SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
CHEMICAL CATEGORY NAME
Sulfosuccinates
SPONSORED CHEMICALS
Butanedioic Acid, Sulfo-l,4-bis(2-ethylhexyl) Ester, Sodium Salt (CAS No. 577-11-7)
[9th CI Name: Butanedioic acid, sulfo-, l,4-bis(2-ethylhexyl) ester, sodium salt]
Butanedioic Acid, Sulfo-l,4-bis(l,3-dimethylbutyl) Ester, Sodium Salt (CAS No. 2373-38-8)
[9th CI Name: Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt]
Butanedioic Acid, Sulfo-l,4-dicyclohexyl Ester, Sodium Salt (CAS No. 23386-52-9)
[9th CI Name: Butanedioic acid, sulfo-1,4-dicyclohexyl ester, sodium salt]
October 2007
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 characterizations.4'6 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.
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SCREENING-LEVEL HAZARD CHARACTERIZATION
Sulfosuccinates Category
Introduction
The sponsor, The SOCMA Sulfosuccinates Group (SSG) of the Synthetic Organic Chemical Manufacturers
Association (SOCMA), submitted a Test Plan and Robust Summaries to EPA for the Sulfosuccinates Category on
July 25, 2001. EPA posted the submission on the ChemRTK website on September 14, 2001
(http://www.epa.gov/chemrtk/pubs/summaries/cYclodim/cl3133tc.htm'). EPA comments on the original
submissions were posted to the website on February 19, 2002. Public comments were also received and posted to
the website. The sponsor submitted updated/revised documents on May 31, 2002, which were posted to the
ChemRTK website on July 19, 2002. The Sulfosuccinates category consists of the following chemicals:
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (ethylhexyl ester) CAS No. 577-11-7
[9th CI name: Butanedioic acid, sulfo-, l,4-bis(2-ethylhexyl) ester, sodium salt]
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (dimethylbutyl ester)CAS No. 2373-38-8
[9th CI name: Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt]
Butanedioic acid, sulfo- 1,4-dicyclohexyl ester, sodium salt (cyclohexyl ester) CAS No. 23386-52-9
[9th CI name: Butanedioic acid, sulfo-1,4-dicyclohexyl ester, sodium salt]
This screening-level hazard characterization is based primarily on the review of the test plan and robust summaries
of studies submitted by the sponsor(s) 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. Structures of the sponsored chemical(s) are included
in the appendix. 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.
Category Justification
The three members of the sulfosuccinates category are sulfosuccinate esters with closely related molecular
structures. They have a succinic ester backbone, in which a carbon alpha to one of the carboxyl functions has a
sodiumsulfo group in place of a hydrogen atom. The only structural difference in the three substances is the alcohol
moiety of the ester function: 2-ethylhexyl-, cyclohexyl- and 1,3-dimethylbutyl. Representative structures are
depicted in the Appendix. The generic molecular structure for all category members is shown below:
R00CCH2CH(S03Na)C00R
where R = 2-ethylhexyl- [CH3(CH2)3CH(CH2CH3)CH2-]
= 1,3-dimethylbutyl- [(CH3)2CHCH2CH(CH3)-]
= cyclohexyl- [cyclic -(CH2)5CH-]
The sponsor grouped the chemicals based on the similarities in structure and physicochemical and toxicological
properties. EPA agreed with the sponsor's category approach. However, for the genetic and developmental toxicity
endpoints, EPA queried the appropriateness of data extrapolation from butanedioic acid, sulfo-, l,4-bis(2-
ethylhexyl) ester, sodium salt to the other category members, stating that different alcohols were generated and
asking the submitter to discuss the likely effects of the three different ester structures by clearly stating the
toxicological similarities considered. EPA suggested that the discussion on metabolism could be strengthened.
In its revised submission, the sponsor expanded the discussion on metabolism by identifying the alcohol moiety
formed for each ester (2-ethylhexanol, methyl isobutyl carbinol [or 4-methylpentan-2-ol] and cyclohexanol). In lieu
of providing a detailed technical discussion in the response to comments the sponsor referred to the evaluation of
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these metabolites in other programs. Data and information on the metabolites are now publicly available (htto://cs3-
hq .oecd.org/scripts/hpv/ for both 2-ethylhexanol and 4-methylpentan-2-ol and
http://www.epa.gov/chemrtk/pubs/summaries/cvclohex/cl3221tc.htm for cyclohexanol). EPA believes these data
support the sulfosuccinate category.
Sum m an-Conclusion
The log k \ allies of the category members indicate their potential lo hioaccuniulale is expected lo he low
l5ulauedioic ;ieid. sulfo-l.4-his(2-elh\ lliew I) ester. sodium sail. is readiK biodegradable. indicating that il is not
expected lo persist in ilie en\ iiounicut I lie remaining two category members ;ire not readiK biodegradable,
indicating 11 i;il ihe> ha\e I lie potential lo persist in I lie eu\ uoiinieul
I lie e\ ;iIii;iIkiii of a\ ;nl;ihle lo\icil> d;il;i lor fish. ;u|ii;ilie 11 in crtchialcs ;ind ;K|ii;ilie plants indie;iles lli;il I lie potential
acute li;i/;ird of llie category memhei's to ;u|ii;iiie organisms is low
The ;ieule oral to\icil> lor llie memheis of ilns category is low Repealed exposures lo nil e;ileiii»i> memhei's \ i;i ihe
oral route iudie;ile lo\icit> lo nils h;ised on decreased weiglil g;im ;md gastrointestinal irritation Reproduction ;md
de\ elopnieiilal siudies w illi hul;iiiedioie ;ieid. sulfo-1,4-hisi 2-elli\ lliew I) esier. sodium s;ili ;ii lugli doses iudie;ile
decreases m parental ;iud fetal hods weighis I )e\ elopnieiilal effects ohser\ed were increases in l'el;il resorpiious
;iud ;i higher pereeui;ige of c\lcriiall> malformed I'eluses l);iia on c\clohc\auol. ;i uiel;ihohie of huiauedioic ;ieid.
suMo-l.4-die\elohe\> I esier. sodium sail. ;iud \IIIJk (a melahohie of \1IHC. which isa metabolite of buiauedioic
aeid. sulTo-1,4-his( I. i-diniclh\ lhui\ 11 esier. sodium sail i also show de\ elopuieuial and iepi'odueli\ e effects The
ealegoiA meuiher. huiauedioic aeid. suMi»-l.4-his(2-elh\ lliew I) esier. sodium sail did uoi show mutagenic potential
w lieu tested in vitro nor did it induce chromosomal aberrations in viini lu addition, information lor the alcohol
metabolites of two category members (MIIJC and cscloheviuoh support the read across ui that all a\ailable data
show negate e results lor gene mutations and chromosomal aberrations (except lor one positi\ e in \ itro result w illi
c\cohe\auol. w Inch showed neg;iti\ e iu \ i\ o results ui a niicrouucleus assa\ in mice).
I lie potential health lia/ard of the sulfosucciiiates category is moderate based on repiodiicti\ e and de\ elopniental
lOMCItS
\o data gaps were identified under the I ll'V Challenge hogram
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
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
LogKow: 1.76 (estimated)
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (CAS No. 2373-38-8)
LogKow: 1.84 (estimated)
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
LogKow: 3.95 (estimated)
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Biodegradation
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
In a ready biodegradation test using activated sludge from Bergen Co., New Jersey as the inoculum, 66.4% of the
test substance had degraded after 28 days.
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt is readily biodegradable.
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (CAS No. 2373-38-8)
In a ready biodegradation test using activated sludge from Bergen Co., New Jersey as the inoculum, 40.3% of the
test substance had degraded after 28 days.
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt is not readily biodegradable.
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
In a ready biodegradation test using activated sludge from a mixed population as the inoculum, 35.9% of the test
substance had degraded after 28 days.
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt is not readily biodegradable.
Conclusion: The log Kow values of the category members indicate their potential to bioaccumulate is expected to be
low. Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt, is readily biodegradable, indicating that it is
not expected to persist in the environment. The remaining two category members are not readily biodegradable,
indicating that they have the potential to persist in the environment.
Table 1. Summaiy i>rPh\sical-('lu-mical I'niperlies and Kin ininmenlal Kale Dala
Endpoints
Butanedioic acid, sulfo-1,4-
bis(2-ethylhexyl) ester,
sodium salt
(577-11-7)
Butanedioic acid, sulfo-1,4-
bis(l,3-dimethylbutyl) ester,
sodium salt
(2373-38-8)
Butanedioic acid, sulfo-1,4-
dicyclohexyl ester, sodium
salt
(23386-52-9)
Melting Point (°C)
153 -157 (m)
349.8 (e)
203 (m)
Boiling Point (°C)
> 300 (e)
Decomposition
> 300 (e)
Decomposition
> 300 (e)
Decomposition
Vapor Pressure
(hPa at 25°C)
<2.2 x 10"11 (e)
< 1.0 x 10"6 (e)
< 1.0 x 10"5 (e)
Log K„w
3.95 (e)
1.84(e)
1.76 (e)
Water Solubility
(mg/L at 25°C)
15,000 (m)
300,000-320,000 (m)
120,000 (m)
Direct Photodegradation
22.9 x 10"12(e)
17.4 x 10"12 (e)
24.6 x 10"12 (e)
Indirect (OH ) Photodegradation
Half-life (t1/2)
5.6 h(e)
7.3 h(e)
5.2 h(e)
Stability in Water1 (Hydrolysis)
(ti/2)
6.7 years atpH 7 (e)
156 years at pH 7 (e)
14.5 years at pH 7 (e)
Fugacity
(Level in Model)
Air (%)
Water (%)
Soil (%)
Sediment (%)
1.6
37.3
59.9
1.3
0.9
38.7
60.3
0.1
0.9
40.8
58.3
Biodegradation at 28 days (%)
66.4 (m)
40.3 (m)
35.9 (m)
(m) = measured data (i.e., derived from testing); (e) = estimated data (i.e., derived from modeling); — indicates that endpoint
was not addressed for this chemical; 'EPA recommended that hydrolysis be measured for one of the category members
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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
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
(1) Bluegills (Lepomis macrochirus; 10/concentration) were exposed to butanedioic acid, sulfo-l,4-bis(2-ethylhexyl)
ester, sodium salt at nominal concentrations of 32, 42, 56, 75 and 100 mg/L under static conditions for 96 hours. All
solutions had undissolved test substance present from time zero, which was still present at the higher concentrations
after 24 hours. By 24 hours, 100% mortality was observed in the 56, 75 and 100 mg/L tanks. Mortality (100%) was
observed at 42 mg/L after 96 hours.
96-h LC50 = 37 mg/L
(2) Rainbow trout (Salmo gairdneri; 10/concentration) were exposed to butanedioic acid, sulfo-l,4-bis(2-ethylhexyl)
ester, sodium salt at nominal concentrations of 10, 20, 40 and 80 mg/L under static conditions for 96 hours. All fish
exposed to 40 or 80 mg/L died within 24 hours of exposure.
96-h LCS0 = 28 mg/L
(3) Rainbow trout (Oncorhynchus mykiss; 10/concentration) were exposed to butanedioic acid, sulfo-l,4-bis(2-
ethylhexyl) ester, sodium salt at nominal concentrations of 0, 6.25, 12.5, 25, 50 and 100 mg/L under static
conditions for 96 hours. At 96 hours, no mortality was observed up to 25 mg/L, where 20% of fish died. All fish
exposed to 50 mg/L and higher concentrations died within an hour of exposure.
96-h LCS0 = 28 mg/L
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (CAS No. 2373-38-8)
(1) Rainbow trout (Oncorhynchus mykiss) were exposed to butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester,
sodium salt at nominal concentrations of 0, 250, 500, 1000, 2000 and 4000 mg/L under static conditions for 96
hours. At 96 hours, no mortality was observed up to 1000 mg/L, where 10% of fish died. Within 24 hours of
exposures at higher concentrations, 100% mortality was observed.
96-h LCS0 = 1200 mg/L
(2) Bluegills (Lepomis macrochirus; 10/concentration) were exposed to butanedioic
dimethylbutyl) ester, sodium salt at nominal concentrations of 0, 100, 180, 320, 560
conditions for 96 hours. All solutions in the range of 100 - 1000 mg/L were cloudy
(10%) was only observed at 1000 mg/L after 96 hours.
96-h LCS0 > 1000 mg/L
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
Bluegills (Lepomis macrochirus; 10/concentration) were exposed to butanedioic acid, sulfo-l,4-dicyclohexyl ester,
sodium salt at nominal concentrations of 0, 240, 320, 420, 560, 750 and 1000 mg/L under static conditions for 96
hours. All solutions in the range of 100 - 1000 mg/L were cloudy at 48 - 96 hours; 1000 mg/L was cloudy at 24
hours. No mortalities were observed up to 320 mg/L. The majority of the mortalities occurred by 24 hours.
96-h ECS0 = 470 mg/L
Acute Toxicity to Aquatic Invertebrates
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
Daphnia magna (20/concentration) were exposed to butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt
nominal concentrations of 0, 5, 10, 20, 40 and 80 mg/L under static conditions for 48 hours. At 48 hours, mortality
was observed at 20 mg/L (5%), 40 mg/L (50%) and 80 mg/L (100%).
48-h EC50 = 36.2 mg/L
acid, sulfo-l,4-bis(l,3-
and 1000 mg/L under static
at 48 - 96 hours. Mortality
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Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
Daphnia magna (20/concentration) were exposed to butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt at
measured concentrations of 0, 8.1, 27, 90, 300 and 1000 mg/L under static conditions for 48 hours. At 48 hours,
immobility was observed at 300 mg/L (15%). At 24 hours, there was 100% immobilization of the 1000 mg/L group.
Individual treatment solutions were prepared as water accommodated fractions (WAFs).
48-h ECS0 = 457 mg/L
Toxicity to Aquatic Plants
The only submitted data for acute toxicity to green algae are for sodium 1,4-dicyclohexyl sulfosuccinate and indicate
no effects on growth or growth rate. In its comments on the original test plan (dated February 14, 2001), EPA
suggested that the sponsor conduct an algal toxicity study on sodium di(2-ethylhexyl) sulfosuccinate because this
chemical is the most lipophilic in the category. In response, the sponsor provided that testing was not needed
because: (1) sodium di(2-ethylhexyl) sulfosuccinate has a consistent 10-fold greater toxicity to fish, daphnia and
terrestrial plants than sodium 1,4-dicyclohexyl sufosuccinate and (2) the algal toxicity for sodium di(2-ethylhexyl)
sulfosuccinate can thus be estimated (up to greater than 100 mg/L). EPA agrees that the available toxicity data for
fish and daphnia of the ethylhexyl ester and algal toxicity data on cyclohexyl ester show low toxicity. Furthermore,
EPA notes that because green algae is the least sensitive species for the anionic surfactant chemical class, algal
toxicity for the ethylhexyl ester can reasonably be estimated to be in a similar range as that for fish and daphnia for
that chemical. Therefore, although its reasoning is different, EPA agrees with the conclusion that algal toxicity
testing is not a data gap under the HPV Challenge Program.
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
Selenastrum capricornutum (Pseudokirchneriella subcapitata) were exposed to butanedioic acid, sulfo-1,4-
dicyclohexyl ester, sodium salt as Water Accommodated Fractions (WAFs) under static conditions for 96 hours.
The loading rates were 0, 8.1, 27, 90, 300 or 1000 mg/L. The effect observed was stimulatory instead of inhibitory
and no EC50 or NOEL could be determined. Incubation for 72 hours stimulated growth by 35.1, 44.1 and 20.2%
(64.5, 57.8 and 38.2% at 96 hours), corresponding to 8.1, 90 and 300 mg/L respectively.
96-h EC50 = Not determined
Conclusion: The evaluation of available toxicity data fish, aquatic invertebrates and aquatic plants indicate that the
potential hazard of the category members to aquatic organisms is low.
Table 2. Siiinni;ir\ nl' l".m inuinu-nlal KITi-ils - A(|ii;ilk Tii\kil> l);il;i
Endpoints
Butanedioic acid, sulfo-1,4-
bis(2-ethylhexyl) ester,
sodium salt
(577-11-7)
Butanedioic acid, sulfo-1,4-
bis(l,3-dimethylbutyl) ester,
sodium salt
(2373-38-8)
Butanedioic acid, sulfo-1,4-
dicyclohexyl ester,
sodium salt
(23386-52-9)
Fish
96-h LCS0 (mg/L)
28 (m)
37 (m)
>1000(m)
1200 (m)
470 (m)
Invertebrate
48-h ECS0 (mg/L)
36.2 (m)
No Data
36.2
(RA)
457 (m)
Alga
72-h ECS0 (mg/L)
No Data
No Data
Growth stimulated (96-h) (m)
No EC50 determined
(m) = measured data (i.e., derived from testing); (e) = estimated data (i.e., derived from modeling); (RA) = Read
Across
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.
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Acute Oral Toxicity
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
(1) Rat. In three separate studies, deaths occurred within 24 hours in at high doses. Signs of depression of varying
intensity,diarrhea, lethrgy, and/or prostration were noted. Yellow fluid was noted in the gastriointestinal tract of
those found dead. No visible lesions were seen in the surviving animals at terminal necropsy.
LDS0 = 200 - 4200 mg/kg-bw
(2) Mouse. In two separate studies, clinical signs of toxicity were depression, diarrhea, irritation and hemorrhage of
the gastrointestinal tract, distended intestine, lethargy, prostration or hypoactivity.
LDS0 = 2643 - 4800 mg/kg-bw
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (CAS No. 2373-38-8)
Rat. All animals treated at 2500 mg/kg-bw died. Severe depression and severe diarrhea was seen in animals that
died. Moderate to severe irritation with hemorrhage of the gastrointestinal tract was seen during necropsy. The
survivors at lower doses were depressed for 24-48 hours. Necropsy of survivors revealed distension of the
intestines.
LDS0 = 1750 mg/kg-bw
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
Rat. All animals treated at 5000 and 10,000 mg/kg-bw died. Signs of toxicity included diarrhea, lethargy,
prostration and coma. None of the animals given 1.25 or 2.5 mg/kg-bw died or appeared intoxicated.
LDS0 = 3540 mg/kg-bw
Acute Dermal Toxicity
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
Rabbit. Clinical signs of toxicity included severe erythema, edema, necrosis of the skin, depression, hind-leg
weakness, irritation, desquamation, Assuring or coriaceousness (coarse skin).
LDS0 > 10,000 mg/kg-bw
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (CAS No. 2373-38-8)
Rabbit. Clinical signs of toxicity included severe erythema, edema, necrosis of the skin, depression, hind-leg
weakness, irritation, desquamation, Assuring or coriaceousness.
LDS0 = 4000 mg/kg-bw
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
Rabbit. One out of 10 rabbits died. Clinical signs of toxicity included hind leg weakness, skin irritation, severe
erythema and severe edema. Gross necropsies of all survivors were normal.
LDS0 > 5000 mg/kg-bw
Repeated-Dose Toxicity
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
(1) Groups of five male Osborne-Mendel rats/dose were administered butanedioic acid, sulfo-l,4-bis(2-ethylhexyl)
ester, sodium salt in the diet at concentrations of 0, 2, 4 and 8% (corresponding to 0 and approximately 1000, 2000
and 4000 mg/kg-bw/day, respectively) for 16 weeks. Animals receiving 8% had severe gastrointestinal symptoms
and died within the first week of treatment. Only one animal at 4% survived for the duration of the study. Rats
receiving 2% gained less weight than controls and had evidence of gastrointestinal irritation upon necropsy.
LOAEL ~ 1000 mg/kg-bw/day (based on low weight gain and gastrointestinal irritation)
NOAEL = Not established
(2) Groups of male and female rats (strain not given) were administered butanedioic acid, sulfo-l,4-bis(2-
ethylhexyl) ester, sodium salt in the diet at concentrations of 0, 0.5, 1.0 and 1.5% (corresponding to 0 and
approximately 250, 500 and 750 mg/kg-bw/day, respectively) for 26 weeks. Females receiving 1.0 and 1.5% had
8
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reduced weight gain during the third week. Two control animals and four test animals (sex not specified) given
1.5% died. Two out of the four treated dead animals had hemorrhagic gastroenteritis. No other effects on body
weights, food consumption, clinical chemistry or histopathology were observed.
LOAEL ~ 500 mg/kg-bw/day (based on low weight gain and hemorrhagic gastroenteritis)
NOAEL ~ 250 mg/kg-bw/day
(3) Beagle dogs (4/sex/dose) were administered butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt via
oral tablet at 0 or 30 mg/kg-bw once a day, 7 days/week for 1 year. No adverse treatment-related effects on body
weights, food consumption, clinical chemistry, hematology and urinalysis parameters or histopathology were
observed. No evidence of gastric irritation was noted.
LOAEL > 30 mg/kg-bw/day
NOAEL = 30 mg/kg-bw/day (based on no treatment related effects at the highest dose tested)
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (CAS No. 2373-38-8)
(1) Male albino rats (10/concentration) were administered butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester,
sodium salt in the diet at concentrations of 0, 0.125, 0.25 and 0.5% (corresponding to 0, 130, 250 and 510 mg/kg-
bw/day, respectively) for 32 days. No clinical signs of toxicity were evident in treated animals over the study
period. No mortality was noted. Mean daily food intake of animals receiving 0.125 % (18.8 g) was markedly lower
than control (19.6 g). Mean weight gain of this group (165 g) also was significantly different (statistics not
provided) from control (177 g). There was no difference in food consumption or body weight gain of the other two
groups with respect to control. Histopathology did not reveal any treatment-related findings.
LOAEL > 510 mg/kg-bw/day
NOAEL = 510 mg/kg-bw/day (based on no effects at the highest dose tested)
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
(1) Wistar rats (10/sex in the control group and 5/sex in the treated groups) were administered butanedioic acid,
sulfo-l,4-dicyclohexyl ester, sodium salt in the diet at concentrations of 0, 0.25, 0.5 and 1% (corresponding to 0,
240, 470 and 960 mg/kg-bw/day, respectively) for 32 days. No mortality or clinical sign of toxicity were noted. No
adverse treatment related effects on body weights, food consumption or gross pathology were observed.
LOAEL > 960 mg/kg-bw/day
NOAEL = 960 mg/kg-bw/day (based on no effects at the highest dose tested)
Reproductive Toxicity
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
In a three-generation reproductive toxicity study, male and female Crl:CD(SD)BR rats were administered
butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt in the diet at concentrations of 0, 0.1, 0.5 and 1%
concentrations (corresponding to approximately 0, 100, 500 and 1000 mg/kg-bw/day, respectively) during
premating, mating (males and females) and during gestation for three generations (F0, Fl, F2) until weaning of the
third generation (F3). Food consumption of F0, Fl and F2 males treated with 1.0% ethylhexyl ester was markedly
less than controls during week 4; weeks 2, 4, 8 and 10; and weeks 2 and 10, respectively. Body weights of Fl males
and females treated with 1.0% were markedly lower than controls, and final weights of Fl and F2 males and females
treated with 1.0% andF2 males treated with 0.5% were lower than their respective controls. Mean birth weight of
male and female pups born to animals treated with 1.0% was markedly lower than control. All three generations of
male and female pups born to animals treated with 0.5 or 1.0% weighed less than controls on day 21. No milk was
found in the abdomens on lactation day 4 in 3 control F2 pups, 7 F2 pups in the 0.1% dose group, 18 F2 pups and 1
F3 pup in the 0.5% dose group, and 10 F2 pups and 17 F3 pups in the 1.0% dose groups. There were no treatment-
related effects on the total number of pups or litters, litter size or sex ratio. Perinatal pup survival across the three
generations was 99% for controls. There were no treatment-related mortality or microscopic observations in any
animals examined (F0, Fl and F2 adults and F3 weanlings).
LOAEL (systemic toxicity) ~ 500 mg/kg-bw/day (based on effect on food consumption and body weights)
NOAEL (systemic toxicity ~ 100 mg/kg-bw/day
LOAEL (reproductive toxicity) ~ 500 mg/kg-bw/day (based on decreased fetal body weight, effect on lactation)
NOAEL (reproductive toxicity) ~ 100 mg/kg-bw/day
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Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (CAS No. 2373-38-8)
and
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
No reproductive toxicity data were submitted for these category members. However, information for the alcohol
metabolites of these category members (MIBC and cyclohexanol) have similar profiles in that MIBK and HMP
(metabolites of MIBC) and cyclohexanol showed reproductive toxicity at high doses. Available data for the
ethylhexyl ester category member address this endpoint for these two category members using read across.
Developmental Toxicity
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
(1) Female Sprague-Dawley rats were administered butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt
in the diet at concentrations of 0, 1 and 2% (corresponding to approximately 0, 500 and 1000 mg/kg-bw/day,
respectively) on days 6 - 15 of gestation. At a 2% dietary intake, reduced weight gain in dams, marked increase in
fetal resorptions and a large percentage of externally malformed fetuses were observed. The abnormalities consisted
primarily of exencephaly, which was frequently associated with spina bifida and microphthalmia. There was also
incomplete ossification of various cranial bones and curved or open vertebral columns.
LOAEL (maternal toxicity) ~ 1000 mg/kg-bw/day (based on reduced weight gain in dams)
NOAEL (maternal toxicity) ~ 500 mg/kg-bw/day
LOAEL (developmental toxicity) ~ 1000 mg/kg-bw/day (based on significant increase in fetal resorptions and a
significant percentage of externally malformed fetuses)
NOAEL (developmental toxicity) ~ 500 mg/kg-bw/day
(2) Female Sprague-Dawley rats were administered butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt
in the diet at concentrations of 0 or 2% (approximately 0 or 1000 mg/kg-bw/day) on days 6 - 16 of gestation. At the
only dose tested, there was a significant decrease in maternal body weight, food consumption and body weight gain.
Fetuses had decreased weight, decreased crown-rump length and increased skeletal anomalies (primarily unossified
sternebra).
LOAEL (maternal toxicity) ~ 1000 mg/kg-bw/day (based on decreases in body weight, food intake and body
weight gain; only dose tested)
NOAEL = Not established
LOAEL (developmental toxicity) ~ 1000 mg/kg-bw/day (based on decreases in fetal body weights and crown-
rump length and increases in skeletal anomalies [unossified sternebra])
NOAEL = Not established
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (CASNo. 2373-38-8)
and
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
No developmental toxicity data were submitted for these category members. However, information for the alcohol
metabolites of these category members (MIBC and cyclohexanol) have similar profiles in that MIBK (a metabolite
of MIBC) and cyclohexanol showed developmental toxicity at high doses. Available data for the ethylhexyl ester
category member address this endpoint for these two category members using read across.
Genetic Toxicity - Gene Mutation
In vitro
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
Mutagenicity potential of butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt was evaluated in Ames
assays using strains of Salmonella typhimurium strains TA98, TA100, TA102, TA1535, TA1537 and TA1538 in the
presence and absence of metabolic activation up to 2,500 ng/plate of test substance. Cytotoxicity was observed at
500, 1000 and 2500 |ig/plate. No increases in mutation frequency were reported at any concentration tested with or
without metabolic activation.
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Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt was not mutagenic in these assays.
Genetic Toxicity - Chromosomal Aberrations
In vitro
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt (CASNo. 577-11-7)
Chinese hamster ovary cells were exposed to the test substance at concentrations ranging from 9.3 - 470 ng/mL
with and without metabolic activation. Appropriate responses were seen for negative and positive controls. The test
substance did not induce chromosome aberrations in cells exposed without metabolic activation. The test substance
was clastogenic at cytotoxic concentrations, but not at non-cytotoxic concentrations.
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt did not induce chromosomal aberrations in
this assay.
Butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt (CASNo. 2373-38-8)
and
Butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt (CAS No. 23386-52-9)
No genetic toxicity data were submitted for these category members. However, information for the alcohol
metabolites of two category members (MIBC and cyclohexanol) support the read across in that all available data
show negative results for gene mutations and chromosomal aberrations (except for one positive in vitro result with
cycohexanol; which showed negative in vivo results in a micronucleus assay in mice). Available data for the
ethylhexyl ester category member address the endpoint using read across.
Conclusion: The acute oral toxicity for the members of this category is low. Repeated exposures to all category
members via the oral route indicate toxicity to rats based on decreased weight gain and gastrointestinal irritation.
Reproduction and developmental studies with butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt at high
doses indicate decreases in parental and fetal body weights. Developmental effects observed were increases in fetal
resorptions and a higher percentage of externally malformed fetuses. Data on cyclohexanol, a metabolite of
butanedioic acid, sulfo-l,4-dicyclohexyl ester, sodium salt, and MIBK (a metabolite of MIBC, which is a metabolite
of butanedioic acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt) also show developmental and reproductive
effects. The category member, butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt did not show
mutagenic potential when tested in vitro nor did it induce chromosomal aberrations in vitro. In addition,
information for the alcohol metabolites of two category members (MIBC and cyclohexanol) support the read across
in that all available data show negative results for gene mutations and chromosomal aberrations (except for one
positive in vitro result with cycohexanol; which showed negative in vivo results in a micronucleus assay in mice).
The potential health hazard of the sulfosuccinates category is moderate based on reproductive and developmental
toxicity.
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Tabic 3. Summary of Human Health Data
Endpoints
Butancdioic acid, sultb-1,4-
bis(2-ethylhexvl) ester,
sodium salt
(577-11-7)
Butancdioic acid, sulfo-1,4-
bis(l,3-dimethylbutvl)
ester, sodium salt
(2373-38-8)
Butancdioic acid, sulfo-1,4-
dicvclohcxvl ester, sodium salt
(23386-52-9)
Acute Oral Toxicity
LDS0 (mg/kg-bw)
2000-4200 (rat)
2600 - 4800 (mouse)
1750
3540
Acute Dermal Toxicity
LDS0 (mg/kg-bw)
> 10,000
4000
>5000
Repeated-Dose Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
(rat)
NOAEL = Not established
(16-wk)
LOAEL ~ 1000 (rat, 16-wk)
NOAEL-250 (26-wk)
LOAEL-500 (26-wk)
(dog)
NOAEL = 30 (1-year)
LOAEL >30 (1-year)
(rat)
NOAEL = 510 (32-d)
LOAEL > 510 (32-d)
(rat)
NOAEL = 960 (32-d)
LOAEL > 960 (32-d)
Reproductive Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
Systemic Toxicity
Reproductive Toxicity
NOAEL-100
LOAEL-500
NOAEL-100
LOAEL-500
(RA)
No Data
NOAEL ~ 100
LOAEL ~ 500
NOAEL -100
LOAEL ~ 500
(RA)
No Data
NOAEL-100
LOAEL ~ 500
NOAEL-100
LOAEL - 500
(RA)
Developmental Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
Maternal Toxicity
Developmental Toxicity
NOAEL-500
LOAEL-1000
NOAEL-500
LOAEL-1000
No Data
NOAEL -500
LOAEL ~ 1000
NOAEL ~ 500
LOAEL ~ 1000
(RA)
No Data
NOAEL - 500
LOAEL - 1000
NOAEL - 500
LOAEL - 1000
(RA)
Genetic Toxicity - Gene
Mutation
In vitro
Negative
No Data
Negative
(RA)
No Data
Negative
(RA)
Genetic Toxicity -
Chromosomal Aberrations
In vitro
Negative
No Data
Negative
(RA)
No Data
Negative
(RA)
Measured data in bold text; (RA) = Read Across
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4. Hazard Characterization
The log Kow values of the category members indicate their potential to bioaccumulate is expected to be low.
Butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt, is readily biodegradable, indicating that it is not
expected to persist in the environment. The remaining two category members are not readily biodegradable,
indicating that they have the potential to persist in the environment.
The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants indicate that the potential
acute hazard of the category members to aquatic organisms is low.
The acute oral toxicity for the members of this category is low. Repeated exposures to all category members via the
oral route indicate toxicity to rats based on decreased weight gain and gastrointestinal irritation. Reproduction and
developmental studies with butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt at high doses indicate
decreases in parental and fetal body weights. Developmental effects observed were increases in fetal resorptions
and a higher percentage of externally malformed fetuses. Data on cyclohexanol, a metabolite of butanedioic acid,
sulfo-l,4-dicyclohexyl ester, sodium salt, and MIBK (a metabolite of MIBC, which is a metabolite of butanedioic
acid, sulfo-l,4-bis(l,3-dimethylbutyl) ester, sodium salt) also show developmental and reproductive effects. The
category member, butanedioic acid, sulfo-l,4-bis(2-ethylhexyl) ester, sodium salt did not show mutagenic potential
when tested in vitro nor did it induce chromosomal aberrations in vitro. In addition, information for the alcohol
metabolites of two category members (MIBC and cyclohexanol) support the read across in that all available data
show negative results for gene mutations and chromosomal aberrations (except for one positive in vitro result with
cycohexanol; which showed negative in vivo results in a micronucleus assay in mice).
The potential health hazard of the sulfosuccinates category is moderate based on reproductive and developmental
toxicity.
5. Data Gaps
No data gaps were identified under the HPV Challenge Program.
13
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APPENDIX
Sulfosuccinatcs Category
CAS No.
Chemical
Structure
SPONSORED CHEMICALS
577-11-7
Butanedioic acid, sulfo-l,4-bis(2-
ethylhexyl) ester, sodium salt
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dimethylbutyl) ester, sodium salt
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Butanedioic acid, sulfo-1,4-
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14
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