, tris(2-methylpropyl) ester]
SUPPORTING CHEMICAL
Tributyl phosphate CAS No. 126-73-8
[9th CI Name: Phosphoric acid tributyl ester]
The sponsor has submitted additional supporting data for the following chemicals: (1) Dibutyl phosphate (CAS No.
107-66-4); 2-Ethylhexanol (CAS No. 104-76-7); 2-Ethylhexanoic acid (CAS No. 149-57-5) and Phosphoric acid
(CAS No. 7664-38-2).
This screening-level hazard characterization is based primarily on the review of the Test Plan and Robust
Summaries of studies submitted by the sponsors) under the HPV Challenge Program. In preparing the hazard
characterization, EPA considered its own comments and public comments on the original submission as well as the
sponsor's responses to comments and revisions made to the submission. The structures of the sponsored chemicals
are included in the appendix. Summary tables of SIDS endpoint data are included in the document. The screening-
level hazard characterization for environmental and human health toxicity is based largely on SIDS endpoints and is
described according to established EPA or OECD effect level definitions and hazard assessment practices.
3
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Category Definition
Structures for the sponsored substances and proposed supporting chemicals comprising the proposed phosphoric
acid derivatives category in the revised submission of December 22, 2005 are shown in Table below.
Phosphoric Acid Derivatives Category Members and Proposed Supporting Chemicals
Name
CAS No.
Structure
7ra(2-ethylhexyl) phosphate
78-42-2
\ /\ °
^ ' O-P-O / X
Bis(2-Ethylhexyl) phosphate
298-07-7
/ °
^ ' O-P-O , v
OH (
Phosphoric acid, 2-ethylhexyl ester
Mixture - percents not reported
12645-31-7
/ °
^ / O-P-O / X
o *» K>
/ O-P-OH
OH
7ra(2-methylpropyl) phosphate
(Triisobutyl phosphate)
126-71-6
/ °
/ I O-P-O /
>\/0 (
Phosphoric acid. mono(2-clhylhcxvl)
esler
(Mono(2-clhylhcxvl) phosphate)
1070-03-7
\ O
^ / O-P-OH
OH
Dibutvl phosphate
107-66-4
0
' o-p-o ,
OH
Tributyl phosphate
126-73-8
/ °
' O-P-O ,
\/^0
2-Elhvlhcxanol
104-76-7
HO y X
2-Elhvlhcxanoic acid
149-57-5
O , s
HO ^
Phosphoric acid
7664-38-2
0
HO-P-OH
OH
Shaded cells = proposed supporting chemicals
4
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In its revised submission the sponsor made the following changes to the originally submitted category: (1) included
bis(2-ethylhexyl) phosphate (CAS No. 298-07-7) as a sponsored category member and not as a supporting chemical;
(2) included triisobutyl phosphate as a new member of the chemical category; (3) identified phosphoric acid, 2-
ethylhexyl ester (CAS No. 12645-31-7) as a mixture of mono- (39 -51%) and bis(2-ethylhexyl) phosphates (45 -
63%) and (4) included four additional supporting chemicals (phosphoric acid; 2-ethylhexanol; 2-ethylhexanoic acid
and mono(2-ethylhexyl) phosphate) to represent metabolites of the 2-ethylhexyl phosphate ester.
Category/Supporting Chemical Justification
The sponsor stated that the category members and supporting chemicals share similar structures and that the
phosphoric acid esters are expected to metabolize via the same hydrolytic pathway. However, EPA does not support
this assertion for the reasons presented below.
Structural Considerations
The proposed category members are of diverse structural types, consisting of branched C8 mono-, di- and tii- alkyl
phosphate esters and a branched C4 trialkyl phosphate ester. The sponsor proposed a branched C8 monoalkyl
phosphate ester (CAS No. 107-03-7) and linear C4 di- and tri- alkyl phosphate esters (CAS Nos. 107-66-4 and 126-
73-8) as supporting chemicals. However, the revised submission does not address how the differences in molecular
weight, polarity, acidity or molecular size and shape among the sponsored and proposed supporting chemicals will
affect their properties, bioavailability or toxicities. In addition, the sponsor did not provide justification for adding
triisobutyl phosphate (CAS No. 126-71-6) to the revised submission. Data are lacking for the repeated-dose,
reproductive and developmental toxicity endpoints to allow assessment of toxicological similarities or differences
among the different structural types represented by the sponsored and proposed supporting chemicals. A read-
across strategy for these endpoints cannot be supported solely on the basis of the available data for acute toxicity and
mutagenicity.
Metabolism of Phosphate Esters
The submitter proposes that, by analogy to tributyl phosphate, tris(2-ethylhexyl) phosphate will be metabolized via
a hydrolytic pathway, yielding bis(2-ethylhexyl) phosphate, mono(2-ethylhexyl) phosphate and phosphoric acid
sequentially, together with 2-ethylhexanol, which is oxidized to 2-ethylhexanoic acid. The submitter uses this
proposed metabolic sequence to justify the proposed supporting chemicals and as partial justification for grouping
the three sponsored 2-ethylhexyl phosphate esters. However, the proposed degradation pathway is oversimplified
and provides insufficient support for this hypothesis. The submitter has not provided an adequate technical rationale
for documenting how the proposed supporting chemicals might be used to assess the toxicity of triisobutyl
phosphate.
In section 2.2 of the test plan, the submitter states that hydrolysis of a tri-ester to a di-ester is expected to be the most
difficult step in the complete hydrolysis of a phosphate ester. This statement is based on unsupported
generalizations and invalid comparisons between process chemistry and metabolic processes, and directly
contradicts the assertion later in the test plan (section 2.3, page 4) that the first hydrolysis step is the fastest. It is not
clear how this section is meant to contribute to the category justification and in fact confounds the sponsors
presentation.
The metabolic studies included in the robust summaries for tributyl phosphate add further confusion to the
discussion. While ester hydrolysis is a likely metabolic pathway, it is not the only one available. The identification
of oxygenated tributyl phosphate in addition to the hydrolysis products in metabolism studies, indicates that
oxygenation of the alkyl side chain can compete with the hydrolytic pathway. The submitter did not address this
issue and its possible significance. Further, the submitter did not discuss the relative metabolism rates of the 2-
ethylhexyl and butyl phosphates. The alkyl chains in /m(2-ethylhexyl) phosphate are twice as large as those in
tributyl phosphate and are also branched, which increases the steric crowding at the phosphate ester group. Because
these steric differences may affect interactions with metabolic enzymes, EPA is rejecting the assumption that the
butyl and the 2-ethylhexyl esters are cleaved at similar rates or to similar completion.
5
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The proposed use of data for 2-ethylhexanol, 2-ethylhexanoic acid and phosphoric acid to satisfy data gaps is not
supported. Phosphoric acid is metabolically far removed from the sponsored substances. The metabolic conversion
of /m(2-ethylhexyl) phosphate to phosphoric acid requires three successive hydrolytic steps that by the submitter's
argument are likely to slow dramatically after the first step (test plan, page 4, section 2.3). Likewise, 2-
ethylhexanoic acid is several metabolic steps removed from any of the 2-ethylhexyl phosphate esters: a phosphate
ester must first be hydrolyzed and the resulting alcohol converted to the aldehyde, and then to the acid. The
submitter did not establish how quickly these processes would occur or consider the influence of any competing
pathways. The submitter did not provide any information to indicate that the toxicities of 2-ethylhexanol,
phosphoric acid and 2-ethylhexanoic acid represent the toxicities of the 2-ethylhexyl phosphate esters.
Therefore, the proposed use of the metabolites (dibutyl phosphate; 2-ethylhexanol; 2-ethylhexanoic acid and
phosphoric acid) as supporting chemicals is not supported for the assessment of mammalian toxicity.
For ecological effects, the revised submission presents considerable data, but does not adequately address how
trends in the data will allow the few remaining endpoints to be appropriately satisfied.
Conclusion
The proposed category is neither justified nor adequately supported as presented. Inclusion of the varied structural
types (mono-, di- and tii- alkyl phosphate esters with C8 or C4 alkyl groups) represented by the proposed category
members ignores their obvious structural differences affecting molecular size, shape, polarity and acidity. The lack
of health effects data (particularly for repeated-dose, reproductive and developmental toxicity endpoints) available
for comparison between /ra(2-ethylhexyl) phosphate and the mono- and di-(2-ethylhexyl) phosphate esters further
weakens support for grouping the proposed members of this category.
The submitter's representation of the expected metabolic pathway for the 2-ethylhexyl phosphate esters is based on
an analogy to a smaller and less hindered supporting chemical. No data were provided to support the hypothesis that
the rate and extent of metabolism would be similar for the butyl and the 2-ethylhexyl phosphate esters. This
representation also considers only one of several possible metabolic pathways and does not account for the known
and well documented formation of other metabolites. The submission lacks a detailed justification for the metabolic
series approach presented for the 2-ethylhexyl phosphate esters as well as a review of existing toxicokinetic data for
the metabolic series starting with /m(2-ethylhexyl) phosphate.
The phosphoric acid derivatives category as submitted does not support data sharing among the diverse category
members. In an effort to utilize provided information and move towards a useful review, EPA has separated the
proposed category into three sub-categories, as described in the Table below with the intent of facilitating the
evaluation of the toxicity endpoints. Read-across between the sub-categories I, II and III is not supported.
6
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EPA-Identifled Sub-Categories for the Evaluation of Toxicity Endpoints
I
ii
III
78-42-2
298-07-7
12645-31-7
1.070-03-7
126-71-6
126-73-8
7W.v(2-ethyl-
hexyl) phosphate
/iiv(2-cthvlhcxyl)
phosphate
Phosphoric acid,
2-ethylhexyl
ester (mixture)
Mono(2-ethyl-
hcxyl) phosphate
Triisobutyl
phosphate
Tributvl
phosphate
/ °
/ °
/ °
\ 0
Of
( o-p-o )
\ | \ /
< O-P-O >
< o-p-o >
( O-P-OH
< ?
' \ °N ' V
\ OH \
\ OH \
\ OH
o-p=o
\ °
o-p=o
,0
i'
/ °
< O-P-OH
OH
Shaded cells = proposed supporting chemicals
11 a/a I'd ( haraclcri/alion
Snb-( Hickory /
The Ion k \aluc i»f iriM2-olli\ lliew I) phosphate iudicalcs ilial Us potential u> hioacciiniulalc is expected li» he liinli
IriMl-cili\ lhcx\ h phosphate is not readils hiodcniadahle. uidicaliiin llial il lias ilie potential u> persist in the
ciin iroiinicui.
The e\ a 11 lal k> 11 of a\ ailahle loxicils data lor lisli indicates dial I lie potential aeule ha/aid of //7m 2-elh\ I hew 11
phosphate lo lisli is expected lo he low ISased ihi llie Ion kim \ allies ill" S and low waler soluhilits. ilie pulenlial
lia/ard In ai|iialie iu\ eriehrales and ai|iialie plains is expected in he km
\eule nral loxicils ill" //v'.s(2-elli\ lliew h pliiispliale in nils and rahhiis. aeule inhalation loxicils lo nuiiiea pins and
aeule dermal loxicils In rahhiis is low //7M2-elh\ lliew h plmsphale is irriialuin in rahhn skin. and iki| irriialuin in
rahhil e\ es S\ siemie loxicils in ilie oral repeated-dose siudies in rals and mice in //7m2-ciIi\ lliew 11 phosphate is
low Repeated-dose inhalation exposures in nuiiiea pins show lunli s\ siemie loxicils. exhibited h\ ehaunes ol" llie
reual parcuchs ma \o data are a\ ailahle for the rcproducli\c de\ clopnieuial toxicils eudpouiis //7m2-ciIi\ lliew li
phosphate did not induce ncuc mutations or chromosomal aberrations in viini. hut induced chromosomal
aberrations in \ i\n //7m2-ciIi\ lliew h phosphate showed c\ idciicc of carciuonciiicils in nils and mice.
The reproduce e and dc\ elopnieutal loxicils eudpoiiiis reniaiu as data naps lor the purposes of the I ll'V ( hallenne
I'ronrani
Snb-( Hickory 11
The Ion k \ allies of //>( 2-eth\ lliew 11 phosphate and phosphoric acid. 2-eth\ lliew I ester indicate llial ilietr
poietilial lo hioaccuniiilale is expected to he low Miosphoric acid. 2-eth\ lliew I esier is not readils hiodemadahle.
iiidicaliun thai it has ilie poietilial lo persist in the eu\ iroumeiii. The hiodenradahihts of/'/M 2-elh\ lliew h phosphate
is ci|iu\ ocal: hased on data lor phosphoric acid. 2-elh\ lliew I ester. //>( 2-elh\ llie.w 11 phosphate has llie poteuiial lo
persist mi llie en\ iroiinieiil.
7
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The e\ ;iIii;iIk dala lor 1'ish. aquatic 11 in cilchrales and at|iialic plants indicates thai I lie poleiilial
acnle and chrome lia/ard of/'/M 2-elh\ I hew 11 phosphate and phosphoric acid. 2-elh\ I hew I ester Id aquatic
ormiinsiiis is low
\cnle oral lo\icil> of/'/.M 2-eth\ lliew h phosphale and phosphoric acid. 2-elh\ lliew I esien niiMiirc) to ralsand
acnle dermal lo\icil> Id rahhils is low />7.m2-ciIi\ lliew I) phosphate ;md nioiioi2-elh\ lliew I) phosphate are limliK
imialiim Id rcihhil skin ;md coitosinc Id lahhil e\es \d d;il;i are a\ ailahle lor llie repcalcd-dose. rcpi'odiicli\ e ;md
de\ elopnieiiial lo\icil> ciidpoinis. />7.s(2-elh\ lliew I) phosphate and phosphoric acid. 2-elh\ lliew I ester did iidi
induce none iiiiiI;iIidiis in \ iirn \d d;il;i are ;i\ ailahle lor llie chromosomal aberrations eiidpoiiil
I lie chromosomal aberrations. repeated-dose. repi'odiicli\ e ;md de\ elopnieiiial lo\icil> eiidpoiiils iviiKiin ;is d;il;i
mips I'orihe purposes of the MPY Challcime hourani
Sub-( Hickory III
The Idu k \;iliic dI" iriisohiils I phosphate indicates lli;il Us potential Id hioacciiniiilale is c\peeled Id he km
Tnisobiilv I plk d;il;i lor fish. ;u|ii;iiie 11 in cilchrales and ;u|ii;iiie plants indie;iles lh;il I he pDlenli;il
;ieule h;i/;ird ol inisohnlv I phosphate ;md InhiiIn I phosphnle to 1'ish is low ;ind Id ;k|ii;iIle iiin cilchrales ;ind ;u|ii;ilie
plants is niodci.ilc The pDlenli;il chrome ha/.ard Id ;k|ii;ilie organisms is moderate
\eule or;il lo\ieil\ of triisohnls I phosph;ile ;md I nhi i In I phosphate (siippoi'lnm chemical) Id nils ;md miee ;md ;ieule
dermal lD\ieil> Id rahhils and miiiica pins is Idw \eule iiih;il;ilion io\icil\ dI" irusohiilsI phosphate in rats is Idw Id
moderate. Triisohnlv I phosphnle ;ind irihnlv I phosphate ;ire irrilaliim Id nil. r;ihhil. human ;ind miinca pm skin. ;ire
iiTilaliim Id lahhil e\es ;md ;ire dermal sensiii/ers in miinca pins hui iidi mi Iiiiiikiiis S\siemie lo\icit\ dI" irihw\ I
pliDspli;iie in oral repcalcd-dose siuclies is moderate. In ;i two-uciicralioii diclars rcprodiicli\ c lo\icil> stud\ mi nils.
inhul\ I phosphale showed low icprodiicli\ c ;ind dc\ elopnieiiial lo\icil> I riisohnn I phosphate ;ind irihnis I
phosphale did iidi mdiiee uene iiiiiI;i1idiis in \ iini ;ind did iidi mdiiee chromosomal aberrations \d e\ idenee of
iieiii'DlD\ieil> w;is seen lor llie siippiirimu eliemie;il. inhnl\ I phosphale I i'ihiil\ I pliDspli;iie. ;i siippiirimu eliemie;il.
sliDwed c\ idenee of carciiiouciiicils iii nils.
\d d;il;i mips were ideiiiified lor llie purpDses dI" llie I llJ\ ( li;illeime I'lDunini
1. Physical-Chemical Properties and Environmental Fate
A summary of physical-chemical properties and environmental fate data submitted is provided in Table 1. For the
purpose of the screening-level hazard characterization, the review and summary of these data was limited to the
octanol-water partition coefficient and biodegradation endpoints as indictors of bioaccumulation and persistence,
respectively.
Octanol-Water Partition Coefficient
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
Log Kow: 4.2 (measured)
9.4
Sub- Category II
Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7)
Log Kow: 2.67 (measured)
8
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Phosphoric acid, 2-ethylhexy ester (CAS No. 12645-31-7)
Log Kow: 2.65 (estimated)
Mono(2-ethylhexyl)phosphate (CAS No. 1070-03-7, Supporting Chemical)
Log Kow: 2.65 (estimated)
Sub- Category III
Triisobutylphosphate (CAS No. 126-71-6)
LogKow: 3.72 (measured)
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
Log Kow: 4.0 (measured)
Biodegradation
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
(1) In a closed-bottle test using domestic sewage as an inoculum, 0% of /r/'s(2-ethylhexyl) phosphate degraded after
28 days.
7Wv(2-ethvlhexvl) phosphate is not readily biodegradable.
(2) In a modified MITI test using activated sludge as an inoculum, 0% of /r/'s(2-ethylhexyl) phosphate degraded
after 28 days.
7Wv(2-cthvlhcxyl) phosphate is not readily biodegradable.
Sub-Category II
Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7)
(1) In a modified MITI test using domestic sewage as an inoculum, 75% of bis(2-ethylhexyl) phosphate degraded
after 28 days.
/iiv(2-cthvlhcxyl) phosphate is readily biodegradable.
(2) In a modified MITI test using activated sludge as an inoculum, 0-17% of bis(2-ethylhexyl) phosphate degraded
after 28 days.
/iiv(2-cthvlhcxyl) phosphate is not readily biodegradable.
Phosphoric acid, 2-ethylhexyl ester (CAS No. 12645-31-7)
In a Modified Sturm test using domestic, activated sludge as an inoculum, 52% of phosphoric acid, 2-ethylhexyl
ester degraded after 28 days.
Phosphoric acid, 2-ethylhexyl ester is not readily biodegradable.
Sub-Category III
Triisobutyl phosphate (CAS No. 126-71-6)
In a modified OECD screening test using treatment plant effluent as an inoculum, 63% of triisobutyl phosphate
degraded after 27 days.
Triisobutyl phosphate is not readily biodegradable.
Tributyl phosphate (CAS No. 126-73-8, Supporting Chemical)
(1) In a modified MITI test using domestic sewage as an inoculum, 77% of tributyl phosphate degraded after 28
days.
Tributyl phosphate is readily biodegradable.
(2) In a closed-bottle test using domestic sewage as an inoculum, 92% of tributyl phosphate degraded after 28 days.
Tributyl phosphate is readily biodegradable.
9
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(3) In a modified OECD screening test using domestic sewage as an inoculum, 89% of tributyl phosphate degraded
after 28 days.
Tributyl phosphate is readily biodegradable.
Conclusion
Sub-Category I: The log Kow value of /to(2-ethylhexyl) phosphate indicates that its potential to bioaccumulate is
expected to be high. 7ro(2-ethylhexyl) phosphate is not readily biodegradable, indicating that it has the potential to
persist in the environment.
Sub-Category II: The log Kow values of bis(2-ethylhexyl) phosphate and phosphoric acid, 2-ethylhexyl ester
indicate that their potential to bioaccumulate is expected to be low. Phosphoric acid, 2-ethylhexyl ester is not
readily biodegradable, indicating that it has the potential to persist in the environment. The biodegradability of
bis(2-ethylhexyl) phosphate is equivocal based on conflicting results from separate ready biodegradation tests.
Sub-Category III: The log Kow value of triisobutyl phosphate indicates that its potential to bioaccumulate is
expected to be low. Triisobutyl phosphate is not readily biodegradable, indicating that it has the potential to persist
in the environment.
10
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Tabic 1. Summary of Physical-Chemical Properties and Environmental Fate Data
Sub-Catcgorv I
Sub-Catcgorv II
Sub-Catcgorv III
Endpoints
7W.v(2-ethylhexyl)
phosphate
(78-42-2)
Phosphoric acid,
2-ethylhexyl ester
(mixture)
(12645-31-7)
/iiv(2-cthylhc\yl)
phosphate
(298-07-7)
Mono(2-ethylhexyl)
phosphate
(1070-03-7,
supporting
chemical)
Triisobutyl
phosphate
(126-71-6)
Tributyl phosphate
(126-73-8,
supporting
chemical)
Melting Point (°C)
<-70
< -20 (m)a
-50
-
<-60
<-70
Boiling Point (°C)
210
(5 hPa)
354.5 (e)
(1013hPa)
240 (decomposes)
(m)
354.5 (e)
272
130
(5 hPa)
Vapor Pressure
(hPa at 25°C)
2.05 x 10"7 (e)
7.12 x 10"7 (e)
2.4 x 10"7 (e)
5.34x 10"7 (e)
2.00 (m)
(103 °C)
3.47 x 10 6 (m)
Log Kw
4.2 (m)
9.4 (e)b
2.65 (e)
2.67 (m)
2.65 (e)
3.72 (m)
4 (m)
Water Solubility
(mg/L at 25°C)
2 (m)
182 - 219 x 103 (e)a
182 (m)
2.19 x 103 (e)
265 (m)
400 (m)
(20 °C)
Direct
Photodegradation
80% degradation
by UV light after 1
h (m)
No Data
No Data
No Data
85% degradation
by UV light after 1
h (m)
Indirect (OH)
Photodegradation (ti/2)
1.3 h(e)
3.9 h(e)
3.9 h(e)
3.9 h(e)
4.3 h(e)
1.6 h (e)°
Stability in Water
(Hydrolysis) (t2)
No Datad
>1 yr (pH 4,7,9)
(m)a
No Data
>1 yr (pH 4, 7, 9)
(RA)d
170 d (m)
(pH 4, 50 °C)
303 d (m)
(pH 7, 50 °C)
Stable after 30 d
(PH 3, 7,11) (m)
Fugacity
(Level III Model)
Air (%)
Water (%)
Soil (%)
Sediment (%)
0.312
10.9
31.2
57.6
0.000703
29
70.8
0.188
0.302
24.5
75
0.226
0.000703
29
70.8
0.188
0.518°
38.8
59.5
1.14
0.0737°
41
56.7
1.52
11
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Tabic 1. Summary of Physical-Chemical Properties and Environmental Fate Data
Sub-Category 1
Sub-Catcgorv II
Sub-Catcgorv III
Endpoints
7W.v(2-ethylhexyl)
phosphate
(78-42-2)
Phosphoric acid,
2-ethylhexyl ester
(mixture)
(12645-31-7)
/iiv(2-cthylhcxyl)
phosphate
(298-07-7)
Mono(2-ethylhexyl)
phosphate
(1070-03-7,
supporting
chemical)
Triisobutyl
phosphate
(126-71-6)
Tributyl phosphate
(126-73-8,
supporting
chemical)
Biodegradation at 28
days (%)
0 (m)
Not readily
biodegradable
52 (m)a
Not readily
biodegradable
75 (m)
0-17 (m)
Equivocal results
63 (m) (27 days)
Not readily
biodegradable
77 - 92 (m)
Readily
biodegradable
(m) = measured data (i.e., derived from experiment); (e) = estimated data (i.e. derived from modeling); (RA) = Read Across; indicates endpoint was not addressed for this
substance; Shaded cells = non-sponsored substances (proposed supporting chemicals)
According to the sponsor, this test was performed for a mixture of mono(2-ethylhexyl)phosphate (CAS No. 1070-03-7) (39 - 51%) and fe(2-ethylhexyl) phosphate (CAS No.
298-07-7) (45 - 63%).
bEPA's statement, "no ecotoxicity testing is recommended because its high estimated log Kow (> 8) and low water solubility suggest a lack of acute or chronic toxicity", indicates
that the estimated log Kow value of 9.4 is preferred to the provided measured value of 4.2.
These data were provided in the test plan, but not the robust summary.
dThe sponsor proposed using a read-across approach to satisfy data gaps for the hydrolysis endpoints of fa's(2-ethylhexyl phosphate) (CAS No. 298-07-7) and fris(2-ethylhexyl)
phosphate (78-42-2). Regarding fe(2-ethylhexyl phosphate), EPA agrees with reading across from phosphoric acid, 2-ethylhexyl ester (CAS No. 12645-31-7) or from
mono(2-ethylhexyl)phosphate (CAS No. 1070-03-7), but not from other category members or supporting chemicals. EPA does not support a read across approach for
fra(2-ethylhexyl) phosphate.
Conflicting results from two separate modified MITI tests were provided in the robust summary.
12
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2. Environmental Effects - Aquatic Toxicity
A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 2. The table also indicates
where data for tested category members are read-across (RA) to untested members of the category.
Acute Toxicity to Fish
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
Zebrafish (Brachydanio rerio) were exposed to ;r/.v(2-ctln lhexyl) phosphate at unspecified nominal concentrations
under static conditions for 96 hours with a reported LC0 of greater than 100 mg/L. The concentration tested was
above the water solubility limit; assuming exposure concentration is the water solubility limit (saturation) for tris (2-
ethylhexyl) phosphate, the no effect concentration would be approximately 2 mg/L.
No effects at saturation
Sub-Category II
Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7)
(1) Rainbow trout (Oncorhynchus mykiss) were exposed to bis{2-ethylhexyl) phosphate at unspecified nominal and
measured concentrations under static conditions for 96 hours.
96-h LCS0 = 48-54 mg/L
(2) Rainbow trout (Salmo gairdneri) were exposed to />/'s(2-ethylhexyl) phosphate at unspecified nominal
concentrations under static conditions for 96 hours.
96-h LCS0 = 30 mg/L
(3) Zebra fish (.Brachydanio rerio) were exposed to bis{2-ethylhexyl) phosphate at unspecified nominal
concentrations under static conditions for 96 hours.
96-h LC50 > 56 mg/L
Rainbow trout (Oncorhynchus mykiss) were exposed to bis(2-ethylhexyl) phosphate for 96 hours in six studies
reported in the ECOTOX data base (http://www.epa.gov\ecotox).
96-h LCS0 = 20-56 mg/L
Phosphoric acid, 2-ethylhexyl ester (CAS No. 12645-31-7)
(1) Rainbow trout (Oncorhynchus mykiss) were exposed to phosphoric acid, 2-ethylhexyl ester at a measured
concentration of 100 mg/L under semi-static conditions for 96 hours. No mortalities were observed.
96-h LCS0 > 100 mg/L
(2) Rainbow trout (Oncorhynchus mykiss) were exposed to phosphoric acid, 2-ethylhexyl ester at nominal
concentrations of 0, 100, 499, 1026, 2026 or 5018 mg/L under static conditions for 96 hours. Measured
concentrations were not provided. No test related mortalities were observed. Cloudy water was observed.
96-h LCS0 > 5018 mg/L
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
In six studies, rainbow trout (Oncorhynchus mykiss), bluegills (Lepomis macrochirus), golden orfes (Leuciscus idus)
or ricefish (Oryzias latipes) were exposed to triisobutyl phosphate under flow-through or static conditions for 24, 48
or 96 hours. Although the studies were missing critical data elements, they are acceptable on a weight-of-evidence
basis.
96-h LCS0 = 17.8 - 23 mg/L
13
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Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
(1) Rainbow trout (Oncorhynchus mykiss) were exposed to tributyl phosphate at nominal concentrations of 0
(solvent control), 1.3, 2.5, 5.0, 10 or 20 mg/L under static conditions for 96 hours. Measured concentrations were 0,
1.2, 2.1, 4.3, 9.3 and 19 mg/L. Mortality was 100% at 19 mg/L; no mortality was seen at lower concentrations.
Sub-lethal behavioral effects were observed in the 9.3 mg/L group as loss of equilibrium, erratic swimming, labored
respiration, quiescence and surfacing.
96-h LCS0 = 11 mg/L
(2) Summaries of 17 additional acute fish studies were presented by the sponsor. The median lethal concentration
values found in these studies ranged from 4.2 to 14.2 mg/L, but because another adequate study was available and
because the additional studies were missing critical information and had no reliability indicators, they were not
reviewed further.
Acute Toxicity to Aquatic Invertebrates
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
The sponsor has not provided data for acute toxicity to aquatic invertebrates. However, based on the log Kow value
of > 8 and low water solubility of /r/'s(2-ethylhexyl) phosphate, the potential acute hazard to aquatic organisms is
expected to be low.
Sub-Category II
Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7)
(1) Water fleas (Daphnia magna) were exposed to />/.v(2-cthvlhc\yl) phosphate at unspecified nominal
concentrations under static conditions for 48 hours.
48-h ECS0 = 60.7 mg/L
(2) Water fleas (Daphnia magna) were exposed to />/.v(2-cthvlhc\yl) phosphate at unspecified nominal
concentrations under static conditions for 48 hours.
48-h ECS0 > 42 mg/L
(3) Water fleas (Daphnia magna) were exposed to />/.v(2-cthylhc\yl) phosphate in 20 studies reported in the
ECOTOX database (http://www.epa.gov\ecotox).
48-h ECS0 = 75 - 83.7 mg/L
Phosphoric acid, 2-ethylhexyl ester (CAS No. 12645-31-7)
Water fleas (Daphnia magna) were exposed to phosphoric acid, 2-ethylhexyl ester at nominal concentrations of 32,
56, 100, 180 or 320 mg/L under static conditions for 48 hours. Measured concentrations were not provided.
48-h ECS0 = 110 mg/L
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
In four studies, Daphnia magna were exposed to triisobutyl phosphate for 24 or 48 hours. Although the studies
were missing critical data elements, they are acceptable on a weight-of-evidence basis.
48-h ECS0 = 11 mg/L
Tributyl phosphate (CAS No. 126-73-8, Supporting Chemical)
(1) Water fleas (Daphnia magna) were exposed to tributyl phosphate at nominal concentrations of 0 (DMF solvent
control), 0 (negative control), 0.48, 0.96, 2.0, 4.0 or 8.0 mg/L under flow-through conditions for 48 hours.
Measured concentrations were 0, 0, 0.32, 0.75, 1.8, 3.5 and 7.8 mg/L, respectively.
48-h ECS0 = 2.6 mg/L
14
-------
(2) Summaries of 15 additional aquatic invertebrate studies were submitted by the sponsor. The median lethal
concentration values found in these studies ranged from 1.7 to 68 mg/L, however, the additional studies were
missing critical information and had no reliability indicators and as such, they were not reviewed further.
Toxicity to Aquatic Plants
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
The sponsor has not provided data for toxicity to aquatic plants. However, based on the log Kow value of > 8 and
low water solubility of /to(2-ethylhexyl) phosphate, the potential hazard to aquatic organisms is expected to be low.
Sub-Category II
Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7)
Algae (Chlorella emersonii) were exposed to bis{2-ethylhexyl) phosphate at nominal concentrations of 0, 50 or 100
mg/L under static conditions for 72 hours. Measured concentrations were not provided.
72-h EC50 (growth) > 100 mg/L
Phosphoric acid, 2-ethylhexyl ester (CAS No. 12645-31-7)
(1) Algae (Pseudokirchneriella subcapitata) were exposed to phosphoric acid, 2-ethylhexyl ester at unspecified
nominal and measured concentrations under static conditions for 72 hours.
72-h EC50 (growth) = 168 mg/L
(2) Algae (,Pseudokirchneriella subcapitata) were exposed to phosphoric acid, 2-ethylhexyl ester at unspecified
nominal and measured concentrations under static conditions for 72 hours.
72-h EC50 (biomass) = 161 mg/L
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
In nine studies, algae (Scenedesmus subspicatus) were exposed to triisobutyl phosphate for 72 hours. Although the
studies were missing critical data elements, they are acceptable on a weight-of-evidence basis.
72-h EC50 (biomass) = 33 mg/L
72-h EC50 (growth) = 34 mg/L
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
In seven different aquatic plants (Chlorella vulgaris, Microcystis aeruginosa, Scenedesmus quadricauda,
Scenedesmus subspicatus, Pseudokirchneriella subcapitata, Chlorella emersonii and phytoplankton) were exposed
to tributyl phosphate for (72 or 96 hours or 2, 7, 8 or 14 days). Although the studies were missing critical data
elements, they are acceptable on a weight-of-evidence basis. Values below are from a study of Scenedesmus
subspicatus; other EC50 values ranged from 3.1 to 10 mg/L.
72-h EC50 (biomass) = 1.1 mg/L
72-h EC50 (growth) = 2.8 mg/L
Chronic Toxicity to Fish
Sub-Category II
Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7)
Rainbow trout (Oncorhynchus mykiss) were exposed to bis{2-ethylhexyl) phosphate at unspecified nominal and
measured concentrations for 62 days.
EC50 (early life stage) = 20.6 mg/L
15
-------
Sub-Category III
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
(1) Rainbow trout (Salmo gairdneri) were exposed to tributyl phosphate at unspecified nominal and measured
concentrations for 50 days under semi-static conditions.
Threshold concentration = 8.3 mg/L
(2) Rainbow trout (Oncorhynchus mykiss) were exposed to tributyl phosphate at unspecified nominal and measured
concentrations for 95 days.
NOEC = 0.82 mg/L
LOEC = 1.7 mg/L
MATC = 1.2 mg/L
Chronic Toxicity to Invertebrates
Sub-Category III
Tributyl phosphate (CAS No. 126-73-8, Supporting Chemical)
(1) Water fleas (Daphnia magna) were exposed to tributyl phosphate at unspecified nominal and measured
concentrations for 21 days.
21-d EC50 (immobilization) > 2.1 mg/L
21-d NOEC (length, days to first brood, Y/D/D) = 0.87 mg/L
21-d LOEC (length, days to first brood, Y/D/D) = 2.1 mg/L
21-d MATC (length, days to first brood, Y/D/D) = 1.35 mg/L
(2) Water fleas (Daphnia magna) were exposed to tributyl phosphate at unspecified nominal and measured
concentrations for 21 days.
21-d NOEC = 1 mg/L
Conclusion
Sub-Category I: The evaluation of available toxicity data for fish indicates that the potential acute hazard of tris(2-
ethylhexyl) phosphate to fish is expected to be low. Based on the log Kow values of > 8 and low water solubility,
the potential hazard to aquatic invertebrates and aquatic plants is expected to be low.
Sub-Category II: The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants
indicates that the potential acute and chronic hazard of bis(2-ethylhexyl) phosphate and phosphoric acid, 2-
ethylhexyl ester to aquatic organisms is low.
Sub-Category III: The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants
indicates that the potential acute hazard of triisobutyl phosphate and tributyl phosphate to fish is low and of aquatic
invertebrates and aquatic plants is moderate. The potential chronic hazard to aquatic organisms is moderate.
16
-------
Table 2. Summary of Environmental Effects - Aquatic Toxicity Data
Sub-Catcgorv 1
Sub-Catcgorv II
Sub-Catcgorv III
Endpoints
7W.v(2-ethylhexyl)
phosphate
(78-42-2)
/iiv(2-cthylhc\yl)
phosphate
(298-07-7)
Phosphoric acid, 2-
ethylhexyl ester
(12645-31-7)
Mono(2-ethylhexyl)
phosphate
(1070-03-7,
supporting
chemical)
Triisobutyl
phosphate
(126-71-6)
Tributyl phosphate
(126-73-8,
supporting chemical)
Fish
96-h LC5o (mg/L)
NESa
30
> 100
-
17.8-21.5
11
Aquatic
Invertebrates
48-h ECS0 (mg/L)
Data Gap - no
testing required
60.7
110
11
2.6
Aquatic Plants
72-h ECS0 (mg/L)
(growth)
(biomass)
Data Gap - no
testing required
>100
168
161
34
33
2.8
1.1
Chronic Toxicity to
Fish
21-day ECS0 (mg/L)
20.6
(Threshold
concentration, 48-d)
No Data
20.6
(Threshold
concentration, 48-d)
(RA)
No Data
NOEC (95-d) = 0.82
LOEC (95-d) = 1.7
MATC (95-d) = 1.2
(RA)
NOEC (95-d) = 0.82
LOEC (95-d) = 1.7
MATC (95-d) = 1.2
Chronic Toxicity to
Invertebrates
21-day ECS0 (mg/L)
No Data
>2.1b
NOEC0 = 0.87
LOEC0 = 2.1
MATC0 = 1.35
(RA)
>2.1b
NOEC = 0.87
LOEC = 2.1
MATC = 1.35
aNES = No effects at saturation (water solubility limit); Based on immobilization; °Based on length, days to first brood, (Y/D/D); (m) = measured data (i.e.,
derived from testing); (e) = estimated data (i.e., derived from modeling); (RA) = Read Across; Shaded cells = non-sponsored substances (proposed supporting
chemicals)
17
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3. Human Health Effects
A summary of health effects data submitted for SIDS endpoints is provided in Table 3. The table also indicates
where data for tested category members are read-across (RA) to untested members of the category.
Acute Oral Toxicity
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
(1) In three studies, rats (strain and number not stated) were administered /m(2-ethylhexyl) phosphate via the oral
route. Although the studies were missing critical data elements, they are considered acceptable on a weight-of-
evidence basis.
LDS0 > 10,000 - 37,080 mg/kg-bw
(2) In two studies, rabbits (strain and number not stated) were administered /m(2-ethylhexyl) phosphate via the oral
route. Although the studies were missing critical data elements, they are considered acceptable on a weight-of-
evidence basis.
LDS0 = 46,000 mg/kg-bw
Sub-Category II
Bis (2-ethylhexyl)phosphate (CASNo. 298-07-7)
(1) Wistar rats (5/sex/dose) were administered bis(2-ethylhexyl) phosphate via gavage at 500, 880, 1260, 2000 or
3000 mg/kg-bw and observed for 14 days. Mortalities were observed at all dose levels. Clinical signs of toxicity
included slight to severe hunched posture. No treatment-related gross pathological alterations were noted during
necropsy..
LDS0 = 1400 mg/kg-bw
(2) Sprague-Dawley rats (5/sex/dose) were administered />/'s(2-ethylhexyl) phosphate via gavage at 500 or 5000
mg/kg-bw and observed for 14 days. Mortalities were observed at the high-dose. Clinical signs included oral/nasal
discharge and diarrhea on the day of dosing. Necropsy findings included severely reddened abdominal walls,
enlarged blood vessels, reddened lining of the gastrointestinal tract, dark red stomach lining, reddened adrenals and
pancreas, red lungs, pale kidneys and darkened thymus.
LDS0 = 500 - 5000 mg/kg-bw
Phosphoric acid, 2-ethylhexyl ester (CAS No. 12645-31-7)
Sprague-Dawley rats (3 females/dose) were administered phosphoric acid, 2-ethylhexyl ester via gavage at 300
mg/kg-bw in arachis oil BP (two groups) or 2000 mg/kg-bw, undiluted (1 group) and observed for 14 days.
Mortalities were observed at the high-dose. Clinical signs of toxicity included hunched posture, lethargy,
piloerection, diarrhea, diuresis, dehydration, ataxia, emaciation, decreased respiratory rate, labored respiration and
tiptoe gait. Necropsy findings included epithelial sloughing and pale appearance of the gastric mucosa and non-
glandular region of the stomach, hemorrhagic lungs and dark livers.
LDS0 = 500 - 1000 mg/kg-bw
Mono(2-ethylhexyl)phosphate (CAS No. 1070-03-7, Supporting Chemical)
(1) Sprague-Dawley rats (5/dose, sex not specified) were administered mono(2-ethylhexyl) phosphate via gavage at
464, 1000, 2150 or 4640 mg/kg-bw and observed for up to 14 days. Mortalities were observed, but not specified by
dose. Clinical signs of toxicity included acute depression, excessive urination and diarrhea. Necrotic tissue in the
stomach was observed during necropsy.
LDS0 = 2710 mg/kg-bw
(2) Sprague-Dawley rats (2 or 3/sex/dose) were administered mono(2-ethylhexyl)phosphate via gavage at 2000,
3160, 5010 or 7940 mg/kg-bw and observed for up to 7 days. No mortalities were observed at the low-dose.
Clinical signs of toxicity included reduced appetite, reduced activity, increased weakness and collapse. Gross
pathological observation included lung hyperemia, liver discoloration and gastrointestinal inflammation.
LDS0 = 4100 mg/kg-bw
18
-------
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
(1) In four studies, rats (strain, sex and group size not specified) were administered triisobutyl phosphate via the oral
route. Although the studies were missing critical data elements, they are considered acceptable on a weight-of-
evidence basis.
LDS0 = 3072 - 12,800 mg/kg-bw
(2) Mice (strain, sex and group size not specified) were administered triisobutyl phosphate via the oral route. This
study was missing critical data elements, but compared with the values found in rats, the data are considered to be
adequate on a weight-of-evidence basis.
LDS0 = 3200 - 6400 mg/kg-bw
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
Sprague-Dawley rats (5 males/dose) were administered tributyl phosphate via gavage at 464, 1000, 2150 or 4640
mg/kg-bw and observed for up to 14 days. All of the animals from the high-dose group died during the study; no
mortality occurred at lower doses. Clinical signs of toxicity included slight to severe depression and excessive
urination. No treatment-related gross lesions were found at necropsy.
LDS0 = 3160 mg/kg-bw
Acute Inhalation Toxicity
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
Summaries of two acute inhalation toxicity studies in rats (exposure duration was 4 hours in one study and not
indicated in the other) and two acute inhalation toxicity studies in guinea pigs (exposure duration was 1 hour in one
study and not indicated in the other) were provided by the sponsor, but were missing critical information. Three of
these studies noted LC50 values of > 0.447, > 0.45 and > 0.46 mg/L, but the remaining study in guinea pigs noted an
LC50 of 450 mg/L (exposure duration not indicated).
LC50 (duration not indicated) = 450 mg/L
Sub-Category III
Triisobutyl phosphate (CAS No. 126-71-6)
Summaries of two acute inhalation studies in rats (exposure durations of 4 and 6 hours) were provided by the
sponsor, but were missing study details.
LC50 (6-hour) = 1.35 mg/L
LC50 (4-hour) > 5.14 mg/L
Tributyl phosphate (CAS No. 126-73-8, Supporting Chemical)
Rats (5/sex/concentration, strain not specified) were exposed to tributyl phosphate at unknown concentrations for 4
hours. Mortality was seen in males, but not in females.
LCS0 > 4.24 mg/L
Acute Dermal Toxicity
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
Rabbits (strain, sex and group size not specified) were administered /r/'s(2-ethylhexyl) phosphate dermally route. No
other study details were provided.
LDS0 = 20,000 mg/kg-bw
19
-------
Sub-Category II
Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7)
New Zealand white rabbits (3/sex/dose) were administered bis(2-ethylhexyl) phosphate dermally at 2000 mg/kg-bw
on to clipped intact and abraded skin under occlusive conditions for 24 hours and observed for 14 days. No
mortalities or clinical signs of toxicity were observed. Severe dermal irritation including eschar and edema were
observed in all animals.
LDS0 > 2000 mg/kg-bw
Mono(2-ethylhexyl)phosphate (CAS No. 1070-03-7, Supporting Chemical)
(1) New Zealand White rabbits (4, sex, strain not specified) were administered mono(2-ethylhexyl) phosphate
dermally at 4640 mg/kg-bw on to clipped intact skin. No mortalities or clinical signs of toxicity were observed.
Severe erythema and edema were noted.
LDS0 > 4640 mg/kg-bw
(2) New Zealand White rabbits (1 or 2/sex/dose) were administered mono(2-ethylhexyl) phosphate dermally at 794,
1260, 2000 or 3160 mg/kg-bw on to clipped intact skin and observed for 14 days. Mortalities were noted at 2000
mg/kg-bw. No statement was provided regarding mortality at 3160 mg/kg-bw and an LD50 was not provided.
Clinical signs of toxicity included reduced appetite, reduced activity, lethargy, increased weakness and collapse.
Gross pathological observation included lung hyperemia, liver discoloration, enlarged gall bladder and slight
gastrointestinal inflammation.
LDlo = 1260 mg/kg-bw
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
Rabbits and guinea pigs (strain, sex and group size not specified) were administered triisobutyl phosphate dermally.
Although the studies were missing critical data elements, they are considered acceptable on a weight-of-evidence
basis.
LDS0 (rabbits) > 5000 mg/kg-bw
LDS0 (guinea pigs) > 9600 mg/kg-bw
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
In five studies, rabbits and guinea pigs (strain, sex and group size not specified) were administered tributyl
phosphate dermally. Although the studies were missing critical data elements, they are considered acceptable on a
weight-of-evidence basis.
LDS0 > 3100 - 19,400 mg/kg-bw
Repeated-Dose Toxicity
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
(1) In the National Toxicology Program (NTP) study, F344/N rats (10/sex/dose) were administered tris(2-
ethylhexyl) phosphate in corn oil via gavage at 0 (vehicle control), 250, 500, 1000, 2000 or 4000 mg/kg-bw/day 5
days/week for 13 weeks. Slight to moderate depression of weight gain was noted at the two highest doses. No
mortality or treatment-related histopathological effects were observed.
LOAEL = 2000 mg/kg-bw/day (based on decreased weight gain)
NOAEL = 1000 mg/kg-bw/day
20
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(2) In the NTP study, B6C3F1 mice (10/sex/dose) were administered /ra(2-ethylhexyl) phosphate in corn oil via
gavage at 0 (vehicle control), 500, 1000, 2000, 4000 or 8000 mg/kg-bw/day for 13 weeks. Slight to moderate
depression of weight gain was noted at the two highest dose levels. Inflammatory lesions in the gastric mucosa were
seen at all doses with increase severity at higher doses. Ulceration was seen in the forestomach of 1 male at 2000
mg/kg-bw/day, 1 female at 4000 mg/kg-bw/day and 1 male and 3 females at 8000 mg/kg-bw/day.. No mortalities
were observed.
LOAEL = 2000 mg/kg-bw/day (based on ulceration in the forestomach)[NOTE: Although inflammatory lesions
were in the gastric mucosa at all doses, NTP has selected 1000 mg/kg-bw/day as the highest dose for the 2-year
study possibly based on ulceration seen at 2000 mg/kg-bw/day and above. Therefore, the LOAEL for the 13-week
study is set at 2000 mg/kg-bw/day rather than 500 mg/kg-bw/day.]
NOAEL = 1000 mg/kg-bw/day
(3) Rats (strain, sex and group size not specified) were administered /ra(2-ethylhexyl) phosphate in the diet at 110
- 1550 mg/kg-bw/day for 30 days. Weight loss was noted at 1550 mg/kg-bw/day. (Limited information was
provided.)
LOAEL = 1550 mg/kg-bw/day (based on weight loss)
NOAEL = 430 mg/kg-bw/day
(4) Guinea pigs (males, group size not specified) were exposed to /r/'s(2-ethylhexyl) phosphate via inhalation at 0,
1.6 or 9.6 mg/m3 (0, 0.0016, 0.0096 mg/L) 6 hours/day, 5 days/week for 3 months. Increased terminal body weight
and inconsistent and reversible changes of renal parenchyma were noted at the highest concentration. No alterations
in red blood cell and plasma cholinesterase activity or abnormalities at necropsy were noted. Sections of the spinal
cord and sciatic nerve stained to demonstrate the myelin sheaths showed no pathologic alteration.
LOAEL = 0.0096 mg/L (based on histological changes of renal parenchyma)
NOAEL = 0.0016 mg/L
(5) Rhesus monkeys were exposed to /m(2-ethylhexyl) phosphate via inhalation at 0, 10.8, 26.4 or 85 mg/m3 (0,
0.0108, 0.0264 or 0.085 mg/L) 6 hours/day, 5 days/week for 3 months. No deaths and no effects were noted on
weight gain, hematological and biochemical parameters, evaluation of trained behavior (visual discrimination test)
and histopathological findings.
NOAEL = 0.085 mg/L (based on no effects at the highest dose tested)
Sub-Category II
Data gap
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
(1) Sprague-Dawley rats (10/sex for low- and mid-dose, 30/sex for control and high-dose) were administered
triisobutyl phosphate in the diet at 0 (control), 200, 1000 or 5000 ppm (equivalent to 0, 13.9 - 16.8, 68.4 - 84.3 or
346.1 - 403.9 mg/kg-bw/day) for 13 weeks. Control and the high-dose animals were observed for 8 weeks post-
exposure. High-dose animals exhibited reduced food intake, limited hematological effects and clinical chemistry
changes No mortality, changes in body weight or organ weight or hematological effects were observed.
LOAEL = 346.1 - 403.9 mg/kg-bw/day (based on limited hematological and clinical chemistry effects)
NOAEL = 68.4 - 84.3 mg/kg-bw/day
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
(1) Sprague-Dawley rats (15/sex/dose) were administered tributyl phosphate via the diet at 0, 8, 40, 200, 1000 or
5000 ppm (equivalent to approximately 0, 0.6, 3, 15, 75 or 375 mg/kg-bw/day) for up to 13 weeks. After 45 days,
blood was collected from 5/sex/dose for hematology and clinical chemistry and these animals were then sacrificed
for histologic examinations. Decreased body weights and decreased food consumption in 375 mg/kg-bw/day
animals were observed. At interim sacrifice, treatment-related effects included elevated mean serum gamma-
glutamyl transferase (SGGT) activity at 375 mg/kg-bw/day males and females and increased mean albumin and
calcium values for 375 mg/kg-bw males. At terminal sacrifice, effects included increased mean SGGT values in 75
mg/kg-bw/day males and 375 mg/kg-bw/day males and females. Animals at 375 mg/kg-bw/day also exhibited
21
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increased partial thromboplastin time and increased mean serum glutamic pyruvic transaminase (SGPT) activity
(males only). Histopathology revealed generalized transitional cell hyperplasia of the urinary bladder in 75 mg/kg-
bw/day males and 375 mg/kg-bw/day males and females.
LOAEL = 68.2 mg/kg-bw/day (measured concentration for 1000 ppm, based on clinical chemistry, hematology
and histopathological changes)
NOAEL = 13.8 mg/kg-bw/day (measured concentration for 200 ppm)
Reproductive Toxicity
Sub-Category I
Data gap
Sub-Category II
Data gap
Sub-Category III
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
Sprague-Dawley rats (30/sex/concentration) were administered tributyl phosphate in the diet at 0, 200, 700 or 3000
ppm (0, ~ 15, 53 and 225 mg/kg-bw/day) for 13 weeks for the F0 generation and 11 weeks for the F1 generation.
Systemic effects included reduced body weight gains in high-dose F0 and F1 generation males and females and mid-
dose F1 females, reduced food consumption in high-dose F0 and F1 males and females or, urinary bladder epithelial
hyperplasia in low-dose (generation and sex not specified) and in mid- and high-dose F0 and F1 males and females
and hepatic centrilobular hypertrophy was noted in mid-dose F0 and F1 generation females and high-dose F0 and F1
males and females. Developmental effects included reduced pup weights in mid- and high-dose F0 and F1
generation offspring. No mortalities or clinical signs of toxicity were observed. No reproductive effects were noted
for mating indices, fertility indices, gestation length, litter size, pup sex ratio and pre- and postnatal loss.
LOAEL (systemic toxicity) = 15 mg/kg-bw/day (lowest dose tested, based on urinary bladder hyperplasia)
NOAEL (reproductive toxicity) = 225 (based on no effects at the highest dose tested)
LOAEL (offspring toxicity) = 53 mg/kg-bw/day (based on reduced pup weights)
NOAEL (offspring toxicity) = 15 mg/kg-bw/day
Developmental Toxicity
Sub-Category I
Data gap
Sub-Category II
Data gap
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
Pregnant CD(SR) BR VAF/Plus rats (25/dose) were administered triisobutyl phosphate via gavage at 0, 100, 300 or
1000 mg/kg-bw/day on gestation days 6 - 15. Clinical signs of toxicity included an increased salivation at all doses.
Increased water consumption and slightly decreased body weight gain were seen at the high dose. Early embryonic
mortality was slightly increased at the high dose. No changes in food consumption or number of fetal abnormalities
were noted.
LOAEL (maternal toxicity) = 1000 mg/kg-bw/day (based on increased water consumption, salivation and reduced
body weight gain, preimplantation loss)
NOAEL (maternal toxicity) = 300 mg/kg-bw/day
NOAEL (developmental toxicity) = 1000 mg/kg-bw/day (based on no effects at the highest dose tested)
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Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
(1) Pregnant Sprague-Dawley rats (24/dose) were administered tributyl phosphate in corn oil via gavage at 0, 188,
375 or 750 mg/kg-bw/day on days 6 - 15 of gestation. Mortality was noted in high-dose dams. Decreased mean
body weight gain and body weights were noted in low-, mid- and high-dose dams, decreased food consumption was
noted in mid- and high-dose dams and increased relative (to body weight) liver weights were noted in high-dose
dams. Developmental effects included decreased mean fetal body weight in high-dose pups. No effects were seen
for mean number of corpora lutea, number of pups per litter, mean number of resorptions sites, number of fetuses or
visceral, skeletal or external malformations.
LOAEL (maternal toxicity) = 188 mg/kg-bw/day (based on decreased body weight and body weight gain)
NOAEL (maternal toxicity) = Not established
LOAEL (developmental toxicity) = 750 mg/kg-bw/day (based on decreased mean fetal body weights)
NOAEL (developmental toxicity) = 375 mg/kg-bw/day
Genetic Toxicity - Gene Mutation
In vitro
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
(1) In four bacterial gene mutation assays, Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537
were exposed to /ra(2-ethylhexyl) phosphate in the presence and absence of metabolic activation. Mutagenicity
was not evident. Limited information was provided.
Tris(2-ethylhexyl) phosphate was not mutagenic in these assays.
(2) InNTP study, Salmonella typhimurium strains TA98, TA100, TA 1535 and TA1537 were exposed to tris{2-
ethylhexyl) phosphate at 100, 333, 1000, 3333, and 10,000 |ig/plate in the presence and absence of metabolic
activation. Positive and negative controls were included and responded appropriately. Tris(2-ethylhexyl) phosphate
was negative for genotoxic effects.
Tris(2-ethylhexyl) phosphate was not mutagenic in this assay.
(3)In NTP study, Mouse lymphoma L5178Y cells were exposed to
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(3) Mouse lymphoma L5178Y/TK+/- cells were exposed to />/.v(2-ctlvvlhc\yl) phosphate at 0, 0.06, 0.065, 0.07,
0.075, 0.08, 0.085 or 0.9 \\LlmL in the absence of metabolic activation and 0, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075
or 0.085 |iL/mL in the presence of metabolic activation. Positive controls were tested, but responses were not
provided. The cytotoxic concentration was 1 |iL/mL. ft's(2-ethylhexyl) phosphate was negative for genotoxic
effects.
/iis(2-cthylhc\yl)|)hosphatc was not mutagenic in this assay.
Phosphoric acid, 2-ethylhexyl ester (CAS No. 12645-31-7)
(1) Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 and Escherichia coli strain WP2uvrA-
were exposed to phosphoric acid, 2-ethylhexyl ester at 0, 15, 50, 150, 500, 1500 or 5000 |ig/plate for all Salmonella
strains and 0, 50, 150, 500, 1500 or 5000 |ig/plate for the Escherichia .coli strain in the presence and absence of
metabolic activation. Vehicle and positive controls were used and produced appropriate responses. The cytotoxic
concentration was 5000 |ig/plate for TA100 in the presence and absence of metabolic activation. No cytotoxic
concentration was noted for Wp2uvrA-. No mutagenicity was evident.
Phosphoric acid, 2-ethylhexyl ester was not mutagenic in this assay.
(2) Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 and Saccharomyces strain D4
were exposed to phosphoric acid, 2-ethylhexyl ester at 0.001 - 5 |ig/plate (solvent control) in the presence and
absence of metabolic activation. Positive controls were tested but their responses were not provided. The cytotoxic
concentration was 5 |ig/platc. in the presence and absence of metabolic activation, except for D4. Phosphoric acid,
2-ethylhexyl ester was not genotoxic.
Phosphoric acid, 2-ethylhexyl ester was not mutagenic in this assay.
(3) L5178y/TK+/- mouse lymphoma cells were exposed to phosphoric acid, 2-ethylhexyl ester at 0.1 - 1.0 ng/mL
(DMSO control) in the presence and absence of metabolic activation. Positive controls were used and produced an
appropriate response. The cytotoxic concentration was 1.0 |ig/mL. Phosphoric acid, 2-ethylhexyl ester was not
genotoxic.
Phosphoric acid, 2-ethylhexyl ester was not mutagenic in this assay.
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
In three studies, Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 (only present in one
of the three studies) were exposed to triisobutyl phosphate at 20 - 5000 ng/plate (Standard Plate Assay) and at 15 -
5000 ng/plate (Preincubation Test) in assay one, 10 - 5000 |ig/plate in study two and up to 5 mg/plate in assay three,
all in the presence and absence of metabolic activation. No other information was provided. Triisobutyl phosphate
showed negative results in these assays.
Triisobutyl phosphate was not mutagenic in these assays.
Tributylphosphate (CAS No. 126-73-8, supporting chemical)
(1) Salmonella typhimurium strains TA102 and TA2638 and Escherichia coli strains WP2/pKM101 and
WP2uvr/pKM101were exposed to tributyl phosphate atO, 31.3, 78, 125, 250, 313, 500, 625, 1000, 1250, 2000, 2500
or 5000 ng/plate in the presence and absence of metabolic activation. Positive controls were tested, but their
responses were not provided. No cytotoxic concentration was provided. Tributyl phosphate showed negative results
in these assay.
Tributyl phosphate was not mutagenic in this assay.
In vivo
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
In NTP study, Drosophila melanogaster were exposed to /r/'s(2-ethylhexyl) phosphate in the feed or injection at
50,000 ppm. Mortality was 40% in the feeding group and 10% in the injection group. There was no effect on
mating. The results were negative
Tris(2-ethylhexyl) phosphate was not mutagenic in this assay.
24
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Genetic Toxicity - Chromosomal Aberrations
In vitro
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
In NTP studies, Chinese hamster ovary cells were exposed to /r/'s(2-ethylhexyl) phosphate at 25.1, 37.5 and 50
Hg/mL in the absence of metabolic activation and at 839, 1253 and 1670 ng/mL in the presence of metabolic
activation. There was no significant increase in cell with aberrations. Positive and negative controls responded
appropriately. No increase in aberrant cells was noted at any concentration.
7Ws(2-ethylhexyl) phosphate did not induce chromosomal aberrations in these assays.
Sub-Category II
Data gap
Sub-Category III
Tributylphosphate (CAS No. 126-73-8, supporting chemical)
Two cytogenic assays were conducted, one using CHO-K1 cells and concentrations up to 0.15 |iL/mL and the other
with mouse embryos at 45 and 144 hours after conception. No other details were provided.
Tributyl phosphate did not induce chromosomal aberrations in these assays.
In vivo
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
(1) In the NTP study, B6C3F1 mice (5 males/dose) were administered /r/'s(2-ethylhexyl) phosphate via
intraperitoneal injection at 0 (corn oil control), 500, 1000, 2000 or 3000 mg/kg-bw. At 24 and 48 hours, animals
were sacrificed, bone marrow samples collected and scored for the occurrence of micronucleated PCE and
PCE/erythrocyte ratios. A positive control was tested and produced an appropriate response. No increase in
micronuclei was noted at any concentration.
7Ws(2-cthylhcxyl) phosphate did not induce chromosomal aberrations in this assay.
(2) In a sister chromatid exchange (SCE) study conducted by NTP, male B6C3F1 mice (4/dose) were administered
/m(2-ethylhexyl) phosphate via intraperitoneal injection at 0 (solvent control), 1250, 2500 or 5000 mg/kg-bw.
Positive controls were used and produced an appropriate response. A positive response was seen.
Tris(2-ethylhexyl) phosphate induced chromosomal aberrations in this assay.
(3) In the NTP study, B6C3F1 mice (8 males/dose) were exposed to /ra(2-ethylhexyl) phosphate via intraperitoneal
injection at 0 (vehicle control), 1250, 2500 or 5000 mg/kg-bw. At 24 and 48 hours, animals were sacrificed, bone
marrow samples collected and scored for the occurrence of micronucleated PCE and PCE/erythrocyte ratios.
Positive controls were used and produced an appropriate response. 7ra(2-ethylhexyl) phosphate was negative in
this assay.
Tris(2-ethylhexyl) phosphate did not induce chromosomal aberrations in this assay.
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
CD-I mice (5/sex/dose/sampling time) were administered triisobutyl phosphate by the intraperitoneally at 0, 300,
600 or 1200 mg/kg-bw. At 24, 48 and 72 hours, animals were sacrificed, bone marrow samples collected and scored
for the occurrence of micronucleated PCE and PCE/erythrocyte ratios. The high dose did not induce increases in
frequency of micronucleated PCEs. Positive controls were tested, but their responses were not provided.
Triisobutyl phosphate did not induce chromosomal aberrations in this assay.
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Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
Sprague-Dawley rats of both sexes were administered tributyl phosphate via gavage at 0, 300, 600 or 1200 mg/kg-
bw. Positive controls were used and produced an appropriate response.
Tributyl phosphate did not induce chromosomal aberrations in this assay.
Additional Information
Skin Irritation
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
(1) In two skin irritation studies in rabbits, /r/'s(2-ethylhexyl) phosphate was considered irritating. Moderate
erythema was noted in one study. (Limited study details were provided)
7W.s(2-ethylhexvl) phosphate was irritating to rabbit skin in this study.
Sub-Category II
Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7)
(1) Rabbits (6, sex, strain not specified) were administered 0.5 mL of bis(2-ethylhexyl) phosphate dermally on to
clipped intact and abraded skin under occluded conditions for 24 hours and assessed for up to 14 days after
exposure. The primary irritation index was 6.2. Effects included erythema and edema.
/iis(2-cthylhcxyl) phosphate was highly irritating to rabbit skin in this study.
(2) Rabbits (6, sex, strain not specified) were administered 0.5 mL of />/.v(2-cthvlhc\yl) phosphate dermally on to
clipped, intact skin under occluded conditions for 48 hours. The primary irritation index was 4.85. Test sites for all
animals were blanched at 4 hours, but had recovered at the 48-hour observation.
/iiv(2-cthylhc\yl) phosphate was irritating to rabbit skin in this study.
(3) Rabbits (6, sex, strain not specified) were administered 0.5 mL bis(2-ethylhexyl) phosphate dermally on to
clipped, intact skin under occluded conditions for 24 hours and assessed for up to 72 hours after exposure. The
primary irritation index was 0.
/iiv(2-cthylhc\yl) phosphate was not irritating to rabbit skin in this study.
Mono(2-ethylhexyl)phosphate (CAS No. 1070-03-7, Supporting Chemical)
Albino rabbits (3, sex, strain not specified) were administered mono(2-ethylhexyl) phosphate dermally on to
clipped, intact skin under occluded conditions and assessed at 4, 24, 48, 72, 120 and 168 hours according to the
Draize method. The average maximum score was 8 out of 8 in 24 hours. No change was observed at termination.
Mono(2-ethylhexyl) phosphate was corrosive to rabbit skin in this study.
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
Two skin irritation studies were conducted in rabbits. The test substance was irritating to rabbit skin, (Limited
information was provided.)
Triisobutyl phosphate was irritating to rabbit skin in this study.
Tributyl phosphate (CAS No. 126-73-8, Supporting Chemical)
Eleven tests were conducted in rabbits, guinea pigs and rats. Values ranged from slightly irritating to highly
irritating. (Limited details were available.)
Tributyl phosphate was irritating to rabbit, guinea pig and rat skin in this study.
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Eye Irritation
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
Rabbits (number, sex, strain not specified) were instilled 0.01 - 0.5 mL /r/'s(2-ethylhexyl) phosphate into the eye .
Slight conjunctivitis was seen up to 0.05 mL and moderate conjunctivitis was seen at > 0.1 mL which cleared up
within 24 hours.
7Wv(2-ethvlhexyl) phosphate was not irritating to rabbit eyes in this study.
Sub-Category II
Bis(2-ethylhexyl) phosphate (CAS No. 298-07-7)
(1) Six rabbits (strain, sex not specified) were instilled bis(2-ethylhexyl) phosphate (0.1 mL) into the right eye. The
treated eyes remained unwashed. Irritation was scored at 1, 2, 3, 4, 5, 6 and 7 days after instillation. Effects on the
cornea, iris and conjunctiva were noted.
/iiv(2-cthylhe\yl) phosphate was corrosive to rabbit eyes in this study.
(2) Six rabbits (strain, sex not specified) were instilled bis(2-ethylhexyl) phosphate (0.1 mL) into one eye. Three
treated eyes remained unwashed, while the other three were washed for 1 minute with warm water 20 seconds after
instillation. The treated eyes were scored for irritation at 1, 24, 48 and 72 hours after treatment. Cornea, iris and
conjunctiva effects were noted in washed and unwashed eyes.
/iiv(2-cthvlhcxyl) phosphate was highly irritating to rabbit eyes in this study.
Mono(2-ethylhexyl)phosphate (CAS No. 1070-03-7, Supporting Chemical)
(1) Three rabbits (strain, sex not specified) were instilled mono(2-ethylhexyl) phosphate (0.01 mL) into one eye.
Evaluations at 1, 24, 48 and 72 hours after treatment found that the average irritation scores were 51.4, 66, 77.9 and
68.3, respectively. The corneal opacity did not improve within 10 days, suggesting possible irreversible/corrosive
effects.
Mono(2-ethylhexyl) phosphate was corrosive to rabbit eyes in this study.
(2) Six rabbits (strain, sex not specified) were instilled mono(2-ethylhexyl) phosphate (0.01 mL) into one eye. The
eyes remained unwashed. Evaluations were made at 1, 24, 48, 72, 120 and 168 hours according to the Draize
method. The average irritation score was 83.3 out of 110 at 24 hours. At 240 hours, opalescent areas of corneal
cloudiness were still present with iris hemorrhagic and showing reaction to light.
Mono(2-ethylhexyl) phosphate was corrosive to rabbit eyes in this study.
(3) Three rabbits (strain, sex not specified) were instilled mono(2-ethylhexyl) phosphate (0.01 mL) into one eye.
Evaluations were made at 24, 48 and 72 hours after treatment. Erythema and edema of the cornea and moderate
opacity were observed. The mean high score at 24 hours was 24 out of 110. The irritating effects were remised in 5
- 7 days.
Mono(2-ethylhexyl) phosphate was corrosive to rabbit eyes in this study.
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
Two eye irritation studies of triisobutyl phosphate were conducted in rabbits. Results were not irritating to irritating.
No other information was provided.
Triisobutyl phosphate was irritating to rabbit eyes in this study.
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
Four studies were conducted in rabbits. Values ranged from slightly irritating to irritating. No other information
was provided.
Tributyl phosphate was irritating to rabbit eyes in this study.
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Sensitization
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
Three sensitization studies were conducted in guinea pigs using the Buehler Test, Guinea Pig Maximization Test and
an unspecified method. No other information was provided.
Triisobutyl phosphate was a dermal sensitizer in guinea pigs in all studies.
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
(1) Tributyl phosphate was not sensitizing in an open epicutaneous test in guinea pigs. No additional information
available.
Tributyl phosphate was a dermal sensitizer in guinea pigs in this study.
(2) In a patch test, 15 applications of tributyl phosphate were applied as less than 25% formulation to 53 volunteers,
on alternate days. No volunteer gave local reactions 24 hours after the final patch, therefore no evidence of
sensitization.
Tributyl phosphate was not a dermal sensitizer in humans in this study.
Carcinogenicity
Sub-Category I
Tris(2-ethylhexyl) phosphate (CAS No. 78-42-2)
(1) In an NTP study, Fischer 344 rats (50/sex/dose) were administered /r/'s(2-ethylhexyl) phosphate via gavage at 0,
2000 or 4000 mg/kg-bw/day (males) and 0, 1000 or 2000 mg/kg-bw/day (females) in corn oil 5 days/week for 2
years. No clinical signs of toxicity, changes in survival or evidence of carcinogenicity in female rats were noted.
Treatment-related effects in males included lower mean body weights throughout the study. A dose-related
increase in the incidence of pheochromocytoma of adrenal glands and a positive trend for increased incidence of
thyroid follicular cell hyperplasia was observed.
7Wv(2-cth vlhcxyl) phosphate showed equivocal evidence of carcinogenicity in male rats in this study.
(2) In an NTP study, B6C3F1 mice (50/sex/dose) were administered /r/'s(2-ethylhexyl) phosphate via gavage at 0,
500 or 1000 mg/kg-bw/day in corn oil 5 days/week for 2 years. An increased incidence of follicular cell hyperplasia
of the thyroid gland was noted in males and females and an increased incidence of hepatocellular carcinoma was
noted in females. No clinical signs of toxicity, depression in body weight or changes in survival were noted.
7Wv(2-cth vlhcxyl) phosphate showed evidence of carcinogenicity in this study.
Sub-Category III
Tributyl phosphate (CAS No. 126-73-8, Supporting Chemical)
(1) Sprague-Dawley rats (50/sex/concentration) were administered tributyl phosphate in the diet at 0, 200, 700 or
3000 ppm (approximately 10, 35 or 150 mg/kg-bw/day) for 24 months. Survival was not affected by treatment.
Clinical signs of toxicity included red discoloration of the urine. Decreased body weight gains were noted among
high-dose animals. Histopathology revealed an increase in the incidence and severity of urinary bladder hyperplasia
and incidence of urinary bladder papillomas in mid- and high-dose males and females. Transitional cell carcinomas
of the urinary bladder in females and a single squamous cell carcinoma in one male were seen at 3000 ppm.
Survival, food consumption, hematology and urinalysis parameters were unaffected by treatment.
Tributyl phosphate showed evidence of carcinogenicity in this study.
(2) CD-I mice (50/sex/concentration) were administered tributyl phosphate in feed at 0, 150, 1000 or 3500 ppm
(approx. 0, 22.5, 150 or 525 mg/kg-bw/day, respectively) for 18 months. Survival, clinical signs of toxicity and
food consumption were unaffected by treatment. High-dose animals exhibited reduced body weight gain, increased
absolute and relative (to body weight) liver weights in both sexes and an increased incidence of hepatocellular
adenomas in males. Increased absolute and relative (to body weight) liver weights were also seen in mid-dose males
and females. Since historical control data show high incidences of hepatocellular adenomas, the hepatocellular
adenomas seen in this study may not be biologically significant.
Tributyl phosphate was not carcinogenic in this study.
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Neurotoxicity
Sub-Category III
Triisobutylphosphate (CAS No. 126-71-6)
Summaries of seven neurotoxicity studies were provided, but were not written in English. These studies were not
reviewed.
Tributylphosphate (CASNo. 126-73-8, Supporting Chemical)
(1) Sprague-Dawley rats (24) were administered tributyl phosphate via gavage at 0, 32.5, 100 or 325 mg/kg-bw/day
in corn oil for 13 weeks. Potential neurotoxicity of tributyl phosphate was evaluated using a functional observation
battery, motor activity battery, and a neuropathological examination. Mortality was noted in males and females
from the mid- and high-dose groups. Body weight loss was seen in high-dose males and females. Clinical signs in
high-dose males and females included muzzle staining, urogenital staining and alopecia on the limbs and body.
High-dose animals also exhibited body weight loss and decreased food consumption. A qualitative functional
observation battery did not reveal any treatment-related differences. There were no significant differences in motor
activity test results between the treated and control animals. Microscopic examination of the nervous system did not
find any treatment-related neuropathology. Brain weight, length, and width measurements showed no treatment-
related differences.
Tributyl phosphate was negative for neurotoxic effects in this study.
Conclusion
Sub-Category I: Acute oral toxicity of /to(2-ethylhexyl) phosphate to rats and rabbits, acute inhalation toxicity to
guinea pigs and acute dermal toxicity to rabbits is low. 7ra(2-ethylhexyl) phosphate is irritating to rabbit skin, and
not irritating to rabbit eyes. Systemic toxicity in the oral repeated-dose studies in rats and mice to /to(2-ethylhexyl)
phosphate is low. Repeated-dose inhalation exposures in guinea pigs show high systemic toxicity, exhibited by
changes of the renal parenchyma. No data are available for the reproductive/developmental toxicity endpoints.
7ra(2-ethylhexyl) phosphate did not induce gene mutations or chromosomal aberrations in vitro, but induced
chromosomal aberrations in vivo. 7ra(2-ethylhexyl) phosphate showed evidence of carcinogenicity in rats and
mice.
Sub-Category II. Acute oral toxicity of bis(2-ethylhexyl) phosphate and phosphoric acid, 2-ethylhexyl ester
(mixture) to rats and acute dermal toxicity to rabbits is low. Bis(2-ethylhexyl) phosphate and mono(2-ethylhexyl)
phosphate are highly irritating to rabbit skin and corrosive to rabbit eyes. No data are available for the repeated-
dose, reproductive and developmental toxicity endpoints. 5/s(2-ethylhexyl) phosphate and phosphoric acid, 2-
ethylhexyl ester did not induce gene mutations in vitro. No data are available for the chromosomal aberrations
endpoint.
Sub-Category III: Acute oral toxicity of triisobutyl phosphate and tributyl phosphate (supporting chemical) to rats
and mice and acute dermal toxicity to rabbits and guinea pigs are low. Acute inhalation toxicity of triisobutyl
phosphate in rats is low to moderate. Triisobutyl phosphate and tributyl phosphate are irritating to rat, rabbit, human
and guinea pig skin, are irritating to rabbit eyes and are dermal sensitizers in guinea pigs but not in humans.
Systemic toxicity of tributyl phosphate in oral repeated-dose studies is moderate. In a two-generation dietary
reproductive toxicity study in rats, tributyl phosphate showed low reproductive and developmental toxicity.
Triisobutyl phosphate and tributyl phosphate did not induce gene mutations in vitro and did not induce chromosomal
aberrations in vitro or in vivo. No evidence of neurotoxicity was seen for the supporting chemical, tributyl
phosphate. Tributyl phosphate, a supporting chemical, showed evidence of carcinogenicity in rats.
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Tabic 5. Summary of Human Health Data
Sub-Category 1
Sub-Category II
Sub-Category III
Endpoints
7'ra(2-cthylhcxyl)
phosphate
(78-42-2)
/iis(2-cthylhc\yl)
phosphate
(298-07-7)
Phosphoric acid,
2-cthylhcxyl ester
(12645-31-7)
Mono(2-cthyl-
hcxyl) phosphate
(1070-03-7,
supporting
chemical)
Triisobutyl
phosphate
(126-71-6)
Tributvl phosphate
(126-73-8,
supporting
chemical)
Acute Oral Toxicity
LD50 (mg/kg-bw)
37,080
1400
500 - 1000
2710
3072
3160
Acute Inhalation Toxicity
LCS0 (mg/L)
450
-
-
-
>1.35
> 4.242
Acute Dermal Toxicity
LDS0 (mg/kg-bw)
20,000
>2000
>4640
1260 (LDlo)
9600
9700
Repeated-Dose Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
NOAEL = 430
LOAEL = 1550
Data Gap
Data Gap
NOAEL = 68.4 - 84.3
LOAEL = 346.1-
403.9
NOAEL =13.8
LOAEL = 68.2
Repeated-Dose Toxicity
NOAEL/LOAEL
Inhalation (mg/L/day)
NOAEL = 0.0016
LOAEL = 0.0096
Reproductive Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
Systemic Toxicity
Reproductive Toxicity
Developmental Toxicity
Data Gap
Data Gap
Data Gap
No Data
NOAEL = Not
Established
LOAEL = 15
NOAEL = 225
LOAEL = Not
Established
NOAEL = 15
LOAEL = 53
(RA)
NOAEL = Not
Established
LOAEL =15
NOAEL = 225
LOAEL = Not
Established
NOAEL =15
LOAEL = 53
30
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Tabic 5. Summary of Human Health Data
Sub-Category 1
Sub-Category II
Sub-Category III
Endpoints
7'ra(2-cthylhcxyl)
phosphate
(78-42-2)
/iis(2-cthylhc\yl)
phosphate
(298-07-7)
Phosphoric acid,
2-cthylhcxyl ester
(12645-31-7)
Mono(2-cthyl-
hcxvl) phosphate
(1070-03-7,
supporting
chemical)
Triisobutyl
phosphate
(126-71-6)
Tributvl phosphate
(126-73-8,
supporting
chemical)
Developmental Toxicity
NOAEL/LOAL
Oral (mg/kg-bw/day)
Maternal Toxicity
Developmental Toxicity
Data Gap
Data Gap
Data Gap
NOAEL = 300
LOAEL = 1000
NOAEL =1000
LOAEL = Not
Established
NOAEL = Not
Established
LOAEL = 188
NOAEL = 375
LOAEL = 750
Genetic Toxicity - Gene
Mutation
In vitro
Negative
Negative
Negative
Negative
Negative
Genetic Toxicity - Gene
Mutation
In vivo
Negative
Genetic Toxicity -
Chromosomal Aberrations
In vitro
Negative
Data Gap
Data Gap
No Data
Negative
(RA)
Negative
Genetic Toxicity -
Chromosomal Aberrations
In vivo
Positive
Negative
Negative
31
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Tabic 5. Summary of Human Health Data
Sub-Category 1
Sub-Category II
Sub-Category III
Endpoints
7'ra(2-cthylhcxyl)
phosphate
(78-42-2)
/iis(2-cthylhc\yl)
phosphate
(298-07-7)
Phosphoric acid,
2-cthylhcxyl ester
(12645-31-7)
Mono(2-cthyl-
hcxyl) phosphate
(1070-03-7,
supporting
chemical)
Triisobutyl
phosphate
(126-71-6)
Tributvl phosphate
(126-73-8,
supporting
chemical)
Additional Information
Skin Irritation
Eye Irritation
Sensitization
Carcinogenicity
Neurotoxicity
Irritating
Not irritating
Carcinogenic
Highly irritating
Corrosive
Corrosive
Corrosive
Irritating
Irritating
Sensitizing
No Data
Carcinogenic
(RA)
No Data
Negative
(RA)
Irritating
Irritating
Sensitizing
Carcinogenic
Negative
Measured data in bold text; (RA) = Read Across; Shaded cells = non-sponsored substances (proposed supporting chemicals)
32
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