Report of the Second Meeting of the
Peer Consultation Pilot for HPV and EHPV Submissions
Meeting Held at:
U.S. EPA, Washington, DC
December 15-16, 2008
Peer Consultation Organized by:
Toxicology Excellence for Risk Assessment
(http://www.tera.org/peer/)
March 4, 2009
Table of Contents
Table of Contents ............................................................................................................................ 1
Introduction ..................................................................................................................................... 2
Panel Discussions of Submissions .................................................................................................. 4
1,4-Cyclohexanedicarboylic acid (CHDA) (CAS No. 1076-97-7) ............................................. 4
Trifluoromethane (CAS No. 75-46-7) ........................................................................................ 5
Residual oils (petroleum), oxidized (CAS No. 64742-99-0) ...................................................... 7
C4-6 Isopentene Rich-Ether Fraction (IRF) Stream (CAS No. 108083-43-8) ......................... 10
C3-5 Butene-Isobutylene-Rich-Ether (BIR) Stream (CAS No. 102479-87-8) ......................... 13
1,3-Propanediol (CAS No. 504-63-2) ....................................................................................... 14
Quarternary TEA esters, C16-18 & C18 unsaturated methosulfate (CAS No. 157905-74-3) . 15
Fatty Acids, Coco, 2-Sulfoethyl Esters, Sodium Salts (Sodium Cocoyl Isethionate or SCI)
(CAS No. 61789-32-0).............................................................................................................. 16
Ethanesulfonic Acid, 2-Hydroxy-, Monosodium Salt (Sodium Isethionate or SI) (CAS No.
1562-00-1)................................................................................................................................. 20
p-Toluenesulfonic Acid (CAS No. 104-15-4) .......................................................................... 22
Revisit of November 2008 Meeting Submissions .................................................................... 23
Benzenamine, N-phenyl-, (tripropenyl) derivatives (CAS No. 68608-79-7) ....................... 23
Dithiophosphate Alkyl Ester Category ................................................................................. 23
Heptanoic Acid, mixed esters with pentaerythritol (CAS No. 68441-94-1)......................... 24
Octanoic Acid, 1.1'-(2,2-dimethyl-1,3-propanediyl) ester (CAS No. 31335-74-7) ............ 24
Soybean oil, sulfurized (CAS No. 68152-90-9).................................................................... 25
Appendix A ?List of Attendees ................................................................................................... 27
Appendix B ?Meeting Agenda ...................................................................................................... 1
Appendix C ?Pre-meeting Comments of Panel Members ............................................................. 4
Dr. Chad Sandusky, PCRM ........................................................................................................ 5
Environmental Protection Agency ............................................................................................ 10
Dr. Hazel (Skip) Matthews ....................................................................................................... 17
Appendix D ?Additional Materials Provided to the Sponsors..................................................... 21
Peer Consultation Meeting Report 1
HPV Pilot
Introduction
On December 15 and 16, 2008 a panel of experts scientists met in a pilot public peer consultation
meeting to provide stakeholder comments on High Production Volume (HPV) and Extended
HPV (EHPV) submissions. The meeting was held at the U.S. Environmental Protection Agency
(EPA) headquarters in Washington, DC. Industry representatives were present in person or by
teleconference to answer the panelists' questions. This report summarizes the key scientific
questions and comments of the panel on ten submissions.
Approximately 40 chemicals have been selected by the American Chemistry Council (ACC) and
EPA to undergo review in this pilot project. The submissions, including robust study summaries
of available data and test plans describing available data and proposing additional studies as
necessary, are being reviewed by the panel members at two 2-day in-person meetings being held
before the end of 2008. The first meeting was held November 18-19, 2008 and this is the report
of the second meeting.
The HPV peer consultation pilot project was designed to provide expert review of HPV chemical
hazard robust study summaries and test plans prepared by industry sponsors under the HPV and
EHPV Programs. Under these programs, companies and consortia voluntarily sponsor chemicals
that are manufactured and/or imported in the U.S. in quantities of 1 million pounds or more
annually. Sponsorship in the original HPV Challenge Program involved providing the EPA with
a test plan and robust study summary, which was then posted on EPA's public website for 120
days, during which time interested stakeholders and EPA could post comments regarding the
content of the test plans and robust study summaries. The industry sponsor was then free to
incorporate or offer further explanation regarding the comments made. If the sponsor did not
agree with comments made, the sponsor prepared and provided a rationale for the rejection. The
American Chemistry Council (ACC), in cooperation with the broader chemical industry, the
EPA, and the Physician's Committee for Responsible Medicine (PCRM), launched the HPV Peer
Consultation Pilot in the fall of 2008.
The purpose of the pilot is to test a new approach to provide stakeholder and EPA input on the
robust study summaries (RSS) and test plans (TP); especially for the EHPV Program. The pilot
will use in-person meetings of a small panel of stakeholder and expert scientists. Panel meetings
will be used to facilitate exchange of expert opinions on the technical soundness of the RSS/TPs
to better inform the ultimate stakeholder comments on the RSS/TPs, as well as ensure
completeness of comments for sponsor consideration. The goal of a revised program is to
expedite the review process for both EPA and stakeholder comments and present opportunities
for the different parties to discuss scientific and technical comments with one another.
Toxicology Excellence for Risk Assessment (TERA), an independent, non-profit scientific
organization, designed the pilot process and convened and facilitated the technical peer
consultation panel meeting. The chemical industry is providing the funding to TERA for this
project. Additional details about the pilot program are available at
http://www.tera.org/peer/hpv/hpvwelcome.htm.
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HPV Pilot
The panel members included expert scientists from two organizations who provided comments
on test plans submitted under the HPV Challenge program (i.e., PCRM and EPA). Panel
members included: from EPA - Dr. Louis (Gino) Scarano (human health endpoints) and Mr.
Larry Newsome (ecological/environmental endpoints) of the Office of Pollution Prevention and
Toxics; from PCRM - Dr. Chad Sandusky; and Dr. Hazel (Skip) Matthews, who authored many
of the comments submitted by Environmental Defense Fund on the original HPV Challenge
submissions. A senior scientist from TERA (Dr. Michael L. Dourson) facilitated the panel
meetings to ensure that all appropriate scientific issues were addressed. Also in attendance at the
meeting was Dr. Nancy Beck of PCRM who assisted Dr. Sandusky, and on occasion provided
clarifying information on behalf of PCRM. Dr. Andrew Maier of TERA took notes and drafted
the meeting report.
A representative of the company or industry consortia that sponsored the submission was also
present in person or on the phone to answer the panel members' questions. These representatives
were also allowed to ask clarifying questions of the panel so that they could ensure their
understanding of the panelist comments.
The meeting was open to the public and interested persons were allowed to attend in person or
by teleconference. Interested persons were invited to submit technical comments prior to the
meeting for panel members' consideration; however, no public comments were received. A
complete listing of attendees is found in Appendix A.
The meeting agenda is found in Appendix B. The meeting began with a welcome by Dr.
Andrew Maier of TERA. He described the background and purpose of the peer consultation
pilot and the panel members introduced themselves briefly. Dr. Michael Dourson, the panel
facilitator, then described how the meeting would be conducted and the ground rules. He noted
that all panelists would have the opportunity to state their positions on the charge items, to ask
one another clarifying questions, and to discuss the issues further. Because this was a peer
consultation, no formal attempt would be made to reach panel consensus positions on the charge
items. For each submission, the panel members were asked to share their comments and discuss
the charge questions:
?Does the information1 provided address the SIDS endpoints?
?If a category is presented, is the rationale for the category reasonably appropriate, and
is the use of read-across scientifically defensible?
Industry sponsor representatives were asked to address the panel questions to the best of their
ability, recognizing that the sponsor representative may not be able to provide an immediate
answer to all questions. Sponsors were also permitted to ask the panel members clarifying
questions to ensure their understanding of panel member comments. Observers were provided
the opportunity to register to make brief technical comments (none did so). Dr. Dourson also
noted that panel members were free to contact sponsors prior to the meeting to obtain further
information or insight that could assist them in developing their opinions. The sponsors
however, were asked not to initiate contact with the panel members regarding the submissions.
1
Note that exposure and use information that is part of the HPV or EHPV submissions was not subject to review in
this Pilot; however, panelists could use this information to help inform their opinions regarding the screening-level
hazard needs.
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HPV Pilot
Panel Discussions of Submissions
The summary below is intended to provide a synopsis of the key discussions and
recommendations resulting from the peer consultation. Each panel member also submitted
additional detailed comments related to the submissions that were discussed. These individual
comments are found in Appendix C of this summary report.
1,4-Cyclohexanedicarboylic acid (CHDA) (CAS No. 1076-97-7)
Sponsor: Eastman Chemical Company
EHPV Submission
(http://www.regulations.gov/fdmspublic/component/main?main=DocketDetail&d=EPA-HQ-
OPPT-2006-1020)
The sponsor began the discussion with an introduction to the submission.
Discussion on Physical and Chemical Property Endpoints
?The panelists made several comments related to physical and chemical property
endpoints. One panelist commented that the melting point and boiling point are helpful
in evaluating other endpoints, and thus, empirical data for these end points are very
desirable. This panelist suggested that the sponsors verify that such data are not available
and recommended searching for the data from material safety data sheet (MSDS)
databases, which often contain such basic information. In response to a sponsor
clarification regarding the acceptability of model estimates for such endpoints, the
panelist indicated that the current TP approach would not be adequate for boiling point
and vapor pressure. Another panelist commented on the presentation of some endpoints.
This panelist noted that the RSS can be viewed more easily in HPVIS
(www.epa.gov/hpvis) using the standard report query. The panelist indicated that the
partition coefficient description was a little unclear. The RSS indicated that this endpoint
was estimated, but it appeared that an experiment was conducted. Also the reason for a
range of values to be presented was unclear. Presumably this was because of the
properties of the isomers. Based on clarifications from the sponsor the panelist indicated
that the entries were sufficient.
Discussion of Environmental Fate Endpoints
?The panelists agreed with the test plan recommendations regarding the environmental
fate endpoints.
Discussion of Ecotoxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the ecotoxicity
endpoints.
Discussion of Mammalian Toxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the mammalian
toxicity endpoints. The panelists commented on the use of data for dimethyl-1,4-
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cyclohexanedicarboxylate (DMCD) for read-across and in particular the documentation
of its metabolism to CHDA and methanol. One panel member commented that between
the available data for the two chemicals, DMCD and CHDA, it appeared that all the
endpoints were adequately covered. The panel member thought that it is highly likely
that DMCD would be hydrolyzed to CHDA by esterases. This has been confirmed in
studies of similar compounds, but not DMCD. The panel member expressed reservation
regarding the use of DMCD data for read-across until DMCD metabolism to CMCD has
been confirmed. Another panel member added that the Heck and Tyl (1985) abstract did
not seem to inform the metabolism issue and the Barber et al. (1994) article which
showed that alcohol formation from diethylhexyl terephthalate and diethylhexyl phthalate
hydrolysis was quite different and does not clarify which metabolic path DMCD would
follow. A panelist commented that there would likely be differences in the toxicity of the
two chemicals because of the ester versus acid moiety, but if anything, the ester (DMCD)
being used for read-across would be more toxic, since it would be more likely to be
absorbed. This panelist also noted that metabolism of DMCD would generate methanol,
and thus, the sponsor might consider adding toxicity data on methanol to the TP.
However, the panel discussed that the effect of methanol seen in the animal toxicology
data would only be a high dose acute affect that would not be relevant for an assessment
at environmentally-relevant doses. Based on this consideration the panel members did
not feel methanol data should be added. The panel members all agreed that there were no
data gaps related to the mammalian toxicity endpoints, but recommended that the
sponsors provide additional data on metabolism of DMCD, if available, and requested
development of the data if it is not available.
Discussion of Other Considerations
?Several panel members commented on issues related to the potential for releases into the
environment. One panel member commented that it appears that there is minimal
potential for environmental release. A panelist asked whether the sponsor had claimed
the material as a closed system intermediate (CSI). The sponsor clarified that they are the
only company that manufactures the material and that a specific technical definition had
not been claimed regarding CSI status, although the material is handled in closed
systems. A second panelist asked whether there was potential for releases in wastewater.
The sponsor responded that the product is sold to make polymers so there may be some
release from customers' sites, but likely in only very small amounts. They also noted that
wastewater containing CHDA is a very small fraction of the wastewater going through
their secondary biological treatment plant. The sponsor was also asked to clarify the
statement in the exposure summary regarding FDA approval and whether this was based
on assessment of potential migration from food packaging materials and how it relates to
the claim that the material in not found in consumer products. The sponsor noted that the
polymer was approved based on evaluation of extraction and exposure potential.
Trifluoromethane (CAS No. 75-46-7)
Sponsor: E. I. du Pont de Nemours & Company, Inc.
Original HPV Submission (www.epa.gov/hpvis)
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In opening comments regarding this submission the sponsor summarized that the material is very
stable, is used in refrigeration and etching, and fire suppression in confined spaces. The material
has a low order of toxicity. The high volatility and low solubility of the material make water
solubility testing difficult. Overall the sponsor felt that data requirements for each of the SIDS
endpoints had been covered. Prior to the discussion of this chemical Panelist Sandusky disclosed
he had a prior meeting with the sponsor and that PCRM had submitted previously written
comments supporting this test plan.
Discussion on Physical and Chemical Property Endpoints
?The panelists agreed with the test plan recommendations regarding the physical and
chemical property endpoints.
Discussion of Environmental Fate Endpoints
?The panelists agreed with the test plan recommendations regarding the environmental
fate endpoints.
Discussion of Ecotoxicity Endpoints
?Table 2 in the Robust Study Summary summarized the ecotoxicity data. The meeting
facilitator noted that the table is unclear as to which endpoints have measured data or
estimated data for data from surrogates. The sponsor clarified that algal toxicity is the
only endpoint without measured data. A second panelist indicated that in absence of
measured data for the algal toxicity endpoint the sponsors needs to provide data from a
surrogate chemical to support the QSAR estimate, since confidence in the prediction for
this compound is marginal. The sponsor noted that for the analog HFC-134a there are
data for the fish and daphnia toxicity endpoints. The sponsor also mentioned that there
were algal toxicity data for HCFC-123, which would likely represent a worst case
surrogate for HFC-23. No measured data are available for the test material itself and
collecting such data is difficult due to its volatility. A panel member suggested that the
sponsor's surrogate chemical is the worst case. The TP should note this. Other panel
members had no additional comments.
Discussion of Mammalian Toxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the mammalian
toxicity endpoints. The panel members agreed with the submission that there were no
outstanding data gaps. One panelist commented that bridging from histopathology data
in repeat-dose studies is sufficient to fill the data requirements for reproductive toxicity.
A second panelist agreed that the material is fairly inert, but recommended that the
sponsor provide some information in the TP on the possibility for suffocation from use in
fire extinguishing applications. The sponsor indicated that this is not likely to be a
significant issue because in such applications there is a pre-discharge alarm and 5-minute
period before release of the material into the space. Moreover, the design requirements
are such that the material reaches a concentration to serve in fire protection, but not to
such a degree that there would be a risk of oxygen deprivation. However, since release in
a confined space is a possible scenario, the comment is appropriate and this information
can be made clear in the TP as well as the MSDS.
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HPV Pilot
Discussion of Other Considerations
?A panelist commented that according to the test plan the chemical is being phased out
and on this basis it is not a good candidate for additional testing. Given this production
status another panel member asked about the potential for exposures related to
transportation and disposal. The sponsor indicated that the material is transported
(mostly in 100 pound cylinders) as compressed gas/liquid and also stored in this form.
Excess material is destroyed by incineration.
Residual oils (petroleum), oxidized (CAS No. 64742-99-0)
Sponsor: Lubrizol Corporation
EHPV Submission
(http://www.regulations.gov/fdmspublic/component/main?main=DocketDetail&d=EPA-HQ-
OPPT-2006-1020)
The sponsor introduced the submission indicating that the current test material is similar to the
Petroleum Oxidates and Derivatives thereof Category and this EHPV submission fits in nicely
with previous category submission.
Discussion of Category
?All the panelists agreed that it is appropriate to include this new petroleum oxidate
substance into the existing category Petroleum Oxidates and Derivatives thereof).
Discussion on Physical and Chemical Property Endpoints
?The panelists agreed with the test plan recommendations regarding the physical and
chemical property endpoints.
Discussion of Environmental Fate Endpoints
?The panelists agreed with the test plan recommendations regarding the environmental
fate endpoints. The panel members agreed with the need to conduct a biodegradation
study.
Discussion of Ecotoxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the proposed testing
for the ecotoxicity endpoints, but also discussed viability of using a read-across approach
as an alternative. One panelist noted that test data are available for some endpoints for a
potential surrogate (CAS No. 64742-98-9). Another panelist asked whether a rationale
could be developed for using testing data for other category members CAS No. 64742-
98-9 (a subcategory 1 chemical) and CAS No. 68603-11-2 (a subcategory 2 chemical). If
in every case the aquatic toxicity is greater for subcategory 1 is there any reason to
assume worst case and use the subcategory 1 chemical for read-across? This panelist also
asked if it is possible to have any low molecular weight components in the test material
that might help to identify additional surrogates. Such data would provide a worst-case
read-across approach if the sponsor did not want to propose testing. The sponsor
clarified that there are probably some smaller molecular weight chemical species present.
If read-across were to be used the aquatic toxicity of the test material is more likely to
Peer Consultation Meeting Report 7
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resemble that of CAS No. 68603-11-2, than the other options. However, the sponsor
indicated that they were not proposing the read-across approach because the physical and
chemical properties for those compounds in the category that do have ecotoxicity
endpoint data are very different (e.g., the water solubility is very different) and these
potential surrogates would not provide an adequate representation for the test material.
Another panelist added that they supported the idea of using read-across, although it is
understandable that the sponsor might not want to read-across from the most water
soluble materials. This panelist also noted that a data gap for chronic reproduction in
daphnia would remain and so testing for that endpoint would still be recommended. This
panelist further indicated that since the test plan material is very lipophilic, if the sponsor
pursues additional testing they would need to follow the guidance for difficult to test
materials. Several suggestions regarding the testing strategy were provided. The panelist
recommended conducting range finding study up to the water solubility limit to
determine where to start testing, rather than relying on loading rates. The panelist also
suggested that a tiered testing approach be employed. Such an approach would rely on an
acute fish test using a suitable carrier (not a surfactant) if needed to get the material into
solution to a concentration of up to 100 mg/L. If no effects were observed in this acute
fish test to the water solubility limit then the panelist suggested not doing the algal and
invertebrate acute studies, rather go straight to a chronic daphnid (21-day) test. This
panel member also noted that the sponsors could contact the EPA if they would like
additional review of testing protocols.
Discussion of Mammalian Toxicity Endpoints
?Although the panelists agreed with the test plan recommendations regarding the
mammalian toxicity endpoints, they discussed the value of the proposed combined
repeated-dose and reproductive/developmental toxicity screening test. One panel
member questioned the proposed use of dermal administration as the dose route for this
study. Based on a clarification that the sponsors had not done any testing to evaluate
potential dose ranges, the panelist was concerned that unless a material is toxic and is
well-absorbed then such studies will not provide a robust quantitative estimate of the
effect level. Such studies are technically difficult due to run-off of the applied liquid if a
large surface area is required to apply an effective dose. This panelist suggested under
such circumstances the typical endpoint testing recommendations may not apply if it is
not practical to get reasonable data out of the traditional methods of testing. The sponsor
agreed with these comments on the difficulties in conducting such dermal studies.
However, an alternative approach using oral dosing would present other issues because
the oral route does not match the typical human exposure route (which might be raised by
others in the risk assessment context) and when dosing orally, secondary effects due to
gasto-intestinal tract irritation, and laxative effects hamper the interpretation of such
studies. Two panel members agreed with this concern and did not support substituting an
oral study for the proposed dermal study.
A second panelist suggested that the sponsor consider evaluating dermal absorption using
an in vitro test system or modeling approach. If there is little or no absorption then the
proposed in vivo toxicity study would not be useful. This panel member added that for
another HPV test plan (commercial hydroxyl ethyl piperizine) EPA found it acceptable to
Peer Consultation Meeting Report 8
HPV Pilot
model dermal absorption and based on evidence for the lack of absorption EPA supported
the decision not to do required testing. The panelist provided a copy of a poster
presentation on the application of this approach (see Appendix D). Another panel
member asked if there was a specific cut point for absorption that would support the
conclusion that testing would not be needed. A panel member clarified that the prior
submission noted as an example of such an approach found essentially no absorption.
The panel members were not aware of guidance on this specific point, rather the
determination would depend on the degree of absorption and whether sufficient
absorption could occur to have a reasonable possibility to identify toxicity from an in
vivo study. The panelist also suggested that the sponsor review the materials from
workshop proceedings by the Institute of In Vitro Sciences, which provided technical
guidance on the issue of conducting in vitro studies (Raabe et al., 2005) and also noted
that there is an OECD protocol for dermal absorption that could be considered. The
sponsor noted that a modeling approach may be difficult since the test material is a
complex mixture, but perhaps an in vitro test system could be used. The panel members
agreed that given the discussion on the dermal exposure issue the approach to evaluate
skin absorption is reasonable. One panel member indicated that they would also review
the prior EPA comments on applications of this approach.
While the panel members considered the approach based on evaluating dermal absorption
as reasonable, the panel also noted the availability of a repeat-dose oral study for one of
the category chemicals (CAS No. 64742-98-9) which identified a NOAEL at the limit
does of 1000 mg/kg-day. The sponsor further noted that this is a lower MW component
and might represent a worst-case scenario. A panel member agreed that these data might
be used for read-across, but that this particular material is the only member of
subcategory 1 in the broader category and thus might be somewhat different from the test
material. However, this panel member also noted that oral testing with the lower
molecular weight material could be used to make the argument that the likely most
bioavailable member of this category showed no toxicity, which would further support
the argument that no testing is needed. A second panel member indicated that a good
argument could likely be built on the basis for the absorption issues, but did not oppose
bringing in this read-across approach.
Discussion of Other Considerations
?The panel discussed the proposed timing of the additional testing. The test plan noted
"that to avoid duplicate animal testing, and limit vertebrate animal testing as far as
possible, the timetable of proposed testing is on hold until 2010 wherein data sharing
with other European manufacturers and importers of this substance will be accomplished
through Substance Information Exchange Forum (SIEF) under REACH." The sponsor
clarified that this statement should not be read to imply that the EHPV Program is not
also a high priority. A panel member reaffirmed support for waiting for the REACH
timeline before proceeding with animal testing as noted in the preliminary comments.
Another panel member noted the possibility that other manufacturers will have data that
can fill some of the endpoints, but this will not be known until the REACH process for
this material unfolds.
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C4-6 Isopentene Rich-Ether Fraction (IRF) Stream (CAS No. 108083-43-8)
Sponsor: ExxonMobil Chemical Company
Original HPV Submission (www.epa.gov/hpvis)
The sponsor noted that following a brief review of the premeeting comments from the panel,
they did not foresee significant problems in addressing the questions and issues raised. Some of
the premeeting comments applied to both the current submission as well as of the C3-5 Butene-
Isobutylene-Rich-Ether BIR) Stream (the next item on the meeting agenda). The sponsor
provided responses to several of the premeeting comments in the opening remarks and these
responses are reflected in the context of the endpoint topics described below.
Discussion on Physical and Chemical Property Endpoints
?A panelist stated that it can be problematic to represent the physical and chemical
property endpoints for complex mixtures based on data for individual constituents. The
sponsor commented that using constituent data is one of the better approaches for his
materials since for endpoints such as partition coefficient, boiling point, and melting
point the characteristics of a complex stream are a range of values depending on the
constituents. The sponsor noted that for the vapor pressure one could argue to use
measured data for the mixture and such data could be submitted. This panelist clarified
that in the current Chemical Assessment and Management Program (ChAMP), risk-based
prioritizations (RBP) are being developed from submitted HPV Challenge data. In the
context of conducting the RBPs, EPA has decided that it is not appropriate to use
individual major constituent data to represent the physical and chemical property
endpoints for complex mixtures, since the actual values will always be a range. Rather
the following general summary statement has been used in such situations - "These
complex mixtures will not have a well-defined molecular weight, melting point, boiling
point or vapor pressure, log Kow, or water solubility." As a result, the panelist suggested
that the sponsor present the RSS as data entries for the material stream, rather than as
RSS for the individual constituent chemicals. In response to comments from another
panel member and the responses by the sponsor on alternative approaches, the panel
member further indicated that it is reasonable to identify the lowest and highest value
based on all significant constituents for each endpoint and represent the physical and
chemical endpoints as the range of these values. This approach is different from picking
a few primary constituents and using their individual properties as representative of the
mixture. For example, in Table 2 on Page 8 of the TP, the sponsor could eliminate the
individual values from major or representative constituents and just present the range of
values for the mixture. Other panel member had no additional recommendations related
to these endpoints.
Discussion of Environmental Fate Endpoints
?The panel also discussed the issue of using representative mixture components in the
context of filling data requirements for the environmental fate endpoints. The sponsor
indicted that one needs to know the main constituents of the mixture for endpoints like
fugacity, atmospheric oxidation potential, and hydrolysis. Such endpoints are difficult to
characterize for the mixture as a whole. Some endpoints are calculated and there is no
other way to address, other than to use constituents since the models require a specific
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HPV Pilot
chemical structure. The sponsor noted that biodegradation is an exception, since it can be
evaluated on a stream basis. However, the sponsor noted that the biodegradability is
fairly low for the methoxy ethers in this stream?so based on the existing data the stream
is best characterized as poorly degradable. A panelist agreed that for biodegredation it
would be better to look at the stream and constituent representation is less informative.
This panelist felt that assessments of photodegradation and fugacity for the mixture
would not be informative and for the RBP process a general statement indicating this
conclusion has been used. Other panel members added that fugacity modeling based on
the individual components would be appropriate since fugacity is chemical specific and
in the environment the mixture would begin to follow the characteristics of the individual
components.
Discussion of Ecotoxicity Endpoints
?The panel discussed the use of QSAR modeling for ecotoxicity endpoints presented in the
TP. A panelist asked the sponsor to comment on whether they felt the ECOSAR
modeling was adequate. The sponsor noted that in this case constituent data can be used
to characterize the stream for aquatic toxicity. Although the C4-C6 materials are more
complex because they have saturated and unsaturated fractions, but in looking at the
stream as a whole the saturated C7 is the predominant driver for toxicity in the aquatic
environment. Based on review of the premeeting comments from the panel the sponsor
also added that some chronic testing might be appropriate. The sponsor suggested using
the Target Lipid Model (e.g., McGrath et al., 2004). Recent analyses for methyl-tert-
butyl ether (MTBE) derived a predicted no-effect concentration (PNEC) of 18.1 ug/L
MTBE while the Target Lipid Model estimated a PNEC of 20.7 ug/L. This model would
be proposed instead of chronic aquatic toxicity testing.
Regarding QSAR modeling performance, a panelist noted that in reviewing Tables 5, 6
and 7 in the TP that tert-amyl-methyl ether (TAME) has significant measured data, but
for n-heptane and cyclohexene measured data were only available for one endpoint to
compare the measured and model estimated values. This panel member stated that
current EPA practice for individual chemicals is to require testing data for the material
itself. If no data are available, then data for a surrogate chemical must be provided in
addition to QSAR modeling to waive the testing requirement. In this case heptanes and
cyclohexene would likely be the most toxic constituents and QSAR estimates as well as
data for surrogate chemicals for these two components need to be presented to waive
testing. With regard to the use of n-heptane to represent the other 5 constituents of the
heptanes fraction, a panelist indicated that n-heptane would have higher aquatic toxicity
than the branched heptanes ?so data for this constituent was conservative. Since the
underlying models have robust data sets it might be possible to pick an analog from the
training set and include that data in the TP justification. The panelist further suggested
that if data are not available for heptanes then the sponsor might consider using data for
hexane with the caveat that it is a lower-end estimate or using octane with the caveat that
it is a higher-end estimate. Another panel member noted that additional data had been
identified by People for the Ethical Treatment of Animals (PETA) and suggested the
sponsor review this additional information for inclusion in the TP. In response to these
recommendations the sponsor noted that they did provide some data that showed that the
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QSAR models agree with the available data when looking at the group of data as a whole.
Nevertheless, they would seek additional data based on the panel member comments.
The sponsor indicated that they did not include surrogates for the primary constituents in
the TP submission since the models appeared to do well and such data would complicate
the test plan.
Discussion of Mammalian Toxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the mammalian
toxicity endpoints. A panelist noted that in contrast to physical and chemical endpoints
and environmental fate endpoints one can make a better argument for assessing
mammalian toxicity endpoints for complex mixtures based on significant constituents.
This panelist did clarify that in reality some of the individual chemicals are representative
of categories of constituents, and therefore, the selected key constituents for which data
were provided represent something close to half of the stream mixture rather than up to
approximately 90% as indicated by the sponsors. The panel discussed the choice of n-
heptane as a representative of the heptanes fraction. A panelist commented that he was
satisfied by this choice, since the other heptanes would not be likely to be metabolized in
such a was as to remove the methyl groups. Therefore, data developed for n-heptane
should be representative of that for other members of the group. The sponsors added that
n-heptane was selected since it was one of the higher percentage components in this
fraction and had toxicity data available. In response to a follow-up question, the sponsor
indicated there were very little data for any of the other chemicals to determine if n-
heptane would be more or less toxic than the other chemicals in that fraction. One
panelist indicated that in premeeting comments a suggestion had been made to evaluate
the potential toxicity of the members of the heptanes fraction using an SAR approach
followed by a potential screening toxicity study. However, this panelist noted greater
comfort in the selection of n-heptane following the panel discussions due to the rationale
regarding differences in branched versus straight-chained molecules, the apparent effort
to identify data for other heptanes, and the observation that for ecotoxicity endpoints n-
heptane appears the most toxic of the constituents. These lines of evidence should be
described in the TP as a justification for selecting representative chemicals for different
fractions (or bins). A panelist summarized the availability of data for mammalian
toxicity endpoints and concluded that the test plan recommendations are appropriate.
Other panelists agreed with this conclusion. This panel member noted that additional
data had been identified by PETA (Brown-Woodman et. al., 1995) for developmental
toxicity. Only an abstract was available for review, but this study might be added if the
full study is available and is found to add to the data set.
Discussion of Other Considerations
?The panel also discussed whether the TP should provide an indication of the potential for
odors to be present in water contaminated with the material. One panelist asked whether
the nuisance odor properties should be mentioned in the TP. A second panelist
commented that the TP is a source of information to the public it might be worth adding
this information. The sponsor was asked if data exist on the taste and odor threshold for
this material or its major constituents and whether the MSDS provides such information.
The sponsor noted that this consideration of including the odor threshold information was
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HPV Pilot
a good point, but in preparing the documents thought this was outside the scope of the
HPV Program, which focuses on hazard data. The document content was limited to data
regarding HPV endpoints. The sponsor also noted that the only use of the test plan
material is as a feedstock, and it would not expected to be released to public, although the
material is a transported isolated intermediate.
C3-5 Butene-Isobutylene-Rich-Ether (BIR) Stream (CAS No. 102479-87-8)
Sponsor: ExxonMobil Chemical Company
Original HPV Submission (www.epa.gov/hpvis)
In opening discussion regarding this submission the panel members noted that several of the
general issues in assessing mixtures raised in the context of the prior discussion also apply to this
stream. Detailed discussion of the underlying issues are described above for C4-6 Isopentene
Rich-Ether Fraction (IRF) Stream (CAS No. 108083-43-8).
Discussion on Physical and Chemical Property Endpoints
?The panelists agreed with the test plan recommendations regarding the physical and
chemical property endpoints, although a panel member noted the issue of appropriate
representation of mixtures as ranges. The panelist did note that in this case a greater
rationale exists for using representative compounds, since the bulk of the material is
limited to MTBE and TAME.
Discussion of Environmental Fate Endpoints
?The panelists agreed with the test plan recommendations regarding the environmental
fate endpoints, although a panel member noted the issue of appropriate representation of
mixtures.
Discussion of Ecotoxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the ecotoxicity
endpoints and had no additional recommendations.
Discussion of Mammalian Toxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the mammalian
toxicity endpoints. A panelist summarized that in this case the toxicity is represented by
primarily two compounds ?mostly MTBE and TAME. The material would have low
toxicity with significant data in IUCLID for each compound. A second panel member
noted that there is a current IRIS assessment for MTBE that might provide additional
data.
Discussion of Other Considerations
? A panelist indicated that as for the C4-6 Isopentene Rich-Ether Fraction (IRF) Stream
the TP should include data related to nuisance odor. A second panelist added that the
HPV Challenge is meant to provide for a minimum data set and does not preclude
including other information. The addition of this information is reasonable even though
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it may not be required. Panel members indicated that the test plan was well done,
although a few typographical errors were noted. One panelist indicated that the CAS No.
entry appeared to have an error. Another panelist noted on page 15 of the TP a
concentration for acute inhalation toxicity of 8.5 mg/L did not appear to match the value
in the RSS.
1,3-Propanediol (CAS No. 504-63-2)
Sponsor: ACC 1,3-Propanediol Panel
EHPV Submission
(http://www.regulations.gov/fdmspublic/component/main?main=DocketDetail&d=EPA-HQ-
OPPT-2006-1020)
The sponsor opened the discussion with a brief introduction of the submission.
Discussion on Physical and Chemical Property Endpoints
?The panelists agreed with the test plan recommendations regarding the physical and
chemical property endpoints. One panelist commented that the RSS descriptions of some
endpoints were short on detail and questioned whether reliance on data from the
compilation by Daubert and Danner 1989) was adequate. However, another panel
member confirmed that this reference is considered by EPA as sufficiently robust for the
HPV Challenge Program endpoints.
Discussion of Environmental Fate Endpoints
?The panelists agreed with the test plan recommendations regarding the environmental
fate endpoints.
Discussion of Ecotoxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the ecotoxicity
endpoints.
Discussion of Mammalian Toxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the mammalian
toxicity endpoints. A panelist indicated that there were no problems with that test plan
and agreed with the use of a weight-of- evidence approach to meet reproductive endpoint
data requirements. The sponsor noted that in premeeting comments there were questions
about one of the toxicity studies and provided some clarification. The sponsor noted that
there was additional evaluation of sperm parameters in the subchronic study (Gingell et
al. 2000) because a prior in vitro study indicated that 1,3-propanediol led to DNA cross-
linking in testes homogenates and postulated that this may occur in vivo. It was
suggested that this rationale be added to the TP. A panelist also asked that the sponsors
clarify the extent of the evaluation of the ovaries in the subchronic study, since this
endpoint was not mentioned in the section on fertility endpoints in the RSS but was
mentioned in the section on repeat-dose toxicity. Moreover, the panelist felt that the
subchronic study should be referenced in the fertility section of the RSS and more
information related to reproductive endpoints from this study should be added.
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A panelist added that it would be useful to include toxicokinetic data to the submission.
Such data help in the interpretation of the toxicity findings even though toxicokinetics is
not one of the endpoints required for the HPV challenge. The sponsor indicated that to
their knowledge no significant metabolic studies had been done since the material was
not found to be particularly toxic, and therefore, no compelling need exists to do such
studies. The panelist agreed that new studies would not be justified and suggested that
the addition of toxicokinetics information should only be for any studies that are
currently available.
Discussion of Other Considerations
?A panelist asked for clarification regarding the potential for exposure during use of the
material for deicing of aircraft, as well as the potential for exposure from use in personal
care products. The sponsors noted that Shell Chemical is no longer selling this material
into the deicing market, but for DuPont this is a current application. The sponsors also
noted that the material is being sold in the Indian market and additional data may become
available.
Quarternary TEA esters, C16-18 & C18 unsaturated methosulfate (CAS No. 157905-74-3)
Sponsor: Evonik Goldschmidt Corporation and Stepan Company
EHPV Submission
(http://www.regulations.gov/fdmspublic/component/main?main=DocketDetail&d=EPA-HQ-
OPPT-2006-1020)
The sponsor representative indicated that issues that could be addressed during the panel
deliberations would be handled, while some others would need to be taken back to the
sponsoring companies for further consideration. There is an EU consortium being formed and
new testing results are being included in a risk assessment document that is in progress (likely to
be published in 2009). The document has not yet been made public and the data are not
available for release. A panel member asked the sponsor whether the risk document was being
developed for ?OECD, REACH, HPV, or another initiative. The sponsor noted that the
document is planned as an independent toxicity summary that is being developed for a class of
quarternary compounds. Based on this, the panelist inquired as to the peer review process that
would be involved, but the sponsor was not aware of this detail.
Discussion on Physical and Chemical Property Endpoints
?The panelists agreed with the test plan recommendations regarding the physical and
chemical property endpoints. One panelist noted that the data summaries look good.
However, the reported water solubility is very high and the levels reported are likely due
to the chemical being dispersible rather than soluble in water. This panelist
recommended that the sponsor verify which is the case and revise the language in the TP
accordingly.
Discussion of Environmental Fate Endpoints
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? The panelists agreed with the test plan recommendations regarding the environmental
fate endpoints.
Discussion of Ecotoxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the ecotoxicity
endpoints for fish and invertebrates. A panel member questioned the robustness of the
algal toxicity data. This panelist commented that the hydrolysis data are not consistent
with the algal toxicity report. In the algal test 92% of the material was removed, which
generates questions about hydrolysis in algal media since in general there should not be
this much breakdown of the test material. Moreover, for this class of compound a greater
degree of toxicity would be expected, one would expect toxicity at less than 1 mg/L. In
light of these discrepancies the panelist suggested comparing this algal endpoint point
finding to other surrogate chemicals.
Discussion of Mammalian Toxicity Endpoints
?The sponsor noted that current testing data for a related material is being done that will
address the data for reproductive and developmental toxicity for the current submission.
The identity of the surrogate is not available, and the data will not be available until the
release of the ongoing risk assessment document. The sponsors noted that the new data
will lead to a substantial revision to the TP related to these endpoints. A panelist noted
that this clarifies the sponsors' intent for filling the current data gaps related to these
endpoints, although the timeline for having these data is uncertain, and the panel
members cannot judge the adequacy of such data until it becomes available.
Discussion of Other Considerations
?The panel discussed additional enhancements to the current TP. Panel members noted
that the material is classified as Unknown, of Variable Composition, or of Biological
Origin (UVCB). Nevertheless it would be helpful if the TP included a representative
chemical structure. The panel members also suggested that a summary table be included
in the TP that provides the type of data being used to fulfill the testing requirement and
the test recommendation for each endpoint. Another panel member questioned the
description of the CAS numbers in the TP and indicated that the second CAS No. noted
in the TP (CAS No. 919995-81-2) was not available in ChemID Plus and was perhaps the
EINECS number. A panel member suggested that the TP also include data on production
volumes. However, the sponsor commented that with only two producers such
information could not be added due to confidential business information (CBI) concerns,
since adding the information would lead to exact knowledge of the production volume of
each manufacturer.
Fatty Acids, Coco, 2-Sulfoethyl Esters, Sodium Salts (Sodium Cocoyl Isethionate or SCI)
(CAS No. 61789-32-0)
Sponsor: Sodium Ethyl Sulfonates Coalition
Original HPV Submission (www.epa.gov/hpvis)
The sponsor opened the discussion with a brief introduction of the submission.
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Discussion on Physical and Chemical Property Endpoints
?A panel member noted that the physical and chemical property endpoints were estimated.
The data for these endpoints should be enhanced using measured values, even if the data
are obtained from secondary sources. The sponsor commented that there are additional
data for certain parameters that they have recently gained access to as part of the REACH
process and none of the new data differs greatly from the estimates presented in the TP.
As additional information becomes available it will be provided. The test material (SCI)
as well as a related material SI (Ethanesulfonic Acid, 2-Hydroxy-, Monosodium Salt)
have been preregistered under REACH so there may be additional studies that are needed
for EU registration. A panelist asked if the available or planned data include a water
solubility test. The sponsor noted the availability of some data, but these data were
difficult to interpret. Thus the sponsors are in the process of conducting additional tests
for water solubility. The values in Table 1 for water solubility are older information.
There are technical difficulties in collecting data for this endpoint due to the nature of the
test material. A second panelist commented that he appreciated the effort by the sponsors
to do physical and chemical property testing and update the submission. This panelist
noted that the EPISuite model gives incorrect results for salts and surfactants because the
model makes the assumption that there is a covalent bond to the sodium ion. .
Discussion of Environmental Fate Endpoints
?The panelists agreed with the test plan recommendations regarding the environmental
fate endpoints. No additional comments related to these endpoints were made by the
panel.
Discussion of Ecotoxicity Endpoints
?A panel member commented that it was not clear whether the ecotoxicity tests values
were reported for the concentration of the test material itself or for a concentration
equivalent of the active ingredient after correcting for the percentage of active ingredient
in the test material. Either is acceptable, as long as it is clear.
The panel discussed that for aquatic toxicity testing, OECD and EPA generally view
effect levels above 100 mg/L as of low concern, but some of the testing results were
presented as greater than a concentration below the value of 100 mg/L. For example in
Table 4 of the test plan a 48-hour EC50 for daphnia was reported as >32 mg/L for SCI.
A panelist noted that the testing as reported does not give a definitive value for
invertebrates in this regard and this endpoint should be retested. The sponsor indicated
that the results indicate that no toxicity was seen at the highest level tested and higher
concentrations were not evaluated because of difficulty in getting material into solution.
In some of these studies precipitation in test solutions was observed. The sponsor also
stated that it is not possible to reach a level of 100 mg/L in aquatic tests without the use
of a solvent, and that no aquatic toxicity is observed up to the limits of water solubility.
Analytical chemistry data were not available at the time the studies were done and results
from that period are often reported as nominal concentrations. Based on this
consideration a panel member reiterated the need for accurate water solubility testing to
help in evaluating whether the daphnia testing was done at the limit of water solubility.
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The panelist suggested that the sponsors consider retesting with a carrier. Alternatively,
the sponsor could enhance their argument for this endpoint using data for a surrogate
chemical, since related materials containing C13 to C14 chains should have been able to
have been tested with no precipitation using a proper carrier. This panelist did confirm
that although the invertebrate data were less than desirable (since they only tested up to
32 mg/L for SCI) if the water solubility is found to be less that this concentration then the
sponsor will not need to do retesting. Other panelist agreed. One panelist noted that in
this study it may have been that 32 mg/L was the highest concentration that could be
tested, but the study did not fully document this limitation in solubility. Another panelist
added that it appears from the robust summary that the authors did a range finding and
found precipitates at 100 mg/L and then lowered the tested concentration to 32 mg/L.
The panel recommended that the extent to which water solubility limitations affected the
aquatic toxicity effect level estimates should be made clearer in the TP.
Discussion of Mammalian Toxicity Endpoints
?The panelists noted agreement with the test plan recommendations for all of the
mammalian toxicity endpoints, except for reproductive and developmental toxicity. The
panel members noted that it is incumbent on the sponsor to justify the decision for no
additional testing if they are proposing existing data as sufficient to fill a data gap. For
these two endpoints the panel members provided recommendations for additional lines of
evidence to consider in making the argument for waiving testing, as well as
recommendations for testing approaches, if additional testing were ultimately determined
to be needed. One panelist noted that the sponsors presented an argument based on a
history of safe use of the material and low toxicity in 28-day repeat-dose studies. This
panelist indicated that the history of safe use argument is not sufficient. The reviewer
also commented that the availability of two 28-day studies might strengthen the
argument, but using repeat-dose studies to address reproductive toxicity usually requires
a 90-day study to ensure that the full spermatogenic cycle is considered. Moreover, the
panelist pointed out the absence of data for developmental toxicity.
As an alternative argument to those presented by the sponsors, the panel members
suggested evaluating whether there is a significant systemic dose from skin contact if
dermal exposure is the focus of the assessment based on exposure patterns. If the
potential for dermal absorption is sufficiently low, this consideration could be used in
making the argument for waiving further testing. A secondary prong of the argument
could then be the history of safe use. The sponsor indicated that there are dermal
absorption data, but this might not have been apparent in the IUCLID since it was placed
in Section 5.10 (other relevant data). A panelist indicated that this was the appropriate
section for such information. An in vitro human skin study is available as well as an in
vivo toxicokinetics study in rats. The data indicate dermal penetration was less than 0.1
to 0.3%. A panelist noted that the document concludes that the material has low to
moderate dermal absorption, and based on the available kinetic data this panelist
suggested developing a systemic dose estimate for humans based on a worst-case
exposure scenario and then comparing this to the systemic dose from the 28-day study
which was negative at the limit dose. A second panelist also agreed this might be a
useful argument, but the approach is not cut and dry, since there is some indication of
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HPV Pilot
absorption, even though it might be limited. This panelist suggested that the authors
could use a parallelogram approach to estimate human systemic absorption potential
since in vitro human, in vitro rat, and in vivo rat data are available. A third panelist
agreed that the degree of dermal penetration is a key point. If such studies show just a
trace of absorption then there would be less of a concern for a chemical such as this one.
This panelist commented that virtually any dermal study will give only qualitative
estimates of effect levels. The sponsor indicated that they would be comfortable with this
approach of extrapolating from the applied dose levels to estimate internal doses and they
have experience in evaluating consumer exposure scenarios to estimate internal doses
taking into account skin penetration data. A panelist agreed that with the presumption
that systemic absorption would likely be low for consumers, but for the ChAMP
occupational exposures are also considered and doses under workplace scenarios can be
different.
A panelist also identified complications that would need to be considered, when using the
dermal absorption data to enhance the TP rationale regarding further testing. This
panelist pointed out that the dermal study was done with the dodecyl material versus the
cocoyl material, and the data would be viewed as read-across to the current submission.
Moreover, there is a range of concentrations in the test materials that might make the
comparison of doses more complex. The panelist felt unsure as to whether the dosages
could be meaningfully clarified if the starting material contains a wide range of SCI
(from 15 to 90%). The sponsor noted that many exposures are tested using finished
product, so the doses of SCI component vary. The sponsor asked whether it would help
to clarify dosing issues if in the document the doses were presented as the amount of
active ingredient that was applied. Panel members indicated that such information would
provide clarification. In addition, while the comparison of internal doses to the 28-day
repeat-dose study could be presented, the approach would not address the normal use of a
90-day study for filling the data requirement for reproductive effects or the absence of a
developmental toxicity study. The panelist thought another approach would be to build
an argument for combining the test data for SCI and SI. This would be useful since they
are added together in product formulations and SCI has more data. If this approach is
adopted and testing is planned, then a reproductive and developmental toxicity study
should be done for SI and used for read-across to SCI, as discussed in greater detail in the
SI summary below. A study conducted by the oral route would be sufficient. The
sponsor commented that since the material will be going through the REACH process
some additional studies may be needed. If a decision was made that another study was
needed, the data would not be available before the end of 2009, so the sponsors would
need to see how this fits into the schedule for REACH as well.
A panelist also asked for clarification from the sponsors as to the degree to which they
relied on QSAR models in arriving at conclusions regarding mammalian toxicity. The
panelist noted that two models appear to have been used - DEREK and TIMES. This
panelist noted that an International Life Sciences Institute (ILSI) workshop report
evaluated available programs for assessing reproductive and developmental toxicity and
concluded there are significant challenges in their application (Birth Defects Research
[Part A], 2004, [70]: pp. 902-911). The sponsor noted that they run several systems and
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look at the results together. Conclusions are reached based on the overall weight-of-
evidence and the QSAR models are really done more for completeness. In response to a
panelist suggestion, the sponsor indicated they could add a paragraph describing the
QSAR models (in particular TIMES since the panel was less familiar with this model)
and include the model outputs in the submission package.
Ethanesulfonic Acid, 2-Hydroxy-, Monosodium Salt (Sodium Isethionate or SI) (CAS No.
1562-00-1)
Sponsor: Sodium Ethyl Sulfonates Coalition
Original HPV Submission (www.epa.gov/hpvis)
Sponsors opened the discussion with an introduction to the submission. The sponsor also noted
that SI is a starting material for making SCI (Fatty Acids, Coco, 2-Sulfoethyl Esters, Sodium
Salts). In addition, SI is added as an ingredient in final consumer product to stabilize SCI. Thus,
in the context of consumer uses, exposure is to both SI and SCI.
Discussion on Physical and Chemical Property Endpoints
?The panelists agreed with the test plan recommendations regarding the physical and
chemical property endpoints. A panelist noted that most endpoints were measured except
for vapor pressure. The panelist recommended enhancing the descriptions where
possible.
Discussion of Environmental Fate Endpoints
?The panelists agreed with the test plan recommendations regarding the environmental
fate endpoints.
Discussion of Ecotoxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the ecotoxicity
endpoints. A panel member thought that the TP and RSS were adequate and the
conclusions were reasonable. This panelist added that for the ecotoxicity endpoints
combining the data for SCI and SI into a single TP would not be recommended. A
second panelist agreed with this comment. Past submissions for related material were
combined for ease of review, but in this case it would be appropriate to just refer to the
TPs for SCI and SI as appropriate, since the data were not being combined for all
endpoints.
Discussion of Mammalian Toxicity Endpoints
?The panelists noted that some of the issues related to this submission are cross-cutting
with those of SCI. Although some of the same issues apply, one panelist noted that there
are less data available for SI. There are acute toxicity data and data for gene mutations,
but no data for chromosome aberrations, no repeat-dose toxicity studies, and no data for
reproductive and developmental toxicity. The QSAR models DEREK and TIMES were
included as part of justification for no further testing. As noted for SCI a panelist
suggested providing additional description of the use of these models and the model
outputs in the submission. Panelists also asked if there were any other data that might
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become available for the material or surrogates that could be used to address the
endpoints in the submission. The sponsor noted that they had completed a
comprehensive literature search on both SI and SCI, as well as on closely related
isethionates, and no additional relevant data were identified. A panelist noted that a SIEF
call will be coming and perhaps there will be an opportunity for other data to be
developed that might address data gaps in this submission.
A panelist felt there were sufficient data gaps that should be filled with testing. The
panelist felt that the chromosome aberrations data for SCI could be read-across to SI.
Additional testing for SI for other endpoints could be used to fill the data gaps for SCI as
noted above. Based on the current data gaps an OECD 422 study was suggested to fill
the data gaps for both chemicals. Another panelist commented that the TP was well
done, but supported the idea of the proposed repeat-dose study that also evaluates
reproductive and developmental endpoints such as an OECD 422 study. This panelist
suggested testing the commercial product. A third panel member agreed that if a study
were to be done, then an OECD 422 would be most appropriate. This panelist agreed
with the idea of testing SI and bridging back to SCI and also indicated a preference for an
oral dosing study, but noted that the sponsor would need to present a rationale for
extrapolating the findings across dose routes. The sponsor commented that other experts
might suggest testing with SCI and bridging to SI based on an argument analogous to the
concept of testing the parent material since the exposure will automatically generate
exposure to any breakdown products (or metabolites). One panelist could see the logic of
testing the parent since essentially this would be tantamount to testing both chemicals. A
second panelist added that in this case the recommendation to test SI, rather than SCI, is
driven by the fact that there are less data available for SI, and there may not be a need to
test all aspects of toxicity if some information is available for each compound that
supports using read-across between the two chemicals. However, this panelist could
support testing of SCI or SI, with read-across to the other. The panel members agreed
that the key point is that if testing moves forward, an OECD 422 is most appropriate, and
the study design should address the considerations of dosing route (oral versus dermal)
and the nature of the test material (commercial product, SCI or SI).
Although the panel discussion focused on potential for additional testing a panel member
also suggested evaluating whether the data would support a testing waiver based on
limited dermal absorption as discussed for the SCI submission. This panelist noted that
the TP indicates skin penetration is limited, but this statement only references a personnel
communication from Unilever. The panelist asked for clarification of the available data
regarding skin absorption for SI and asked if absorption for SCI could be used for
estimating dermal absorption potential of SI. The panelist noted that the extent of the of
dermal absorption data for SI in the IUCLID, was less than was available in the IUCLID
section 5.10 for SCI. A panelist commented that any dermal kinetics study that is done
should radiolabel the SI moiety, since there is good understanding of the kinetics of fatty
acids. It is likely that if SCI is absorbed, the SI portion of the molecule will be
hydrolyzed from the fatty acid. Therefore, since the fate of fatty acids is well understood,
placing the label in the SI portion of the molecule would provide information on the fate
of that portion of the molecule.
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p-Toluenesulfonic Acid (CAS No. 104-15-4)
Sponsor: p-Toluenesulfonic Acid Coalition
Original HPV Submission (www.epa.gov/hpvis)
The sponsor opened the discussion by providing a brief history of this submission. The material
was an orphan chemical and not sponsored under the initial HPV Challenge Program, but was
subsequently adopted by the sponsor group for the EHPV Program. The sponsor also noted that
they had reviewed the preliminary comments from the panel members, which appeared to be
consistent with their recommendations for no new testing for this chemical.
Discussion on Physical and Chemical Property Endpoints
?The panelists agreed with the test plan recommendations regarding the physical and
chemical property endpoints. One panelist noted that the description of some endpoints
should be enhanced since the RSS did not specify if they were measured or estimated. A
panelist noted that these endpoints appeared to be measured based on the descriptions in
the product MSDS. The sponsor noted that the presentation reflected a limitation of the
IUCLID document that was available as a source of data summaries for the current
submission and they were not sure of the procedures related to the editing rights for the
IUCLID document.
Discussion of Environmental Fate Endpoints
?The panelists agreed with the test plan recommendations regarding the environmental
fate endpoints.
Discussion of Ecotoxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the ecotoxicity
endpoints. A panelist indicated that the test plan was done well and that base set of
testing had been completed. Another panel member commented on the description of
which endpoints were based on read-across data. Data were provided for the test material
as well as a proposed surrogate, benzenesulphonic acid. The TP indicates that for algal
toxicity the surrogate was used for read-across, but it was less clear if surrogate data were
being used for the daphnid toxicity endpoint. The panelist suggested that the TP should
make more clear which endpoints were based on read-across to benzenesulphonic acid.
Discussion of Mammalian Toxicity Endpoints
?The panelists agreed with the test plan recommendations regarding the mammalian
toxicity endpoints. A panelist had submitted comments in agreement with the test plan
recommendation of no further testing regarding the mammalian toxicity endpoints. The
panelist further noted that there is a data gap for reproductive and developmental toxicity.
One repeat-dose study was available, but a full description was not provided in the RSS.
Nevertheless, due to the corrosive nature of the material, additional testing would not be
useful since any such data would be confounded by corrosive effects. This panelist also
suggested that the TP make clear the purpose of including the data for benzenesulphonic
acid, since the data for this chemical were provided in a table, but a sentence in the TP
states that the data were not being used as read-across to fill the endpoint requirements.
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A second panelist indicated that there is support for the use of data from
benzenesulphonic acid because the sulphonic acid moiety is the primary driver for
toxicity and any difference between the benzene and the toluene moiety would be
insignificant given the level of corrosivity.
Discussion of Other Considerations
?In a discussion of the potential for exposure, a panel member suggested that the TP
include a statement that there are no consumer exposures and the material is not found in
consumer products. The sponsor confirmed that the material is used primarily as a
catalyst and would not be present in consumer products.
Revisit of November 2008 Meeting Submissions
Lubrizol Corporation sponsored a number of submissions that were discussed during the
November 18 and 19, 2008 Peer Consultation. The sponsor provided written responses to the
draft Peer Consultation report. The sponsor requested thoughts from the panel on these
responses. The panel facilitator noted the panel would not be providing formal agreement or
non-agreement with the responses, since there had been only limited time to review the
comments. However, the panel agreed that they were comfortable providing clarification or
indicating that further evaluation would be needed before a clarification could be given. In some
cases the written responses provided by Lubrizol were of a clarifying nature that were noted, but
not further discussed during the December meeting. Such clarifying comments are not described
here as they are available in the written attachment from the sponsor. In a few cases the written
responses from the sponsor generated additional panel discussion. These discussions are
summarized below for the various November submissions.
Benzenamine, N-phenyl-, (tripropenyl) derivatives (CAS No. 68608-79-7)
? The panelists discussed the clarification related to the potential for bioaccumulation. The
panelist noted that the sponsor had clarified the issue of data availability. However, they
questioned the value of including the interpretation of such data based on the referenced
methodology from the Texas Natural Resource Conservation Commission. One panel
member indicated that he was not familiar with this guidance document and could not
comment on its justification. A panelist commented that the second part of the sponsor's
written response is an interpretive question and not necessary for this submission.
Dithiophosphate Alkyl Ester Category
? For this submission the panel members discussed the response from the sponsor
regarding the rationale for using the zinc containing material as a surrogate for the non-
zinc materials in this category. One panel member felt that the additional justification
from the sponsors was not satisfactory and that the characteristics of the zinc-containing
material would be different ?the significant difference in molecular weight was noted.
Moreover, the claim that the zinc-containing material will not biodegrade to the mono
acid would be an argument that it is not an acceptable surrogate.. Another potential
difference in chemical properties that might occur is the degree to which the acid moiety
Peer Consultation Meeting Report 23
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is free to react in the zinc-containing material. This panelist recommended that a
biodegradation test be conducted. Another panel member agreed that the zinc-containing
material is substantially different from the material covered in this TP, but could agree to
the read-across approach, if the conclusion is that the material will not biodegrade. A
panelist indicated that the sponsor could request additional EPA review from appropriate
experts on this issue. This panelist felt that the sponsor may be correct that the material
would not be biodegradable, but thought it would be to their benefit to test the material,
since they were making the conservative assumption that it would not biodegrade.
Another panelist asked the sponsors to clarify whether the zinc salt will undergo aerobic
attack or hydrolysis. The sponsor noted that they are reporting that this is the case and
that the zinc salt does not degrade back to the dithiophosphate alky ester. The panelist
suggested that the TP should clarify this point and provide additional supporting
information. In addition, the panelist asked whether the zinc salt would break down in
water. The sponsor indicated they would need to check on these issues. The sponsor
indicated disagreement with these concerns related to read-across for biodegradation,
based on their opinion that the molecular weight difference would not be relevant to this
endpoint and that the submission is indicating the materials are not biodegradable, so the
read-across issue would seem less of a concern since a conservative approach had been
taken.
A limited discussion of other issues also occurred. One panelist indicated that the
sponsors seem to have addressed some of the issues on corrosivity. Another panelist
reserved judgment on the closed system intermediate claim, although the new paragraph
looks good. The new text was significantly different from the information in the 2003
submission for this category, which was rejected by EPA. A panelist offered to take the
revised wording to the EPA staff who review these.
Heptanoic Acid, mixed esters with pentaerythritol (CAS No. 68441-94-1)
? The panel discussed the suggestions related to alternative read-across surrogates and the
potential reactivity of the suggested analog with the carboxylic acid group (CAS No.
68130-55-2). The sponsor provided a response to the suggestions regarding alternative
read-across surrogates and accepted the panel member suggestion for the mammalian
toxicity endpoint by removing CAS# 68130-55-0 from the read-across list for repeated dose
systemic toxicity, and only bridging to CAS# 67762-53-2, which give a NOAEL estimate of 2000
mg/kg-day. With regard to the read-across for acute invertebrate toxicity the sponsor
suggested retaining the read-across to the surrogate with the carboxylic acid group, but
also suggested an additional chemical from the category for read-across (identified as
Figure D in the sponsor response to the November Meeting Report). One panel member
indicated a need to evaluate more closely the newly suggested surrogates.
Octanoic Acid, 1.1'-(2,2-dimethyl-1,3-propanediyl) ester (CAS No. 31335-74-7)
? A panelist noted that as recommended in the November Meeting report the sponsors
provided additional references related to the potential for enzymatic hydrolysis of the test
material. The panelist indicated that he would need additional time to review these
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references. Two panel members also noted that some of the cited references might be
difficult to obtain. In addition, a panelist indicated that for some prior submissions EPA
has asked for bench analysis of hydrolysis to enhance this type of theoretical argument.
A panelist indicated agreement with the sponsor's approach of attempting to make the
argument, but agreed with another panelist that it might be easier to do the study.
Soybean oil, sulfurized (CAS No. 68152-90-9)
? The panel discussed the further descriptions of the testing protocols for ecotoxicity
endpoints provided in the sponsor response. A panelist noted that the main point is that
due to such lipophilic nature of the material no further testing would be needed, but when
using WAFs it is best to describe as much as possible the approach used. The panel
members said that they would need to evaluate more complete methodology descriptions
before judging whether the additional details provided were adequate.
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References
Barber, E.D., Fox, J.A., and Giordano, C.J. (1985) Hydrolysis, absorption, and metabolism of
di(2-ethylhexyl) terephthalate in the rat. Xenobiotica 24:441-450.
Brown-Woodman, P.D., et al. (1995). Induction of birth defects by exposure to solvents: An in
vitro study. Teratology 51(4):288.
Daubert, T.E. and Danner, R.P. (1989) Physical and thermodynamic properties of pure
chemicals: Data Compilation. Taylor & Francis, Washington, DC, USA.
Gingell, R., Kirkpatrick, J.B. and Steup, D.R. (2000) Subchronic toxicity study of 1,3-
propanediol administered orally to rats. Int. Journal Toxicol. 19:27-32.
Heck, H., d'A, and Tyl, R.W. (1985) The Induction of bladder stones by terephthalic acid,
dimethyl terephthalate, and melamine (2,4,6-Triamino-s-triazine) and its relevance to risk
assessment. Reg. Tox. Pharmacol. 5:294-313.
McGrath, J., Parkerton, T., and Toro, D. (2004). Application of the narcosis target lipid model to
algal toxicity and deriving predicted-no-effect-concentrations. Environmental Toxicology and
Chemistry 23(10):2503?517.
Raabe, H., Curren, R., Ward, S., Harbell, j. (2005) Report from an in vitro dermal absorption
assay workshop. In Vitro Percutaneous Absorption Expert Users Workshop, July 20-21,
Gaithersburg Hilton, Gathersburg, USA.
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Appendix A ?List of Attendees
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December 15-16,
Pilot Peer Consultation Panel to Review HPV Submissions 2008
Attendees
*Ms. Susan Blevins Dr. Andrew Maier
Panel Members
Exxon Mobil Toxicology Excellence for
Dr. Skip Matthews Risk Assessment (TERA)
Matthews Toxicology Mr. Richard Davi
Consulting Company ExxonMobil Biomedical Mr. David Mallon
Sciences, Inc. Unilever
Dr. Chad Sandusky
Physicians Committee for Dr. James Deyo Mr. Jack Murray
Responsible Medicine Eastman Chemical p-Toluene Sulfonic Acid
Company Coalition
Dr. Louis (Gino) Scarana Mr. Larry Newsome
U.S. Environmental *Eliot Deag U.S. Environmental
Protection Agency Unilever Protection Agency
*Ms. Carol A. Fairbrother Ms. Pat Rizzuto
ExxonMobil Chemical Co. BNA
Facilitator
Dr. Michael Dourson *Mr. Robert Foster *Dr. Steven Signs
Toxicology Excellence for NOTOX B.V. The Lubrizol Corporation
Risk Assessment (TERA)
Ms. Christina Franz Dr. Douglas Winkelmann
American Chemistry ExxonMobil Biomedical
Council Sciences, Inc.
Attendees
Dr. Ammie N. Bachman *Dr. Ralph Gingell
ExxonMobil Biomedical Shell Oil Company
Sciences, Inc.
*Dr. Gary W. Jepson
Dr. Nancy Beck DuPont *Participating via
Physicians Committee for Conference Cal
Responsible Medicine *Dr. David J. Kent
Keller and Heckman, LLP
*Mr. Philip Benes
Nease Corporation *Ms. Kathy Kiibler
Shell Oil Company
*Ms. Leigh A. Belcher,
M.S., D.A.B.T. Dr. Wendy H. Koch
DuPont Haskell Global Epona Associates, LLC
Centers for Health &
Environmental Science *Dr. Yafan Li
The Lubrizol Corporation
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Appendix B ?Meeting Agenda
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AGENDA
Peer Consultation Pilot of HPV and EHPV Submissions
Monday, December 15, 2008
7:30 Registration
Meeting Convenes2
8:00
Welcome, Description of Pilot, and Introductions: Dr. Andrew Maier, TERA
Meeting Process: Dr. Michael Dourson, Facilitator, TERA
For each submission, the panel members will share their comments and discuss the charge
questions:
Is the information provided adequate to support the conclusions for each relevant SIDS
endpoint?
If a category is presented, is the rationale for the category reasonably appropriate, and is
the use of read across scientifically defensible?
The panel members and sponsor representatives may ask one another clarifying technical questions.
Observers may provide brief technical comments (2-3 minutes maximum), if they have pre-registered
to do so.
8:30 Panel Discussion of Submissions
?1,4 Cyclohexanedicarboylic acid
Sponsor: Eastman Kodak
?Trifluoromethane
Sponsor: DuPont
?Residual oils, oxidized
Sponsor: Lubrizol
?Revisit/Follow up to Lubrizol November Submission discussions
12:00 Lunch (attendees on own for lunch)
1:00 Submission Discussions Resume
?C4-6 IRF Stream
Sponsor: Exxon Mobil
?C3-5 BIR Stream
Sponsor: Exxon Mobil
?1,3-Propanediol
Sponsor: ACC 1,3 Propanediol Panel
?Quaternary TEA
Sponsor: Evonick Goldschmidt and Stepan Chemical
5:00 Meeting Adjourns
2
The facilitator will call for mid-morning and mid-afternoon breaks at appropriate times.
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Tuesday, December 16, 2008
8:30 Meeting Reconvenes
Panel Discussion of Submissions
?Na Caocyl Isethionate (SCI)
Sponsor: Sodium Ethyl Sulfonates Coalition (SESC)
?Na Isethionate (SI)
Sponsor: Sodium Ethyl Sulfonates Coalition (SESC)
12:00 Lunch (attendees on own for lunch)
1:00 Submission Discussions Resume
?p-Toluenesulfonic acid
Sponsor: para Toluenesulfonic Acid Coalition
?Revisit earlier submissions as necessary
5:00 Meeting Adjourns
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Appendix C ?Pre-meeting Comments of Panel Members
NOTE: This appendix contains the preliminary comments prepared by the individual panel members prior
to the meeting. Note that these issues and questions were discussed by the panel and the reader is referred
to the body of the meeting report for a summary of the discussions.
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Pre-meeting Comments on December 2008 HPV Pilot Submissions
Dr. Chad Sandusky, PCRM
Chemical Comments
Existing data satisfies all SIDS endpoints, except for reproductive and
1,4-Cyclohexanedicarboxylic
developmental toxicity, which are met with data from an
Acid
analog/metabolite. As has been noted in previous stakeholder
comments by Environmental Defense and PETA, the manufacturer may
want to consider inclusion of data for methanol as an additional
metabolite/analog to further strengthen the weight of evidence
approach used here.
Some clarification is in order regarding exposure potential. The plan
mentions that CHDA is approved by FDA for use in food
packaging but also states that CHDA is not used directly in any
consumer products. The plan suggests that exposure potential is low
because CHDA is manufactured in a closed system at one site
involving less than 25 workers and an estimated 50-75 downstream
users, but it also states that there is some release of CHDA in
wastewater.
CHDA has been detected in wastewater and while toxicity to fish and
daphnia is quite low, there is higher toxicity to algae, which may be of
concern.
In previous HPV submissions, analogue DMCD was used to support
CHDA and the reverse is being applied here. Previous reviews by EPA
(2003) and AP agreed with this approach.
All SIDS endpoints are met with data from HFC-23 and supported by
Trifluoromethane
data from the analog HFC-32
Use of histopathology data on reproductive organs from a repeat dose
study is appropriate for addressing reproductive toxicity.
Likelihood of exposure is low because HFC-23 is handled in
closed, pressurized systems so there is no direct contact with
workers. Additionally, the manufacturer limits environmental release of
this chemical because it is a greenhouse gas with high global warming
potential.
In addition to the low inherent toxicity and low likelihood of
exposure, production of the chemical is purportedly being phased out,
further obviating the utility of additional testing.
Phys/chem, environmental fate and aquatic toxicity endpoints (read
across for algal inhibition) have been addressed.
The Lubrizol Corporation has made a sound argument that the
Residual Oils (Petroleum
physiochemical properties of oxidized residual oils (CAS# 64742-99-0)
Oxidates and Derivatives)
warrant their categorization with and comparison to subcategory 2
petroleum oxidates and derivatives.
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Based on these similarities, the Lubrizol Corporation has made a case
for extrapolating mammalian acute toxicity information of subcategory
2 members to CAS# 64742-99-0 in place of additional animal testing.
Could Lubrizol also make the case for extrapolating from the
subcategory 1 chemical (CAS # 64742-98-9) to meet the acute fish
toxicity and repeat dose/repro dev endpoints? The study on the single
subcategory 1 chemical (CAS # 64742-98-9) would represent the worst
case conservative estimate for these 2 endpoints. Comparison of the
single LC50 in fish on the 1 of 8 subcategory 2 chemical (CAS 3
68603-11-2; lower molecular weight and higher bioavailability?)
suggests this may be the case.
Most of the RSS on key studies were not in the submission.
It is not clear that testing before 2010 is appropriate pending additional
information from other manufacturers. The meaning of this statement is
unclear.
Finally a dermal OECD 422 is proposed. In some cases it would seem
appropriate to assess potential dermal percutaneous absorption before
conducting in vivo dermal testing. If there is little or no dermal PA,
then systemic toxicity via dermal exposure would not be anticipated
and testing by this route may be waived.
ExxonMobil Chemical Company proposes to use data from
C4-6 Isopentene Rich-Ether
representative constituents from the methoxypentanes and heptanes
Fraction Stream
along with cyclohexene to fill all SIDS endpoints. Specifically, there
are mammalian SIDS data available for TAME (addressing the
methoxypentane olefins comprising 43 ?6-% of the stream) and
cyclohexane (addressing the C6 cyclic olefins comprising 6 ?9% of the
stream) but only a repeat dose study for heptanes (comprising 18 ?24%
of the stream). Are the additional data identified in Peta original April
12, 2008 (Brown-Woodman et. al., 1995) useful in addressing the
developmental endpoint for the heptanes?
Although fish toxicity data are not available for n-heptane, measured n-
heptane data are available for a freshwater invertebrate species. The
measured n-heptane data compares favorably with data calculated by
the ECOSAR model, and ECOSAR is considered appropriate to
estimate the aquatic toxicity for this class of chemicals. In addition,
Peta identified several studies that may contain relevant fish data (Peta
April 12, 2008). We recommend ExxonMobil investigate these
potential data sources. Finally does Exxon Mobile feel that the QSAR
data on the individual components adequately address the toxicity of
the mixture?
As noted above, reproductive and developmental toxicity data are not
available for n-heptane; however acute oral and inhalation toxicity and
repeated dose toxicity are low. We note that use profile and potential
exposure information is lacking from the test plan. This information
would be useful is assessing the data needs for n-heptane.
ExxonMobil Chemical Company proposes to use data from the three
C3-5 Butene-Isobutylene-Rich
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constituent methoxypentanes (MTBE, TAME, MSBE) to fill all SIDS
endpoints.
Measured acute aquatic toxicity data were not available for MSBE. The
calculated data compare favorably with the measured and calculated
data for MTBE and TAME. ECOSAR applies an equation for neutral
organics to estimate aquatic toxicity and is therefore considered
appropriate to estimate aquatic toxicity for this class of chemicals.
MSBE is also volatile and once in the atmosphere, it will be largely
degraded through physical processes at a relatively rapid rate.
Genetic, repeated dose, reproductive and developmental toxicity data are
not available for MSBE (comprising only 4% of the stream). These
data are available for MTBE (65% of stream) and TAME (28% of
stream). The weight of evidence suggests that neither is genotoxic.
Repeated exposure to these constituents demonstrates a low order of
toxicity and is not expected to cause harm to reproduction or the
developing fetus. Therefore, based on the SIDS data for the 2 major
components of the C3-5 stream, no further in vivo testing is needed
(for MSBE).
There is little to no information of use profile or exposure in the test
plan, and this would be useful is assessing potential data needs.
The manufacturers of this chemical have made a genuine effort to
1,3-Propanediol
fulfill the SIDS data points with a weight-of-evidence strategy; the use
of reproductive organ effects in a repeated-dose study and
developmental data completely appropriate.
Additionally, all the studies for mammalian and fish toxicity offered in
the robust summaries are rated a reliability score of 2 or higher; most
are done according to OECD guidelines.
The test plan for this chemical could be improved by providing the
Quaternary TEA esters, C16 &
structure of the test chemical, but otherwise it is complete and well-
C18 unsaturated methosulfate
organized.
The use of another quaternary ester to fulfill the reproductive toxicity
endpoint appears reasonable; however it is difficult to evaluate the
appropriateness of this particular analog because the identity and
structure is not provided, nor is the "Human Health & Environmental
Risk Assessment" referred to in the test plan provided.
It is not immediately apparent how the developmental endpoint is to be
addressed.
The Sodium Ethyl Sulfonates Coalition (SESC) has performed a
Coco, 2-sulfoethyl esters,
qualitative analysis and concluded that there is sufficient data, given the
sodium salts (Sodium Cocoyl
totality of what is known about SCI, including human experience, that
Isethionate)
certain endpoints need not be tested, specifically the repro/dev
endpoint, for which there are no data specifically. The reproductive
endpoint is partially addressed using reproductive organ histopathology
data from 28-day repeated-dose studies. This approach is a weight-of-
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evidence strategy, although 90-day studies are better for this purpose.
The SESC also argues convincingly that the developmental toxicity
endpoint need not be tested, based on a long history of safe use,
particularly consumer products.
In addition to a long history of safe use, many studies have been
conducted in which SCI-containing products were applied to the skin of
volunteers. Results demonstrate that SCI is only minimally irritating to
the skin.
The potential for worker exposure during manufacturing and distribution
is limited by operational controls including the use of closed reactors
and local exhaust ventilation and PPE. Engineering controls are also in
place to minimize releases to the environment. Consumer exposure is
via dermal route thru soaps and related personal care products.
On page 2 and 14 of the test plan it is stated that there is "low or low to
medium dermal absorption." If this is true, this should be thoroughly
investigated prior to any new in vivo testing, where the dermal route of
exposure is of concern. Any data (Howes, 1975; Howes and Cordell,
1974; page 14 of test plan; we could not locate these studies in the
RSS) that demonstrates little or no dermal penetration would obviate
the need for any dermal tests to assess potential systemic toxicity,
specifically an OECD 422. This approach has been used in past HPV
submissions to reduce animal testing while meeting the intent of the
HPV program.
Regarding above comment, are there data on other relevant anionic
surfactants regarding percutaneous absorption (or modeling of same) or
repeat dose/repro-dev toxicity?
If it's decided that an OECD 422 is needed to meet the requirements of
the HPCV program, it is strongly encouraged that only one study be
done (perhaps on SI below) to meet the needs for both data sets.
The Sodium Ethyl Sulfonates Coalition (SESC) has performed a
Sodium Isethionate
qualitative analysis and concluded that there are sufficient data, given
the totality of what is known about SI, including human experience,
that certain endpoints need not be tested, specifically repeat
dose/repro-dev.
In addition to a long history of safe use, many studies have been
conducted in which SCI-containing products were applied to the skin
of volunteers. Since some SI is also present in final products that use
SCI as the primary ingredient, several of these studies were conducted
on products that contain up to 15% SI. Results demonstrate that SI is
only minimally irritating to the skin.
SESC notes that these SCI and SI are closely related. SCI is produced
from SI, and ADME studies indicate that SCI is metabolized to SI by
hydrolysis. The SESC therefore appropriately suggests that read across
from the SCI data set could address some endpoints for SI, in
particular repeated dose and reproductive toxicity and chromosomal
aberration.
The potential for worker exposure during manufacturing and
distribution is limited by operational controls including the use of
closed reactors and local exhaust ventilation and PPE. Engineering
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controls are also in place to minimize releases to the environment.
The reference to personal communication with Unilever on page 13
stating that "dermal penetration is low" should be further elaborated in
the test plan. See last 3 comments above for SCI on OECD 422.
Data from p-TSA and a seemingly appropriate analog are provided for
p-Toluenesulfonic Acid
aquatic toxicity endpoints as well as several mammalian toxicity
endpoints. The only SIDS endpoints not fulfilled are reproductive and
developmental toxicity.
This test plan proposes no further testing due to the acidic,
corrosive nature of the chemical which caused burns in skin irritation
studies and gastrointestinal injury in acute oral studies. We agree that
additional testing should not be conducted on the basis of animal
welfare considerations and the fact that interpretation of the data would
be confounded by the corrosive effects of this chemical.
Some information on potential for human and environmental exposure
would be helpful.
Phys/chem., environmental fate and aquatic toxicity endpoints have
been addressed.
Past reviews of benzenesulfonic acid in HPV program also waived
mammalian testing due to corrosive nature of strong acids.
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Pre-meeting Comments on December 2008 HPV Pilot Submissions
Environmental Protection Agency
Chemical Comments
In this particular case, the sponsored chemical (known as CHDA) was
1,4-Cyclohexanedicarboxylic
used as a surrogate for another HPV chemical (DMCD), which is being
Acid
used as a surrogate for CHDA here.
Physical-chemical properties ?With the exception of boiling points, all p/c
properties are adequate for the purposes of the Challenge Program. We
didn't quite understand the partition coefficient robust summary ?although
it says estimated, it appears that an experiment was conducted. Was it
because the isomers were separated on the HPLC column that there is a
range of values given? The vapor pressure was estimated and not
measured. EPA comments on the DMCD submission suggested that the
VP be measured if estimated value is greater than 10-5 Pascals (equivalent
to 7.5 x 10-8 mm Hg). The estimated value for CHDA is 8.7 x 10-6 mm Hg.
Instead of the calculated boiling point value provided, EPA preferss
measured values.
Environmental fate ?Appears reasonable....no comments.
(L) Aquatic toxicity ?Adequate acute toxicity data are available for these
endpoints for the purpose of the Challenge Program.
Mammalian toxicity ?All the endpoints appear to be addressed properly.
The issue about the relevance of DMCD as a surrogate for CHDA for the
reproductive and developmental toxicity endpoints boils down to two
issues: (1) the assumption that DMCD is metabolized to CHDA and (2) if
(1) occurs, what about the other metabolite (likely methanol)?. Both issues
were mentioned in comments to the DMCD submission (submitted by the
same sponsor back in 2003). For the presumed demethylation issue, EPA
considered it reasonable, but requested references for the statements. The
sponsor did provide two citations and they are provided in both the revised
DMCD submission and the CHDA submission (Heck and Tyl, 1985 and
Barber et al., 1994). I could not get the full Heck and Tyl article, but the
abstract did not inform the metabolism issue. In terms of the Barber
article, it appears that the alcohol formation from DEHT and DEHP
hydrolysis was quite different (DEHT being hydrolyzed at both ester
linkages whereas DEHP only on one side). Understandably, these are
larger alkyl chains (C8 vs methyl group for DMCD), but does the sponsor
have any idea why there was differential hydrolysis and which path
DMCD would follow?
Other ?br>
Physical-chemical properties ?Adequate data are available for the
Trifluoromethane
Challenge Program.
Environmental fate ?Adequate data are available for the Challenge
Program.
(G) Mammalian toxicity ?The use of difluoromethane (HFC-32) is a
reasonable surrogate for the repeated-dose and reproductive endpoints for
HFC-23. All mammalian toxicity HPV Challenge endpoints appear to
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have been met.
(L)Aquatic toxicity ?Analog test data provided is considered adequate to
asses the acute fish and invertebrate hazard of the sponsored chemical the
Challenge Program. To support the submitted SAR algal endpoint data on
the sponsored chemical an analog with test data needs to accompany the
predicted results.
Other ?br>
This chemical is being added to an existing HPV category ("Petroleum
Residual Oils (Petroleum
Oxidates and Derivatives Thereof"). This category has eight members and
Oxidates and Derivatives)
is divided into two subcategories; Subcategory I with only one substance
and Subcategory II with the remaining substance. The EHPV chemical
(CASRN 64742-99-0) is proposed as an addition to Subcategory II and this
appears reasonable.
Physical-chemical properties ?The sponsor is to be commended for
measuring all of the physical-chemical properties (except vapor pressure)
for this complex mixture.
Environmental fate ?I agree with the proposal to perform a biodegradation
test on 64742-99-0; all other endpoints are acceptable. This reviewer also
appreciates the attempt and documentation to perform the hydrolysis
study.
(L) Aquatic toxicity ?EPA agrees with the TP to conduct acute fish,
invertebrates, algal, and daphnia chronic reproduction toxicity testing, but
does not agree with using loading concentrations. EPA suggests testing
chemicals of this type at or below the water solubility limit. All tests
should be conducted analytically using flow through method, mean-
measured concentrations, and with a recognized solvent carrier (surfactants
should not be used) of < 100 mg/L.
Mammalian toxicity ?I agree with the proposal to perform an OECD 422
on 64742-99-0.
Other ?This reviewer also agrees with the sponsor's idea to wait until
2010 to perform the intended testing to await the outcome of REACH/data
sharing.
The sponsor proposes to use surrogate data for this stream by using data
C4-6 Isopentene Rich-Ether
from three of the 13 constituents listed on p. 6 of the Test Plan. Although
Fraction Stream
it is true that these three constituents make up to 91% of the stream, that is
based on each of the three making up 100% of their "chemical group" (this
does not apply to cyclohexene, which is in its own group, but does to the
others as representatives of methoxypentanes or heptanes). In fact, the
three chosen constituents can make up to only 56% of the stream.
Physical-chemical properties ?For mixtures such as this stream, it is not
practical to pick constituents to represent the mixture for physical-
chemical properties. As EPA is starting to do in its ChAMP/RPB
assessments, perhaps the best way to approach this is with a statement such
as: "These complex mixtures will not have a well-defined molecular
weight, melting point, boiling point or vapor pressure, log Kow, or water
solubility."
Environmental fate ?As with physical-chemical properties, perhaps a
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similar statement would apply to photodegradation and fugacity (both
usually estimated values ?so difficult to do with a mixture because you are
forced to pick a representative chemical).
(L)Aquatic toxicity ?The acute aquatic measured data for each endpoint
on each major chemical component of the stream has not been performed
to satisfy data adequacy for the purposes of the Challenge program. For
the heptane and cyclohexene components only a single daphnia and fish
tests, respectively, have been performed. EPA believes that in this case
QSAR predictive values alone does not provide enough confidence that the
streams will behave toxicology as a mixture in the absence of more
measured acute and chronic data for these two components. EPA suggests
testing the mixture to help determine the overall acute toxicity to daphnia
and algae. Specifically acute toxicity for fish and a chronic daphnia 21-d
reproduction tests are recommended. To prevent loss of any test material,
zero head space, flow-through methods and measured concentration should
be employed.
Mammalian toxicity ?I have no problem with the data provided for the
three consitutents on their own. The issue mixtures: do you test the
mixture, or do you pick an appropriate representative chemical(s). In
terms of which to pick, it comes down to two things ?either the one(s)
thought to be the most toxic or the one(s) present in the highest
concentration. I guess I question both of these for mammalian toxicity for
the C4-6 stream. As mentioned above, TAME and n-heptane may not fit
either of these criteria. In terms of toxicity, what about considering methyl
hexane vs. heptane? Some thoughts on how to proceed:
?SAR on all constituents to see which might be most toxic for the
various endpoints and then do SIDS on that one chemical.
?Perform 28-day study on stream and compare to available data
from constituents
?Are there any data on other constituents that could inform this
issue?
Other ?NOTE: The robust summaries were difficult to read/understand
from pp. 32-157 and pp. 233 ?282 (were these duplicate outputs from a
IUCLID report?). However, the summaries for cyclohexene and TAME
were very thorough. In terms of heptane, the same applies, but I was
surprised there were no repro or developmental toxicity data.
The approach to address the HPV Challenge endpoints for this stream is
C3-5 Butene-Isobutylene-Rich
similar to that used for Case #12 (C4-6 IRF Stream). However, in this
case, there are only four constituents identified (see Table 1 on p. 6 of the
test plan) with another row in the table devoted to a fifth one called "other
VOCs"; this last of which comprises only 2.8% of the stream. Thus,
unlike the C4-6 IRF stream, a constituent approach based on concentration
may be more appropriate here (because of a lower number of constituents
and a higher concentration of each one).
Physical-chemical properties ?As mentioned for the C4-6 IRF stream, it is
not practical to pick constituents to represent the mixture for physical-
chemical properties. As EPA is starting to do in its ChAMP/RPB
assessments, perhaps the best way to approach this is with a statement such
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as: "These complex mixtures will not have a well-defined molecular
weight, melting point, boiling point or vapor pressure, log Kow, or water
solubility."
Environmental fate ?As with physical-chemical properties, perhaps a
similar statement would apply to photodegradation and fugacity (both
usually estimated values ?so difficult to do with a mixture because you are
forced to pick a representative chemical).
Mammalian toxicity ?For mammalian toxicity, I do not see the value of
adding MSBE ?there is only one data point and it is for acute inhalation
toxicity. The available information in the robust summaries appear
thorough and reasonable for all endpoints for both TAME and MTBE. Of
course, MTBE has been a well-characterized chemical and there is a
current IRIS assessment that is ongoing.
(L)Aquatic toxicity ?Adequate data are available for the Challenge
Program.
Other ?The CASRN for methyl sec-butyl ether is wrong in the opening
paragraph of the test plan (p. 5); it should be 6795-87-5 instead of 994-05-
8 ?it is correct in Table 1. Also, as in the C4-6 IFR submission, the robust
summaries were difficult to read/understand from pp. 48-335 and pp. 429-
457 (were these duplicate outputs from a IUCLID report?).
Physical-chemical properties ?robust summaries are a bit skimpy and
1,3-Propanediol
don't indicate whether some values are measured or estimated
Environmental fate ?looks good....no comments
(L)Aquatic toxicity ?Adequate measured data are provided for acute fish,
invertebrates, and algal toxicity and compare well to QSAR predicted
values.
Mammalian toxicity ?A couple of observations regarding reproductive
and developmental endpoints. For reproductive toxicity, the evaluation of
various sperm endpoints seems more detailed than normal ?why was this
done? On the other hand, in that same robust summary (p. 38 in robust
summary file) there is no mention of the evaluation of female reproductive
organs. The fact that no effects on ovary organ weights were seen (from p.
29 in robust summary file) should also be mentioned in the fertility
section. For developmental toxicity, although only two dose groups were
used (plus control), the information appears minimally acceptable for HPV
Challenge purposes.
Other ?br>
(G)Physical-chemical properties ?looks like all properties were
Quaternary TEA esters, C16 &
measured....it is interesting that the log Kow is > 6.5 but the water
C18 unsaturated methosulfate
solubility is > 2000 mg/L (I guess it is a property of quats/surface active
agents??).
(L)Physical-chemical properties ?Reported measured data are adequate
for screening level purposes of the Challenge Program. Water solubility
reported at such high levels is likely to be results of the chemical being
dispersible rather than soluble in water. Sponsor should review results and
verify that the chemical is actually water soluble or dispersible given such
a high log Kow value.
(L)Environmental fate ?Hydrolysis (ester) in water was reported at >120
hrs, but during algal testing it was reported that ester hydrolysis (37%
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degradation) occurred within 72 as a result of microbial attack under test
conditions. It would be helpful if a table of algal growth above and below
the curve, and composition of algal growth medium are provided to help
interpret test results. (see below under aquatic toxicity)
(L)Aquatic toxicity ?Adequate data are available for all aquatic endpoints
with the exception of the algal test. Data adequacy for algae is pending the
submission of a more enhance robust summary i.e., table of algal growth
above and below the curve, and any information on test medium to verify
the possibility and amount of microbial degradation occurring during
testing. In addition, it was reported at 72 hours only 8% of nominal
concentration was present. If this is the case the 72-h EC50 may be less
than that reported for this study. Based on SAR results this chemical is
expected to be toxic to algae between < 1 to 5 mg/L. Any explanation to
these questions and statements would help in interpreting test result.
Mammalian toxicity ?The acute toxicity, repeated-dose toxicity and
genetic toxicity endpoints look good and have good summaries. I cannot
comment on the repro/dev endpoints because the submission is not
complete ?it points to a future report that will describe results in another
substance that will be used to fulfill these endpoints. I have a few
questions:
?What analogs or surrogates will be used for the
developmental/reproductive endpoints?
?What is the venue or forum for the report (i.e., is it OECD HPV,
US HPV, REACH)?
?What is the status of this report?
Other ?Why are there two different CAS numbers to describe the same
UVCB? What is the mixture identified in the inventory? Also, ChemID
Plus (http://chem.sis.nlm.nih.gov/chemidplus/) did not recognize the CAS
No. 919995-81-2 ?is this possibly the EINECS number?
Physical-chemical properties ?All properties are estimated.
Coco, 2-sulfoethyl esters,
(L)Aquatic toxicity ?It is not known whether all tests were corrected for
sodium salts (Sodium Cocoyl
100 percent active ingredient in the case of DEFI Base 66%. In addition,
Isethionate)
these tests should have been conducted in high enough concentration to
determine if there are no acute effects at 100 mg/L. The testing as reported
does not give a definitive value for invertebrates in this regard and should
be retested. To reduce observed physical toxicity due to precipitation, a
recognized carrier (surfactants should not be used) should be used at
concentration of no greater than 100 mg/L. All concentration should be
analytically monitored.
Mammalian toxicity ?The acute toxicity studies appear fine, however, it is
assumed because of the different test substances used that the doses
presented reflect the dose of the test substance and not SCI. For example,
in the first study (p. 20 of robust summary) 5000 mg/kg of a 47.5% SCI
test substance reflects the dose of the test material and not calculated as
SCI. Similarly, all other acute toxicity studies were performed with test
materials that contained as low as 15% SCI or 20% SCI ("DEFI"). Since it
is not believed to be acutely toxic, I am not concerned about toxicity and
do not think more acute toxicity studies need to be performed, but am just
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interested in accuracy in reporting. For repeated-dose toxicity studies, the
two 28-day studies are acceptable (one with a 72.4% SCI test material and
the other with 90% Jordapon test material). The genetic toxicity endpoints
of gene mutation and chromosomal aberrations have been met through in
vitro tests....although one of the two Ames assays used a 66% SCI
formulation. According to the existing HPV Challenge guidance, the
developmental and reproductive toxicity endpoints have not been
met....use of a 28-day study to evaluate reproductive organs is not a long
enough exposure period.
Other ?There are issues with the purity of the test substances (range from
15-90%) in the mammalian toxicity tests.
Physical-chemical properties ?Most of the properties are estimated, with
Sodium Isethionate
some (apparently) measured values being reported from secondary
sources.
Environmental fate ?Looks good ...no comments
Mammalian toxicity ?Two of the endpoints are acceptable ?acute toxicity
and gene mutations. This reviewer believes the chromosomal aberration,
repeated-dose toxicity, reproduction and developmental toxicity endpoints
have not been met for the purposes of the HPV Challenge Program. The
arguments for no more testing are (from pdf page 14, labeled page 13 of
the test plan): (1) no acute toxicity; including no irritation; (2) SAR
analyses confirming no gene mutation affects and suggesting that the
compound does not penetrate skin; (3) some information exists with SCI
(see Case #8); and (4) not much knowledge would be gained by
performing longer-term animal testing. Taking these arguments
individually:
1. I agree that there is no acute toxicity, but this does not necessarily
mean there would be no toxicity observed in longer-term studies;
2. More information on this statement is needed: several SAR models
are identified (DEREK and TIMES) and personal communication with
a Unilever representative. My questions: What were the DEREK
estimates for all the other "icities"? I am not familiar with TIMES ?br>
what is it?
3. I understand the apparent relationships between SCI and SI (SI being
both an intermediate to make SCI and a metabolite of SCI) and think it
is reasonable to have tests in one apply to the other. However, as stated
by this reviewer on the SCI case (#8), there are HPV data gaps for
reproductive and developmental toxicity. Also, this reviewer could not
find the citation (Howes 1975) mentioned in the test plan (again, pdf
page 14, labeled page 13).
4. I understand this statement and so propose the following: perhaps a
path forward for SCI and SI would be to perform an OECD 422 with SI
and have it apply to both SCI and SI? Also, perhaps the chromosomal
aberration endpoint can be met by using the SCI data
(L)Aquatic toxicity ?Adequate data are available for the Challenge
Program.
Benzenesulfonic acid is proposed as a surrogate for p-TSA for many of the
p-Toluenesulfonic Acid
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HPV Challenge endpoints. Although it is not being used for mammalian
toxicity, this reviewer does wonder whether the known and documented
difference in the toxicity of benzene vs. toluene (based on distribution in
the body and very different target organs ?blood for benzene and brain for
toluene) is applicable to some of the other endpoints. However, the fact
that it has such a low (estimated) pKa of -2.58 suggests that it is a very
strong acid and dissociation at environmentally relevant (and even
physiologically relevant) pHs would likely not occur.....
Physical-chemical properties ?The robust summaries for these endpoints
(for p-TSA) have virtually no information except for the value for each
endpoint. They should be amplified (i.e., method used, measured or
estimated, etc.).
Environmental fate 璑one of the biodegradation tests individually meet
the HPV Challenge endpoint for biodegradation. The sponsor's
assessment for biodegradation is reasonable.
Mammalian toxicity ?Available data exist for acute toxicity and genetic
toxicity (gene mutation and chromosomal effects). This reviewer does not
agree that the 28-day study is acceptable; however, I do agree that no
further testing is necessary given the corrosive nature of the compound.
(L) Aquatic toxicity ?Adequate data are available for the Challenge
Program.
(L) Other ?EPA agrees with supporting data for benzene sulfonic acid to
satisfy aquatic endpoints for sponsored chemicals were data gaps exist.
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Pre-meeting Comments on December 2008 HPV Pilot Submissions
Dr. Hazel (Skip) Matthews
Chemical Comments
1,4-Cyclohexanedicarboxylic acid (CHDA), manufactured by one company,
1,4-
Eastman Chemical Co., at one site, is produced and used in a largely closed
Cyclohexanedicarboxylic
system, though there is some potential for workplace exposure and minimal
Acid
environmental release. Though CHDA is apparently of low toxicity and is a data
poor chemical, review of this Test Plan indicates data addressing each of the SIDS
elements for CHD are available and/or estimated, or derived from a surrogate
chemical by approved methods. Data previously developed for a similar
compound, dimethyl-1,4-cyclohexanedicardboxylate, is proposed to address most
of the SIDS endpoints for the physicochemical, environmental fate, ecotoxicity,
and human health effects needed for 1,4-cyclohexanedicarboxylic acid (CHDA).
The use of surrogate data is justified by stating that the surrogate chemical will be
readily metabolized to CHDA by esterase enzymes. This has been confirmed for
the surrogate chemical, but not for DHDA.
CHDA has limited potential for release into the environment and, with exception
of algae, appears to be of low toxicity to all organisms tested. Given these facts
and the fact that CHDA is used exclusively as an industrial intermediate and does
not appear in any consumer products, it might be assumed that this chemical poses
little threat to the environment or human health.
The only obvious problem with this submission is the fact that most of the data in
the Robust Summaries exist as some sort of computer gibberish that can not be
read. It is assumed that this problem will be easily remedied.
Review of the Test Plan and Robust Summaries submitted for trifluoromethane
Trifluoromethane
(HFC-23) indicate this small, volatile chemical is virtually chemically and
biologically inert. Environmental problems associated with its production and
uses are due almost exclusively to its chemical stability, persistence in the
atmosphere, and resulting effect on global warming. Data addressing the required
SIDS end points for HFC-23 are described in some detail in an IUCLID Data Set
which serves as a Robust Summary. Whereas studies of HFC-23 are not available
to address all the required end points, data developed for structurally related
fluoroethanes, difluroethane and tetrafluoroethane, are appropriately bridged to
address these end points as necessary. All studies indicate that HFC-23 toxicity is
largely limited to sedation when animals or humans are exposed to high
concentrations.
It is assumed that HFC-23 is transported from its site of production to numerous
sites of use. It is also noted in the Test Plan that more HFC-23 is produced than is
used and that the excess is transported for incineration. Frostbite on direct
exposure to the vapor is mentioned as a possible human health risk. It is assumed
that a second human health risk, suffocation, might be associated with this
chemical on exposure to high concentrations in a confined space such as could
occur in an accidental release in the course of its transport and/or use. This fact
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may be mentioned in the MSDS for this chemical, but might also be mentioned
here.
This material which acts as a lubricant and rust inhibitor, consists of a complex
Residual Oils (Petroleum
combination of high molecular weight carboxylic acids. As such, it is somewhat
Oxidates and
undefined, and has not been the subject of a number of studies to determine its
Derivatives)
environmental fate and toxicity. However Petroleum Oxidates and Derivatives
(POD) share a number of properties with similar petroleum derivatives that have
been subject to at least minimal testing and may serve as a source of "read across"
data to address required SIDS elements. Additional testing is proposed to
determine each of the ecotoxicity endpoints, as well as repeated dose toxicity and
reproductive/developmental effects.
In summary, this submission consists of a well organized Test Plan and Robust
Summary that clearly describe the limited data available and propose appropriate
testing using OECD protocols to address data gaps. However, it stated that
decisions for additional testing are said to await the input of other producers which
is anticipated prior to 2010. Thus, it would seem appropriate to reserve approval
of this submission until plans for the necessary testing are confirmed.
Environmental and human risks associated with exposure to this complex mixture
C4-6 Isopentene Rich-
of chemicals has been evaluated by review of data previously developed for its
Ether Fraction Stream
three major components: tert-amyl methyl ether (TAME); n-heptane, and
cyclohexene. This seems a very reasonable approach as these three chemicals
and/or very closely related chemicals account for 67 to 91% of the stream, and
other components of the stream are structurally similar. No component of the
stream, accounting for greater than 1% appears to have any unique toxicity or
potential for accumulation in the environment.
Each of the major components of this mixture of chemicals on which this
submission is based has been the subject of significant toxicological
characterization. Review of the extensive information provided indicates that
virtually all of the required SIDS endpoints have been addressed for each of these
major components. This work is described primarily in unpublished lab reports,
but most of these studies were conducted under GLP and appear very sound.
Robust Summaries of the resulting data are presented in the form of an IUCLID
Data Set for each chemical. On reviewing these summaries it is somewhat
bothersome that they contain many pages of numbers and notes that add
significantly to the bulk of the report without adding significant information. If
permitted, I would recommend eliminating any pages that do not contain relevant
information. Otherwise, this submission satisfactorily addresses the requirements
of the HPV Challenge and no further work is recommended.
Note: It might be pointed out that TAME is an organic ether. Organic ethers are
generally of low toxicity but, like TAME, may be very persistent in water. They
are also detected by human taste and smell at very low concentrations. Thus,
environmental contamination with such compounds may be a particular problem
not addressed by the SIDS end points used by the HPV Challenge. To my
knowledge, we do not have a way to point out potential problems such as
"nuisance contamination." When this or another similar problem is well known,
should they be pointed out or should these reviews be restricted to the standard
SIDS end points?
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This submission addresses a hydrocarbon stream, C3-5 butene-isobutylene-rich,
C3-5 Butene-
which consists primarily, >95%, of three compounds methyl-tert-butyl ether
Isobutylene-Rich
(MTBE), tert-amyl-methyl ether (TAME), and methyl-sec-butyl ether (MSBE),
the latter of which accounts for a relatively minor portion, ~ 3.6% of the total.
Thus it is appropriate , as proposed, that the Test Plan and Robust Summaries
focus on these three chemicals with emphasis on MTBE and TAME. The Test
Plan describing available data for these major constituents of the stream is well
organized and referenced to address each of the requested SIDS endpoints. Each
of the subject chemicals is of relatively low toxicity, but has significant potential
for persistence in the environment. The Robust Summaries are presented in the
form of IUCLID Data Sets and, as such, are carefully organized and presented.
(The considerable number of pages containing only numbers and/or brief notes is,
however, somewhat distracting and add considerably to the bulk of the Robust
Summaries. Would it be permissible if they were eliminated for purposes of the
HPV Challenge?)
In summary, the C3-5 butene-isobutylene rich stream is adequately addressed by
available data describing the fate and toxicity of its major constituents; thus, no
further testing is recommended.
Note: Organic ethers such as those described here are generally of low toxicity
but, as seen with these compounds, they may be very persistent in water. They are
also detected by human taste and smell at very low concentrations. Thus,
environmental contamination with organic ethers, as has been observed with
MTBE, is a particular problem not addressed by the SIDS end points required by
the HPV Challenge. To my knowledge, we do not have a way to point out this and
similar problems of which we are aware, but are not addressed by the SIDS
endpoints. Should such problems be pointed out, or should these reviews be
limited to the required SIDS endpoints?
This Test Plan provides a concise summary of the relatively extensive Robust
1,3-Propanediol
Summary for 1,3-propanediol. It appears that this chemical has little or no toxicity
in all systems tested and that all the necessary SIDS have been addressed.
Relatively minor comments or suggestions we might make are the following.
1. In section 2.2.1, Sources of Environmental Exposure, it is stated that
environmental exposure occurs primarily through accidental spills. This
statement seems somewhat in conflict with that in Use Patterns, section 2.1
where it is stated that 1,3-propanediol may also be used in deicing fluids,
engine coolants and personal care products, uses that may also be significant
sources of Environmental Exposure.
2. Whereas numerous references are given for other data, no reference is given
for the lack of occupational exposure limits or consumer exposure.
3. Though it is not required and we do not think the data would raise concerns
regarding the use of 1,3-propanediol, it would be of interest to have some data
on the toxicokinetics, metabolism, and distribution of this chemical in
mammals. Since this chemical is formed naturally, and is relatively polar, we
can probably assume that it distributes with total body water and is rapidly
metabolized by 1,3-propanediol dehydrogenase and excreted as the parent
compound and metabolites.
The Test Plan for quaternary TEA esters, C16 & C18 unsaturated methosulfate,
Quaternary TEA esters,
provides a concise, well organized description of data to address most of the SIDS
C16 & C18 unsaturated
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endpoints required for the HPV Challenge. The respective studies are described in
methosulfate
more detail in well-organized and referenced Robust Summaries. Review of the
summaries of these studies indicates that most used a recommended protocol,
OECD or other, and were conducted under GLP. The only deficiencies noted in
this submission were the failure to provide a structural formula, quantity produced,
and failure to address the developmental toxicity/teratogenicity endpoint. This
latter deficiency is noted in the Test Plan which also says "studies are proposed".
This Test Plan and Robust Summaries represent a very thorough discussion of
Coco, 2-sulfoethyl esters,
information addressing the production, use, and safety evaluation of sodium
sodium salts (Sodium
cocoyl isethionate. The Test Plan is very well written and referenced to describe
Cocoyl Isethionate)
available data addressing the results of extensive toxicity studies, virtually all of
which indicate sodium cocoyl isethionate is a very safe chemical. Most of the
references are in the form of company reports and, as such, are not available in the
open literature. However, review of summaries of these studies in the Robust
Summaries of this submission indicates that most of the toxicity studies were
conducted under GLP and that the results were derived from carefully designed
studies. Thus, this submission very satisfactorily meets and/or exceeds the
requirements of the HPV Challenge.
Sodium Isethionate (SI) is used primarily as an intermediate in the production of
Sodium Isethionate
sodium cocoyl isethionate (SCI) and, according to this Test Plan may be present in
bath detergent bars containing SCI, up to 15%. However, results of studies
described in this Test Plan and Robust Summaries indicate SI poses little threat to
the environment or human health. The mix of GLP and non-GLP studies
described in company reports addressing the fate and toxicity of SI are concisely
described in referenced in the Test Plan and Robust Summaries. It appears that,
with exception of repeated dose toxicity and reproductive/developmental toxicity,
all required SIDS endpoints have been adequately addressed. Though it is
unlikely that significant toxicity would be observed, these three endpoints could,
and given the level of human exposure, probably should be determined by a repeat
dose/reproductive/developmental study.
p-Toluenesulfonic acid is a strong acid and, as such, its primary mechanism of
p-Toluenesulfonic Acid
toxicity, corrosion, is well understood. Nevertheless, most of the SIDS endpoints
required for submission under the HPV Challenge have been addressed by one or
more studies of this chemical or bridged from a proposed surrogate chemical,
benzenesulphonic acid. Benzenesulphonic acid is a very appropriate surrogate for
p-toluenesulfonic acid, and bridging of data from one chemical to the other should
be encouraged to minimize further testing. A review of data, available or bridged,
for this chemical and the respective Robust Summaries indicates that, with
exception of reproductive/developmental data, all necessary SIDS endpoints have
been addressed. Given the fact that results of these studies indicate observed
toxicity is due to corrosion, it is proposed that no further animal toxicity studies be
conducted. We strongly support this proposal.
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Appendix D ?Additional Materials Provided to the Sponsors
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Peer Consultation Meeting Report 1
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