## Testing of Certain High Production Volume Chemicals S econd Group of Chemicals; Final Rule

Response to Public Comments

Prepared b y the Chemical Information and Testing Branch, Office of Pollution Prevention and Toxics, Office of Pesticides, Prevention, and Toxic Substances, U.S. Environmental Protection Agency November 22 , 20102 T 

### able of Contents Unit Title Page A . Introduction 3 

### B . The Use of Existing Information 3 C . Comments on Proposed Test Methods 5 1. Test guidelines 5 2. Acute toxic ity

test method 6 3. Aquatic tox icity

test method 7 4. Genetic toxicity

test method 9 5. Reproductive and developmental toxicity screening 9 D . Animal Welfar e Considerations 10 E . Chemical Specific Comments 10 1. Acetaldeh yd e (CAS No. 75 - 07 - 0) 10 2. 1,3 - Propanediol, 2,2 - bis[(nitrooxy )meth yl ] - , din itrate(e ster) (CAS No. 78 - 11 - 5) 14 3. 2,4 - Hexadienoic acid, (E,E) - (CAS No. 110 - 44 - 1) 15 4. Ethanedioic Acid (CAS No. 144 - 62 - 7) 16 5. D - gluco - Heptonic acid, monosodium salt, (2.xi.) - (CAS No. 31138 - 65 - 5 ) 1 7 6. C.I . Leuco Sulphur Black 1 (CAS No. 66241 - 11 - 0) 1 7 7. Castor oil, sulfated, sodium salt (CAS No. 68187 - 79 - 8) and 18 oxidized (CAS No. 68187 - 84 - 8) 8. Benzenediamine, ar,ar - diethyl - ar - methyl (CAS No. 68479 - 98 - 1 21 9. Alkenes, C12 - 24, chloro (CAS No. 68527 - 02 - 6) 2 3 10. Hydrocarbons, C>4 (CAS No. 68647 - 60 - 9) 25 11. Phenol, 4,4’ - methylenebis[2,6 - bis]1,1 - dimethylethyl) - (CAS No. 118 - 82 - 1) 25 12. Phosphorochloridothioic acid, O,O - di eth yl est er (CAS No. 2524 - 04 - 1) 26 Bibliograph y 273

Appendix 33 A . Introduction This document contains a summary of the comments received b y EPA in response to the TSCA section 4 proposed test rule entitled “Testing of Certain High Production Volume Chemicals, Second Group of Chemicals” (73 FR 43314 ; July 24, 2008) along with EPA’s responses to those comments . The proposed rule and comments are available in EPA’s public docket and e - docket for the final test rule under Docket No . EPA

–HQ

– OPPT

–2007

– 0531 . EPA received comments from industry , including :  T he Acetaldeh yde Working Group (AWG) of the Vinyl Acetate C ouncil,

 Albemarle Corporation (Albemarle) ,  American Chemistry

Council (ACC),  Chlorinated Paraffins Industry Association (CPIA),  Dy no Nobel, Inc. (Dy

no Nobel) , and  Vertellus Specialties, Inc (Vertellus) . EPA also received comments from a number of A nimal Welfare O rganizations ( AWOs ) . Man y AWOs submitted comments under the letterhead of People for the Ethical Treatment of Animals (PETA), and contained comments on behalf of PETA , the Phy sicians Committee for Responsible Medicine (PCRM), the Alternati ves Research Development Foundation, and the American Anti Vivisection Society . Additional comments from PCRM were also on behalf of the Doris Day Animal League (DDAL), and the Humane Societ y of the United States (HSUS) . EPA also received comments from numerous private citizens. ACC (ACC 2008), as an original partner in the HPV Challenge program with EPA , expressed strong support for this rule and the development of screening level studies for HPV chemicals . However, ACC also expressed concern that EPA relied on the information submitted under the 2006 In ventory Update rule ( IUR) to determine whether a substantial number of workers and consumers are exposed to the 19 HPV orphan chemicals that would be subject to the rule, when none of that information i s publicly available . ACC urged EPA to make the 2006 Inventory Update rule ( IUR) data available as soon as possible, and before it publishes the final rule . EPA has done so. B . The Use of Existing Information (Including the use of Databases, Structure - Activity Relationships[SARs] and the Development of Categories) Comment. EPA received comments from AWOs that EPA (and a ffected chemical companies) should carefully examine all publicly

available chem ical data bases, including the Organisation for Economic Co - operation and Development ( OECD ) e - chemportal and the HPV Challenge Program Web site as well as the (Q)SAR tools EPA has made available on its EPI Suite site and OECD on its QSAR site before conduc ting any

animal testing . It was further suggested that there be a better attempt at pooling available knowledge b y grouping chemicals into categories to characterize hazard and minimize animal testing.4

Response . In the voluntary HPV program, sponsors were provided with the opportunity to use all tools available, including Quantitative Structure Activity Relationship (QSAR) models, EPI Suite, and any other sources of information that would obviate the need for further testing of a compound of interest . P ersons who believe that a chemical under this proposed rule can be dealt with using a category or SAR approach were encouraged to submit appropriate information, along with their comments which substantiate this belief

. If, based on submitted information a nd other information available to EPA, which uses literature search engines (see Appendix) and has full access to all HPV challenge information submitted during challenge program, the Agency determines that a chemical meets the requirements for considerati on under a category or SAR approach, and that practicable measures are available at the time to modify the testing requirement, EPA w ou l d take such measures as are necessary to avoid unnecessary

testing . However, no data were brought forward b y a sponsor o r commente r that enables the use of a category or SAR approach. Comment . AWOs commented that weight - of - evidence approaches, such as those proposed at a December 2007 OECD workshop titled Integrated Approaches to Testing and Assessment, should be recommen ded and utilized before any new in vivo testing is sponsored . AWOs also commented that existing test data may

be sufficient to adequatel y evaluate a particular hazard or risk without additional testing in some instances . AWOs recommended that ongoing work on developing weight - of - evidence approaches b y such agencies as OECD, the EPA, the International Life Sciences Institute (ILSI) and the Dutch National Institute for Public Health and the Environment (RIVM) should be (continuall y considered) and emplo ye d wh erever possible. Response . EPA agrees and encourages such approaches . However, no sponsor submitted a supportable weight - of - evidence approach for any of the test substances listed in the HPV2 final rule . Comment . AWOs commented that, in cases where chemical properties and environmental fate data are lacking, no toxicity

tests should be conducted until after such basic testing is completed, as certain chemical/fate properties may preclude the need for further (toxicity) testing . Response . While it is true that phy sical chemical propert y and fate data can be useful in determining how specific toxicity

tests are performed, few chemical and fate properties negate the requirement for testing altogether . Those phy sical prop erties that are most related to bioavailablity , the water solubility and octanol - water partition coefficient are readily estimated should these data be necessary for experimental design . With the exception of intrinsic chemical reactivity , knowledge of a c hemical’s environmental fate is generall y not necessary prior to assessing its toxicity . It is agreed that highl y reactive chemicals that undergo instantaneous destruction upon exposure to the environment should not be tested for toxicity . However, reactiv ity of this nature is generally well known to those who manufacture, transport, use or otherwise handle the chemical in question . In addition, the reactivit y of the parent does not necessarily preclude testing of the degradation products . Therefore, unless there is a question regarding the reactivity of the chemical, there is no reason to withhold toxicity testing until all of the chemical/fate propert y testing has been conducted. Comment. AWOs commented that the proposed rule does not make sufficient us e of category approaches, quantitative structure - activity relationships, weight - of

- evidence approaches or integrated testing strategies as compared to the (voluntary) HPV Challenge Program.5

Response . EPA disagrees . EPA welcomes the use of all of the above - stated approaches in determining the need for additional testing . P ersons who believe that a chemical under this proposed rule can be dealt with using a category or SAR approach were encouraged to submit appropriate information and their comments s ubstant iat ing this belief . However, no data were brought forward b y a sponsor or commenter that enables the use of a category or SAR approach. Comment. AWOs commented that testing of variable mixtures may not provide additional useful data beyond that of using existing data on the major constituents of such mixtures. Response . Regardless of the known toxicity of major constituents of variable mixtures (i.e., mixtures containing various and unrelated chemical substances), it is most often impossible to know the potential interactive and toxic effects of chemicals until they are tested in a mixture . Inthe case of variable mixtures, such as those that may be ob served among petroleum streams, for example, EPA prefers that several versions of the mixture, each representing different proportions of the major mixture components, be tested to determine toxicity , rather than rel yi ng on one representative version of th e complex mixture. Comment. AWOs commented that the proposed rule response - to - comment period (120 day s) was inadequate to the purpose of allowing commenters to supply existing data not otherwise available to EPA. Response . When providing a comment period in its proposed rules, EPA seeks to balance sufficient time for comment with a reasonable timeframe for final rulemaking after proposal . EPA expects that companies potentially

affected by

the proposed testing requirements will submit data relevant t o the chemicals which they

manufacture (or process) only . EPA anticipates that these data will be readil y available or obtainable by the companies . If additional time is needed, a request for an extension of the comment period may

be submitted for EPA’s co nsideration . Comment. AWOs commented that EPA in the proposed rule bases its need for testing on production volume alone. Response . Under EPA’s “B policy , ” production volume greater that one million pounds per year is necessary for an exposure - based (“ B”) finding, but two additional findings must also be met before EPA proposes or requires testing under TSCA section 4(a)(1)(B): 1) that there is also substantial or significant human exposure, or substantial environmental release; and 2) that data are nec essary (i.e., there are no, or inadequate, existing data upon which EPA can base a risk assessment) . EPA has made the necessary

findings for this rule. C . Comments on Proposed Test Methods 1 . Test guidelines.6

Comment . EPA received comments from Albemarle Corporation (Albemarle) suggesting that the test rule state that OECD, instead of ASTM, guidelines be used, since OECD methods have been tested in a round - robin comparison, are widel y accepted globally , and, the HPV program is satisfying OECD scr eening testing. Response . While EPA has based the screening testing required in this rule on the testing endpoints of the OECD SIDS program, the testing in this rule is being required under TSCA section 4 rulemaking . With rulemaking, issues of enforceabil ity become a concern . Both the ASTM or TSCA 799 series guideline , but not the OECD guidelines , make clear which steps are mandatory and which steps are only recommended . Accordingl y, in order to comply with this test rule, testing must be conducted in acco rdance with the specified mandatory and enforceable requirements in the ASTM or TSCA 799 s eries guidelines . EPA's 799 series guidelines, however, have been harmonized with the OECD guidelines. ASTM standards, like the TSCA guidelines, are internationally a ccepted testing standards developed through a process involving broad public participation and extensive involvement of the scientific community . For this reason, and because ASTM guidelines make clear which protocol elements are mandatory , ASTM guidelines are considered adequate as alternative guidelines for conducting testing that will be in compliance with the test rule. If, however, a test sponsor believes that use of an OECD guideline is preferable, the test sponsor may request a modification to the t est requirement (see 40 CFR 790.55). 2. Acute toxicity test method. Comment . AWOs commented that evidence indicates that more than 85% of industrial chemicals are non - toxic (Kinsner, A. et al., 2008) and that efforts to validate the in vitro 3T3 NRU cy totox assay (HVAM, 2006) also indicate that this assay correctly discriminates non - toxic chemicals from toxic ones . They

further stated that the European Center for the Validation of Alternative Methods (ECVAM) is currently

conducting a definiti ve validation of this hy pothesis with thousands of chemicals, with data expected in earl y 2009 . AWOs suggested that EPA wait for these results in order to avoid unnecessary in vivo oral acute toxicity testing . In a d d ition, an emerging method to estimate to xicity for exposures via the “inhalation route” (Veith, G. et al., 2008; Mackay , D. et al., 2008) should also be pursued. Response . While EPA generall y agrees that, for a variet y of reasons, test methods which minimize the use of live animals are desirabl e, a new in vitro method, such as one that would estimate toxicity for exposures via the “inhalation route , ” must be validated before in vivo testing can be partially or completely

eliminated . In the case of the 3T3 NRU cy totoxicity assay , EPA agrees with the conclusion of a 2006 ICCVAM Test Method Evaluation Report (I CCVAM/NTP 2006); namely , that data from the 3T3 NRU cy totoxicity assay may be used in a weight - of

- evidence approach, where appropriate, for determining starting doses for in vivo acute oral s ys temic toxicity studies (EPA 2008 b ) . EPA also agrees with I CCVAM’s conclusion that these in vitro test methods are not sufficiently

accurate to replace animals for regulatory labeling and hazard classification purposes (EPA 2008 b ) . EPA acknowledges that this use of this approach may result in the reduction of animals used in acute oral toxicity

testing. Although EPA agrees that the 3T3 NRU assay can be used in a weight - of - evidence approach, it should be acknowledged that the conclusions of the I CCVAM rep ort, as well as an OECD (2009) draft guidance document on the use of the 3T3 NRU cytotox assay for the purpose of estimating starting doses for acute oral sy stemic toxicity tests, were based on validation studies conducted on onl y 727

chemicals . EPA agrees that an evaluation of thousands of chemicals using the 3T3 NRU cy totoxicity assay would be more desirable in determining the true validity of the assay . The results of the validation by

ECVAM using thousands of chemicals are not available for EPA to evalu ate as of this writing . In the meantime, EPA continues to allow the use of man y approaches, including SAR approaches and an y other information to determine which industrial chemicals are most likely to be toxic. 3. Aquatic toxicity test method . Comment. Albemarle disagree s with the OECD SIDS Program’s selection of aquatic toxicity testing based on log Kow . Instead, they agree with EPA’s approach (see OPPTS guidance and P2 Framework and EPI Suite software/PBT Profiler) . Albemarle further commented that, a s a practical matter, either acute and/or range - finding tests would generall y need to be performed in order to properl y s elect test concentrations for a chronic study . Thus, proceeding immediatel y into chronic studies based on log Kow is generally

not poss ible . Response . The reason for requesting that chronic testing be performed on Daphnia when the log Kow ≥ 4.2 relates to the observation that substances with lower solubility are more likely

to exhibit toxicity

at lower concentrations when present over a longer period of time . In man y cases where chronic testing needs to be conducted on a substance, attempts at acute toxicity testing may

have already

been done on the substance; and, in these cases, the concentrations from the acute studies may be useful i n providing guidance for test concentrations for the chronic study . If conducting an additional acute or range finding stud y would be helpful in selecting dose levels for a chronic study, EPA recommends that range - finding be conducted prior to conducting the required testing . Comment . Albemarle commented on log K ow 4.2 or 4.3 as indicative of bioconcentration . This is consistent with the Agency ’s 1999 Final Policy Statement under TSCA section 5 entitled Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances . However, it is inconsistent with OPPTS current practice, e.g., as in the P2 Framework/EPI Suite software/PBT Profiler, which recognizes that bioconcentration declines with increasing log Kow values

– Albemarle recommends that this language in the rule be consistent with the P2 Framework. Response . EPA disagrees. EPA has been consistent in expressing concern for bioconcentration potential for substances with log Kow greater than 4.2 . L og K ow has been used as an indicator of bioconce ntration potential in part because a bioconcentration factor (BCF) is frequentl y not available for HPV chemicals. To better refine bioconcentration potential when log K ow would suggest concern, valid fish bioconcentration studies are preferred b y EPA . Inthe absence of measured values, the EPA EPI Suite s ys tem is used to estimate bioconcentration potential. OPPTS P2 Framework/EPI Suite software/PBT Profiler is also consistent in predicting that, in general, bioconcentration increases with increasing log Kow v alues . In addition , the model predictions from EPI Suite for BCF estimation reflect the nonlinearity

of the Kow - BCF relationship (i.e., beyond a maximum Kow range, BCF decreases with increasing Kow). Comment . AWOs suggested that toxicity testing should f

irst be conducted on aquatic plants and invertebrates, as toxicity

to these organisms (fish food supply) might obviate the need for fish toxicity testing.8

Response . EPA disagrees . T he reason aquatic plants and invertebrates are included with vertebrates ( fish) in evaluating aquatic toxicity is to be able to test three different taxonomic levels of the aquatic ecos ys tem . In addition, it is possible that a chemical substance may be much more toxic to fish than to aquatic plants or invertebrates. Therefore , i t is essential that all three tests be performed to adequately assess the risk to aquatic organisms . Comment . AWOs commented that the DarT test, using fertilized zebrafish eggs as a surrogate for living fish, has been nominated for development into an O ECD test guideline and should be used as a replacement for (acute) fish toxicity testing . If fish acute toxicity testing is still required, a threshold (step - down) test (e.g., Jerama, S. et al., 2005) should be used, with an additional refinement also poss ible to terminate testing after 24 hours of exposure in some cases (Hutchinson, T.H. et al., 2003). Response . EPA notes that the DarT test has received attention as a potential in vitro replacement for the current acute fish toxicity testing (e.g., Brannen et al., 2009) . However, until the DarT test has been adequatel y validated, the Agency will continue to recommend approved guidelines studies and not studies under development , which may in fact not be adequatel y predictive. The acute fish toxicity test conducted in vivo will continue to be required . Acute aquatic toxicity

testing determines an LC 50 ; i.e., the concentration at which 50% mortality is observed . The Hutchinson et al. (2003) method appears to suggest that testing be terminated at 24 h ours of exposure when lethality and /or serious morbidity are observed in two out of five fish (as described b y AWOs ) . This does not appear to be a viable alternative to determining the correct L C 50 . Comment. AWOs commented that EPA’s requirement of aquatic toxicity tests on fish is unnecessary given the understanding of aquatic microorganisms and the availability of in vitro test methods . AWOs stated that the in vitro Tetrahymena test, also known as the TETRATOX test (Schultz), should be used instead of the in vivo fish acute toxicity test. Response . EPA does not agree that the TETRATOX test is a valid substitute for the fish acute test for the following reasons:

 The test organism (in TETRATOX Tetrahymena , a protozoan ) represents an entirely unrelated p hyl um from that of fish (LeBlanc 1984 ) . Extrapolating from such a wide phylogenetic gap would introduce considerable uncertaint y in EPA’s ecological effect assessments (EPA 2004b) .  The endpoints are different: the acute fish test evaluates mortality whereas the TETRATOX test evaluates cell proliferation (EPA 2004b) .  The TETRATOX test contains substances which may mitigate or mask toxicity (Larsen, et al. 1987 and EPA 2004b) .  Unlike results from the fish acute test, those from the TETRATOX test do no t enable EPA to extrapolate to chronic effects; nor do they permit EPA to identify

toxicity caused b y metabolic activation or other mechanisms (EPA 2004b) .9

4 . Genetic toxicity test method . Comment . AWOs suggested that the genetic toxicity sections of the rule should be amended to mandate (rather than encourage) the use of in vitro genetic toxicity testing; with the requirement that any company proposing to use an in vivo method instead provide before testing a compelling justification for an exemption from the in vitro test methodology , with opportunity for public comment. Response . In the proposed rule, and in its comments to sponsors, EPA has made it clear that in vitro testing is preferred for collecting screening data for genetic toxicity endpoint s . Inthe HPV Challenge Program, and in the proposed rule, EPA has asked sponsors who submit test plans for in vivo genetic toxicity testing to include justification for the in vivo method instead of the in vitro method . EPA does not mandate that genetic t oxicity testing be in vitro in the HPV program because, as stated in the proposed rule, chemical properties may preclude use of the in vitro method . Also, extant in vivo genetic toxicity

data for an HPV chemical or supporting HPV chemical compound may be adequate to fill the genetic toxicity

endpoints without further testing being required . Incases where an HPV chemical requires genetic mutation or chromosomal aberration s testing, EPA permits the use of in vivo testing, but only

after those providing the testing present a strong justification for in vivo testing in lieu of in vitro testing . 5 . Reproductive and developmental toxicity screening. Commen t . AWOs commented that EPA should amend the proposed rule to require companies to use the combined repeated - dose toxicity study with reproduction/developmental screen unless, before testing, a compelling justification for an exemption from the combined protocol is provided, with opportunity

for public comment available. Response . EPA does, in fact, recommend use of the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (40 CFR 799.9365) . However, EPA acknowledges that there may be valid reasons to test a particular chemical using both 40 CFR 799.9355 and 40 CFR 799.9305 to fill the Mammalian Toxicity - Repeated Dose/Reproduction/Developmental data needs, and is requiring in the final test rule that anyone who uses the combinatio n of 40 CFR 799.9355 and 40 CFR 799.9305 in place of 40 CFR 799.9365 to submit to EPA a rationale for conducting these alternate tests. Comment . AWOs commented that, with respect to developmental toxicity testing, an embryonic stem cell test has been val idated by the European Centre for the Validation of Alternative Methods (ECVAM) as a test for embryotoxicity , which indicates developmental toxicity (Genschow, E. et al., 2002), and could be appropriately used to classify

chemicals which test positive as p robable developmental toxicants without further testing. Response . EPA does not agree . In a recent article on the embryonic stem cell test (EST; Buensen et al. 2009), the authors and developers of the original EST assay acknowledge that the version of the test that was validated b y the ECVAM has since been shown to have some significant drawbacks . The main drawback s , from EPA’s perspective, are the test’s reliance on a morphological endpoint (contracting cardiom yocyt es) and the training and validation requ ired to ensure that personnel can10

reliably obtain repeat assessments for this endpoint . T he measurement for this endpoint is subjective rather than objective . In an attempt to address these issues, as well as the issue of time and expense of testing , the a

uthors have established a new version of the EST, which they refer to as molecular fluorescence activated cell sorting (FACS) - EST . However, the authors acknowledge that further studies which incorporate a much wider selection of test compounds are necessary to assess the capabilities and limitations of the new technique. D . Animal Welfare Considerations Comment . AWOs suggested that chemicals which readil y h ydrol yz e into well - characterized products in an aqueous environment at low pH need not be tested via oral exposure. Response . EPA agrees that, in the case where an HPV chemical is known to readily hydroly ze into on ly well - characterized products in an aqueous environment at low pH, oral toxicity testing may

not be necessary under certain circumstances . However, even among well - characterized individual hydrol ysis products, it is not alway s clear how the hydrol ys is pro ducts may interact as separate entities mixed together in vivo (i.e., one hydrol ys is product may enhance the absorption of another hydrol ys is product) . A substance may be well - characterized as an individual entity when given by

the oral route, but that res ult does not necessarily predict its toxicity

when combined with another well - characterized, or not well - characterized, hydrol ys is product. Comment . AWOs commented that confounding factors due to acidic/corrosive/irritating materials should be carefully evaluated before initiating in vivo testing which may provide meaningless results. Response . EPA agrees and, in fact, routinel y evaluates confounding factors such as these to eliminate unnecessary in vivo testing . Comment . AWOs indicated that mammalian and/or ecotoxicity testing with highl y reactive chemicals may not be feasible. Response . EPA agrees and, where it appears that mammalian or ecotoxicity testing with a highly reactive chemical may

not be feasible, EPA may not require testing for some or a ll of those endpoints . Whether EPA decides to forego testing on an y endpoint based on the reactivity of the chemical in question depends upon information which suggests that testing of the chemical would not be feasible . This is why

it is important for a c ompan y to present as much information as possible on the properties of the chemical in question . E . Chemical Specific Comments: 1 . Acetaldehyde (CAS No. 75 - 07 - 0). Comment . AWG commented that acetaldehyde is highl y volatile with greater than 93% of its TRI releases to air . EPA’s AirData database includes acetalde hyde atmospheric measurements f r o m 212 monitors in 175 locations, including most urban and industrial areas of the U.S. (AWG’s attachment A) . The annual mean values for these monitoring stati ons in 2006 ranged from 0.16 to 5.58 ppb, with11

most mean values falling in the lower portion of this range . Given these data, AWG concludes it is likely that most environmental inhalation exposures to acetaldehyde will fall w ith in this low ppb range of con centrations. Response . EPA does not agree . The AirData monitoring data for acetaldeh yd e appear to be ambient air samples, with a good representation of urban areas that should have been tested, since those are the places where acetaldeh yd e might be found in more abundance . The actual levels range from as little as 0.32 ppb (in Maryland) up to 11.16 ppb (in California). Comment . AWG provided exposure modeling results using the exposure model ConsExpo 4.1 (AWG attachment B) and commented that acetaldeh yd e has low p otential for consumer exposure . AWG, in an evaluation of actual potential exposure from consumer products found very low concentration of acetaldehyde in a small subset of consumer products (3 of 378 adhesives and 1 of 55 roof products) . AWG als o stated that acetaldehyde is not an intentional ingredient in consumer products but may be a very minor impurity in certain polymer formulations . Even given those exposure scenarios, exposure modeling for these products indicated exposures of acetaldehyde by these products are all generally within or below the range of ambient air concentrations reported from monitoring stations. Response . EPA does not agree . The information from the National Institute of Health’s (NIH) - Household Products Database (HPD) provided b y AWG is misleading . While there is information on 4 products (3 adhesives and 1 roofing product) , onl y one of the 3 adhesives products had a concentration provided . One product mentioned by AWG was a consumer product, specifically “Pond Patch”, which would not be used on a roof as stated in the exposure assessment . Furthermore, even if AWG is correct that acetaldehyde is “not an intentional ingredient in consumer products” and that there are low levels of acetaldeh yde in two products listed in the NIH HPD, EPA does not believe that these data can be used to support AWG’s claim . The data supplied in the NIH - HPD is a sampling of information on MSDSs and only 2 of the 4 products had concentrations listed . Other data in the literature supports the use of acetaldeh yde in latex paints (Source Ranking Database http://www.epa.gov/opptintr/exposure/pubs/srd.htm ), as another consumer product that would have a wider potential exposed population . With regard to the use of the exposure model ConsExpo 4.1, EPA acknowledges that this is a well - reviewed model that is one of the tools being used in the evaluations under the European Union’s REACH , and that if the inputs as listed in AWG’s comme nts are used , the output s will be as provided in AWG’s Attachment B . However, EPA does not agree that the results from these two scenarios support the conclusions drawn b y AWG, that “... it does not appear that use of consumer products will generate an y si gnificant additional acetaldeh yd e exposure, especially given the short duration and periodic nature of these exposures in comparison to the constant daily exposure to ambient air.” The acetaldeh yde concentrations used in these scenarios are from only two products, not from all consumer products; hence , this general statement is too limited . In addition , there is evidence that acetaldeh yd e is also contained in other t ypes o f products (SRD http: //www.epa.gov/opptintr/exposure/pubs/srd.htm ). Comment . AWG commented that its member companies have collectivel y sponsored hundreds of chemicals under the HPV Challenge and OECD SIDS program and are committed to providing the SIDS on HPV chemicals, but question the inclusion of acetaldeh yde in this rule . EPA’s exposure findings fail to recognize that acetaldeh yd e is a normal human metabolite and that endogenously12

produced levels are likely to be higher than those from exogenous sources ; i.e., more acetal deh yd e may be provided in normal metabolism than from the environment . Further, exposure to acetaldeh yde from industrial sources will be limited by the regulatory controls already in place

– e.g., HAP and VOC regulations

– and also the fact that it is used primarily as a chemical intermediate in carefully controlled closed s ys tems due to its high volatility . Response . EPA does not agree that testing is unnecessary . The fact that an HPV chemical is produced as a normal human metabolite cannot in and of its elf exclude a requirement for the chemical to be tested for its potential toxicity to humans . In deed, man y chemicals considered essential for human health (e.g., metals such as copper and manganese; vitamins) can be toxic to humans at sufficiently

high lev els of exposure . While EPA agrees that endogenous levels of acetaldeh yde may in some cases be higher than would be expected through environmental exposures due to industrially produced acetaldeh yde, e nvironmental exposures will add to the burden of acetald eh yde produced through metabolism, and testing is necessary to assess whether these additional levels may be of concern. In regards to acetaldeh yd e being primaril y a chemical intermediate in closed systems , as noted in the propos ed rule, a chemical which is used solely as "closed sy stem intermediates," may be eligible for a reduced testing battery which substitutes a developmental toxicity study for the SIDS requirement to address repeated dose, reproduction, and developmental toxicity . EPA requested perso ns who believe their chemical is used solely as a closed s ystem intermediate to submit appropriate information along with their comments which substantiate this belief . EPA has not received such claims from any potential industry

test sponsor . Comment. AWG commented on the test rule for aquatic toxicity testing for acetaldehyde . AWG indicated that data are found in the EPA ECOTOX website, that daphnia EC 50 s have 4 values available (4.7 - 48 mg/L), and that one study , Randall and Knopp (1980) which was cons idered to be unreliable by EPA should be considered reliable . Therefore, EPA should re - evaluate its conclusion and also consider the other data . AWG also indicated that three algal studies have been reported in 3 separate algal species and that these addre ss the proposed testing endpoint . AWG also suggested that EPA should take into account acetaldeh yde’s short life - (residence ) time in water . Response . EPA has reviewed the data available in ECOTOX for daphnia and algae and maintains its position that the data cited are inadequate to fill the toxicity to aquatic invertebrate and toxicity to aquatic plant endpoints . The algae test results provided were deficient in that they did not provide adequate testing details and/or the tests were not perform ed in the required way ; i.e., the test must be performed such that an EC 50 value is achieved . Many of the tests described as being performed on algae were, in fact, performed on blue - green algae, which is considered to be a bacterium and is thus not a repres entative organism for toxicity to aquatic plants . The daphnia studies, as well, are lacking adequate details of testing, including the study b y Randall and Knopp (1980) . EPA agrees that a cetaldeh yde should have a short residence time in natural surface wat ers and that its lack of persistence should help mitigate risk to the aquatic environment. Ho wever, knowledge of toxic effects is also needed to evaluate potential risk (EPA, 1992) . Therefore, EPA continues to require acute daphnia and aquatic plant toxici ty testing for acetaldehyde.13

Comment . AWG commented that acetaldehyde has a significant toxicology database and there are data available to address each of the endpoints that EPA has identified . In addition to providing a review of the available data and robust summaries for several unpublished studies, AWG is also including a review of the developmental and reproductive toxicity data for acetaldeh yd e. Response . AWG provided two robust summaries of oral developmental studies on acetaldeh yde . The two summ aries provided documentation of studies conducted in female Cr1:COBS and Sprague Dawley rats in which the rats were provided with either one dose (400 mg/kg) or one of three doses (40, 200, or 400 mg/kg) . In the stud y in which a single dose was used, no te ratogenic effects were found, nor were there any significant differences in mortality or measures of ovarian, uterine litter and fetal data between treated and untreated rats . In the other stud y, no differences in mortality, bod y weights, water consumption , number of corpora lutea per ovary , the number and placement of uterine implantations, and numbers of resorptions and live and dead fetuses were noted between treated and untreated animals . Gross pathology findings were also reported; among them was incre ased evidence of distended uteri among the high - dose animals. Although these findings may provide useful information on developmental and, to some extent, reproductive toxicity , the studies were not conducted in accordance with guidelines accept able to EPA for the determination of reproductive toxicity . T he studies sh ould have at least needed to approach the limit dose of acetaldeh yd e by the oral route from day s 6 through 15 of presumed gestation . Reproductive toxicity

studies need to be conducted using adult male and female rats or mice, with both sexes dosed during the mating period and onl y females dosed thereafter (through pregnancy and nursing period) . Because the studies provided as robust summaries by AWG include no indication that males were dose d during the mating period, these studies cannot be considered as fulfilling the reproductive and developmental toxicity endpoint . Therefore, EPA has determined that the testing proposed in the rule for reproductive and developmental toxicity is still requ ired. Comment. AWOs commented that a search of acetaldehyde in the DART database yielded 332 unique citations . According to AWOs , the data in these citations indicate that acetaldehyde causes adverse developmental effects . AWOs also commented that a study in IRIS showed that acetaldehyde causes growth retardation . AWOs suggested that reproductive and developmental data on ethanol could also be applied to acetaldeh yd e . For these reasons, AWOs believed that the screening - level dat a for acetaldeh yde are clearl y adequate and that no further reproductive and developmental testing is required . Response . The Developmental and Reproductive Toxicology Database (DART) does yield a large number of citations for acetaldeh yd e . A review of these studies however indicates that none of them adequatel y cover developmental and reproductive effects . While there are data that show acetaldeh yde producing significant developmental effects in rats, these data were collected by administering acetaldeh yde to the animals via injection . The injection route is not an acceptable route of exposure for developmental testing in the HPV program. OECD guidelines indicate that toxicity testing for this compound should be conducted via the oral route . Although a l arge assemblage of data does exist for the reproductive and developmental toxicity of ethanol, and acetaldeh yd e is a major metabolite of ethanol, a comparison of LC 50 data from ethanol and acetaldeh yde indicates that acetaldeh yd e is at least 10 times more toxic than ethanol via the oral route of exposure in rats (European Chemicals Bureau, 2000a and 2000c; Sprince et al., 1974) . Therefore, EPA has determined that reproductive and developmental testing of acetaldeh yde is required by the oral route . Moreover, because of the14

magnitude of difference in toxicities, ethanol cannot be used as a supporting chemical for the reproductive and developmental effects of acetaldehyde. 2 . 1,3 - Propanediol, 2,2 -bis[(nitrooxy)methyl] - , dinitrate(ester) (CAS No. 78- 11 - 5). C omment. Dy

no Nobel submitted comments on 1,3 - propanediol, 2,2 - bis[(nitrooxy )meth yl ] - , dinitrate(ester); also referred to as pentaery thritol tetranitrate or PETN . Dy no Nobel indicates that this particular substance is a highl y sensitive explosive and that i t was included in the Final Test Rule for the Testing of Certain High Production Volume Chemicals (71 FR 13708, March 16, 2006) . The final rule required the following testing: n - Octanol/Water Partition Coefficient; Water Solubility ; Environmental fate and pathway s – Inherent biodegradation; Toxicity to plants (Algae); and Reproduction/Developmental Toxicity Screening Test . Due to the chemical’s explosive properties, a great deal of difficult y was encountered in having the test performed . Such testing was fi nally completed in earl y 2008 and the reports submitted to EPA in March 2008 . The reports stated that the water solubility

for PETN was determined to be 2.13 mg/L at 20 degrees C . The log of the octanol/water partition coefficient was determined to be 2.04 . Attempts to determine the rate at which PETN degraded in naturally occurring water samples failed to reach solubility limits of PETN determined from previous experiments with pure water, suggesting breakdown exceeded rate of solubility . Dy

no Nobel indicates that results from the water solubility tests suggest that PETN dissolves very

slowl y in water to reach a relatively low water solubility limit of 2.13 mg/L . Results from the biodegradation assay suggested that the rate of biodegradation exceeded that o f solubility . Therefore, Dy

no Nobel respectfull y submits that since degradation rates exceed water solubility rates, there is no logical justification for completing an y additional aquatic toxicity tests . Response . EPA does not agree that no further aquatic toxicity testing is warranted . The proposed test rule indicates that when a substance requiring aquatic toxicity testing has a measured log K ow of < 4.2, it belongs to Test Group 1 . Substances in Test Group 1 are required to have acute aquatic toxi city testing, including testing of acute toxicity to fish and Daphnia . The log Kow of PETN was determined to be 2.04; therefore, acute aquatic toxicity testing is required . Even if the rate of biodegradation precludes the attainment of the water solubility limit of 2.13 mg/L , the chemical may still be acutely toxic at concentrations less than the solubility limit. Additionally , degradation products may be acutely toxic to aquatic organisms. For testing of fish and Daphnia , use of flow - through conditions w ith anal yt ical monitoring is recommended to maintain and quantify test substance concentrations over the course of the studies . Regarding the sponsor’s argument that the rate of biodegradation exceeds the rate of solubilization of PETN, EPA disagrees wi th the implication that PETN is unlikely to be found in environmental surface or ground waters . Environmental monitoring studies at DOE facilities identified PETN in contaminated soil and groundwater samples from at least one site (Riley et al. 1992) . In addition, the HPV2 rule lists methods that measure ultimate degradation, not primary degradation as in the testing discussed b y Dy no Nobel . Even if Dyno Nobel is correct in its assertion that the test material degrades so fast that the required initial nom inal levels canno t be achieved ( which EPA cannot evaluate without access to the full test report ) loss of identity of the parent material does not provide an y information on possible degradation products, the toxicity of which may

be of concern . Further more, acute toxicity

in fish test data obtained for a structural analog of PETN, 1,2,3 - propanetriol, trinitrate (CAS No. 55 - 63 - 0), indicate that the L C 50 for PETN may be lower than its15

maximum attainable concentration (HPVI S, CAS No. 55 - 63 - 0) . Therefore, E PA continues to require testing for acute toxicity

to fish and Daphnia for PETN . Comment. AWOs commented that aquatic toxicity data are available for PETN, as it has been tested in fathead minnows and bluegill (Bentley , R.E. et al., 1975) . For this reas on, AWOs believe that aquatic toxicity testing should not be required for PETN. Response . EPA disagrees. The Bentley et al. (1975) study

of PETN in fathead minnows and bluegill was judged b y EPA to be invalid due to questionable methodology . The study pr otocol describes a procedure for desensitizing the chemical, which includes boiling the chemical in water under chemical reducing conditions for four hours . To prepare the desensitized compound for the assay , the PETN was boiled in a solution of water, sod ium hydroxide and atomized aluminum . These processing procedures yi elded a compound for testing that is most likely different from the original compound intended for testing . Moreover, a requirement of an acute toxicity study in fish is that oxygen levels be monitored and must be at ≥ 60% of air saturation value . While the Bentley et al. report indicates that oxygen levels were monitored, there is no indication that the appro priate level was achieved and maintained throughout the study . Therefore, EPA continues to require the acute toxicity to fish testing on PETN. 3 . 2,4- Hexadienoic acid, (E,E) - (CAS No. 110- 44- 1) . Comment. EPA received comments from AWOs on 2,4 - hexadieno ic acid, (E,E) - ; also known as sorbic acid, that reproductive and developmental toxicity testing is not needed as several multi - generation studies in mice and rats report no adverse effects of sorbic acid on reproductive function or post - natal development (Demaree, G.E. et al., 1955; Shtenberg, A.I. and Ignat’ev, A.D., 1970; Gaunt, I.F. et al., 1975) . AWOs stated that EPA must review these studies and reconsider its testing requirement for this substance in the proposed test rule . AWOs also commented that s orbic acid is a naturall y - occurring fatty acid metabolized in mammals in a similar manner to other fatty acids; therefore, EPA should use analog data to evaluate this chemical . AWOs also comment that the Food and Drug Administration (FDA) lists sorbic acid as generall y recognized as safe (GRAS) as a preservative for direct addition to food (FDA, 2008) . Because of this, AWOs commented that EPA should reconsider its testing requirement for sorbic acid in the proposed test rule. Response . EPA appreciates that AWOs informed EPA of existing studies pertaining to reproduction/developmental toxicity screening testing for sorbic acid . EPA reviewed these studies referenced b y AWOs , as well as three other studies (Walker 1990; Food and Drug Research Labs 1975; Anon 1 988) to determine if they could satisfy

the data need for a reproductive and developmental toxicity

screening test of sorbic acid . EPA’s review of the studies found that, although the studies were dated, there was no evidence in the multi - generation reproduction studies (Demaree 1955; Anon 1988) to suggest that the chemical is a reproductive toxicant at the concentrations tested, and also that there is no evidence in the teratological study (Food and Drug Research Labs) to suggest that sorbic acid is a deve lopmental toxicant at the concentrations tested (EPA 2004a) . Therefore, EPA is not finalizing the reproduction/developmental toxicity screening test proposed for sorbic acid . However, the other tests proposed for sorbic acid to develop data on aquatic t oxicity are required in the final test rule and are listed in Table 2 and described in Table 3 in § 799.5085(j) of the regulatory text of the final test rule (EPA 2006).16

4 . Ethanedioic Acid (CAS No. 144- 62 - 7) . Comment. AWOs commented that aquatic toxicity data are available for ethanedioic acid; also known as oxalic acid, as it has been tested in goldfish and bluegill (Ellis, MM, 1937; Buzzell, J.C. et al. 1968) . For this reason, AWOs commented that aquatic toxicity testing should not be required for ethanedioic acid. Response . EPA disagrees . The study by Ellis (1937) is not acceptable for addressing the acute toxicity to fish endpoint because the monitored endpoint was behavior rather than mortality , and the stud y report wa s missing details needed to assess study adequacy

(e.g., water hardness, organic carbon) . Likewise, the study

by Buzell et al. (1968) is not acceptable for addressing this endpoint because the study report was missing details needed to assess study adequac y (e.g., pH, water hardness, organic carbon) . Therefore, EPA continues to require acute toxicity to fish testing on ethanedioic acid. Comment. AWOs commented that data on genotoxicity and reproductive and developmental effects of ethanedioic acid are req

uested despite the availability of numerous studies which address these endpoints, including data from the National Toxicology Program (NTP); therefore, the test rules for chromosomal aberrations and reproduction and developmental toxicity are not needed. Response . EPA agrees in part. NTP did conduct a drinking water study on the reproductive effects of ethanedioic acid in mice (NTP 1985). The study was conducted under NTP’s Reproductive Assessment by

Continuous Breeding (RACB) protocol. This two - generatio n study protocol was developed b y the NTP for use in identifying potential toxic effects on male and/or female reproduction, to characterize that toxicity , and to define the dose - response relationships for the tested compound (Chapin and Sloane, 1997). The NTP RACB study of ethanedioic acid was performed by a laboratory under contract to the National Institute of Environmental Health Sciences (NIEHS) using Good Laboratory

Practices. Although this NTP study does not conform entirely to current OECD reproduc tive and developmental testing guidelines, upon further consideration, it is considered adequate to eliminate the need for further reproductive and developmental testing under a test rule. As such, EPA has determined that it will not require further repro ductive and developmental testing on ethanedioic acid. The only available study

on the chromosomal aberrations endpoint appears in a paper by Ishidate et al. (1984) in which 242 food additives in Japan were tested both for mutagenicity and clastogenicity . However, the test rule, as well as the OECD 473 guideline for the in vitro mammalian chromosome aberration test, indicates that cell cultures are exposed to the test substance both with and without metabolic activation. The Ishidate et al. paper indicates that “no metabolic sy stems were applied” in the course of testing. The paper also indicates that the results for ethanedioic acid were negative, and that for substances having negative results in their testing, the results presente d in a table were for those that did not produce chromosomal aberrations “at the highest non - cy totoxic dose used in the experiment.” No information was provided on the chromosomal aberrations potential of concentrations higher than the highest non - cy totoxi c concentration tested. The OECD 473 guideline indicates that “where cy

totoxicity occurs, these concentrations should cover a range from the maximium to little or no toxicity .” The highest concentration tested should be one that does, in fact, produce cy

t otoxicity . The Ishidate et al. paper reports only the results of a “maximum dose” of17

ethanedioic acid tested; i.e., 0.125 mg/ml, a dose which was quite low and apparentl y not cytotoxic. Thus, the study

reported in the I shidate et al. paper does not provi de adequate information on the chromosomal aberration potential of ethanedioic acid. EPA has determined that reproductive and developmental testing is not required for ethanedioic acid, but EPA does continue to require chromosomal aberrations testing o n this substance. Comment. AWOs indicated that water solubility and octanol - water partition coefficients should be determined for ethanedioic acid prior to conducting acute fish toxicity testing. Response . EPA disagrees that w ater solubility and octan ol - water partition coefficients need to be determined for this chemical substance prior to conducting acute fish toxicity testing. According to EPIWI N, the log Kow is - 8.23 and the water solubility is 220,000 mg/L (SRC, 2010 a) . As such, the compound is est imated to have a high degree of solubility , and it is reasonable to conduct acute fish toxicity testing on ethanedioic acid. 5 . D - gluco - Heptonic acid, monosodium salt, (2.xi.) - (CAS No. 31138- 65- 5). Comment. AWOs commented that D - gluco - heptonic acid, monosodium salt, (2.xi.) - ; commonly known as sodium glucoheptonate, is listed by the FDA as a secondary

direct food additive permitted in food for human consumption, and, as such, EPA must reconsider its testing requirements for sodium glucoheptonat e in the test rule . AWOs recommended that the ph ys icochemical data be generated prior to any animal testing, as these data may preclude further tests in animals. Response . EPA acknowledges that sodium glucoheptonate is listed by FDA as a secondary

direct food additive permitted in food for human consumption (21 CFR 173.310) . Sodium glucoheptonate is permitted by

the FDA for use as a boiler water additive that may be safel y used in the preparation of steam that will contact food . However, the food safet y e valuation inherent in this permitted use (which itself is limited per the terms of section 173.310(b)) does not necessaril y extend to the potential hazard of workplace exposure levels or environmental contamination levels . Sodium glucopheptonate is a chelating agent routinel y used to clean industrial tubs to prevent calcium rings or clumps from forming . While it has been reported that an estimated 75,000 workers nationwide come into contact with this chemical on a regular basis (JSOnline, 2008), little to n o health effects data exist on this chemical . According to the EPI Suite estimation method, sodium glucoheptonate is expected to be completely

water soluble; as such, the generation of phy sicochemical data prior to any animal testing is not necessary (SRC, 2010b) . Moreover, the ready solubility of this compound suggests bioavailability . Despite the FDA’s permitted use as a secondary food additive, the absence of publically available health and environmental data on this chemical necessitates EPA’s continued requirement for testing of sodium glucoheptonate. 6. C.I. Leuco Sulphur Black 1 (CAS No. 66241 - 11 - 0). Comment. AWOs commented that acute toxicity testing is not needed for C.I . Leuco Sulphur Black 1 since acute toxicity

data for this chemical are available . AWOs also commented that EPA must review studies in IUCLID that summarize data from industry studies of acute toxicity

in mammals and fish18

that report an LD 50 of greater than 2000 mg/kg - bw in rats and an LC 50 of 401 mg/L in salmon trout, respectivel y, and reconsider these proposed testing requirements. Response . EPA substantiated the existence of a single acute oral toxicity study in rats and a single acute toxicity

to fish study

in rainbo w (or steelhead) trout ( Salmo gairdneri ) with the LD 50 and L C 50 reported b y AWOs . These studies were located in the IUCLID data set for C.I . Leuco Sulphur Black 1 (European Chemicals Bureau, 2000d) . However, insufficient study details were provided in the IUC LID data set; therefore, the adequacy of these studies to address the endpoints under consideration cannot be determined b y EPA . Although a stud y need not conform exactly to the current OECD guidelines to be considered adequate to fill a required endpoi nt for testing, the acute oral study in rats reported in the IUCLID data set provides no information on the rat strain, dose levels or number of doses tested . Most importantly , it does not include information on the number of day s that animals were observe d after dosing . In general, f or an acute oral study

to be considered adequate, animals must be observed for at least 14 day s after dosing . The description of the acute study in rainbow trout is missing essential details on the results of anal yt ical monito ring of the dosed water; i.e., dose levels in the water, ox ygen levels and pH . Information on doses of the test chemical used in the study was not provided, nor was information provided on the number of fish tested at each dose . Moreover, in both the acute oral and acute fish toxicity studies, the test substance is described in the IUCLID data set as “other TS”, indicating that the test substance used in these studies was not C.I . Leuco Sulphur Black 1 . Given the information provided in the IUCLID data set, EPA has determined that data gaps exist for the acute toxicity

to fish and acute oral endpoints and, for that reason, testing of these endpoints is required . 7. Castor oil, sulfated, sodium salt (CAS No. 68187 - 76 - 8) and oxidized (CAS No. 68187 - 84- 8). Comment. AWOs commented that mammalian acute toxicity testing, combined repeated - dose with reproduction/developmental toxicity testing, and fish acute toxicity testing of castor oil, sulfated, sodium salt and castor oil, oxidized are not needed . AWOs indicated that a 1982 study reports fish acute toxicity

data, including a mean LC 50 of 2.1 mg/L for medaka (Tonogai, Y.W., et al., 1982) . AWOs also argued that castor oil is a natural vegetable oil obtained from the castor bean that is used in pharmaceuticals, food and other industries and that FDA lists castor oil as generall y recognized as safe (GRAS) for over - the - counter use as a laxative . Mo reover, Health Canada lists castor oil, sulfated, sodium salt as a substance not requiring further work for human health at this time. Response . With two exceptions, EPA disagrees that no further toxicity testing is needed on castor oil, sulfated, sodium salt , and castor oil, oxidized . A review of Tonogai et al. (1982) produced no evidence that either substance was tested for fish toxicity . EPA has not located an y adequate mammalian or aquatic toxicity

data on castor oil, sulfated, sodium salt ; but has re ceived adequate acute mammalian toxicity data f or castor oil, oxidized . Inaddition , EPA agree s that aquatic toxicity testing for castor oil, oxidized would not provide useful results, and is not requiring that testing for this substance . H owever, while EP A agrees that aquatic toxicity testing is no longer needed for castor oil, oxidized, because of poor water solubility , the same rationale does not apply for castor oil, sulfated, sodium salt . While also poorly soluble, c astor oil, sodium salt is a surfactant . Water solubility , per se, is less a consideration for aquatic toxicity testing of th is sub stance . As noted in an EPA guidance document, since s urfactants will be self

- dispersing in water , they should be tested at or below their dispersability limits ( EPA 1996) . Therefore, although EPA is not requiring water solubility testing for castor oil, sodium salt , as noted below ; aquatic toxicity testing of this chemical is still possible and is still required.19

In regards to mammalian toxicity , i t is unclear h ow and to what degree sulfation or oxidation would modify

the toxicity

of castor oil . On the one hand, the NTP has conducted 13 - week dosed - feed studies in rats and mice using castor oil (CAS No . 8001 - 79 - 4) and has found little evidence for toxicity (NTP, 1 992) . It is also true that castor oil has been designated as generall y recognized as safe b y FDA for certain purposes (FDA 2008) . A review of information from the DART database indicates that castor oil has been contraindicated for use in pregnancy (Anon, to 1984); additional references refer to the labor - inducing potential of this substance, especially toward the end of pregnancy (e.g., Anon, 2007; Gosselin et al., 1976; Garry et al., 2000) . Much of the data on the effect of castor oil on pregnancy

have b een collected in humans, while less information is available for laboratory animals . These data on humans are of limited use. D osing of humans during pregnancy is limited and generally anecdotal , while dosing in animals would be regimented and, when condu cted correctl y, provide a dose response for targeted endpoints) (Anon, 2007) . A labor - inducing effect implies the possibility of toxic effects during earlier stages of pregnancy , some of which could also impact fetal development . The NTP (1992) studies did not test castor oil on pregnant animals nor were an y developmental studies of castor oil conducted . Therefore, the suggestion that castor oil may be an adequate supporting chemical for castor oil, sulfated, sodium salt and castor oil, oxidized requires acknowledgement of the possibility

that unmodified castor oil, while recognized as having low toxicity under man y exposure scenarios, may

be somewhat more toxic to a pregnant women and her fetus . The best way to determine the effect of sulfation or oxidation on castor oil toxicity is through testing of the substances themselves . However, EPA has received f rom another commenter, Vertellus, adequate data for acute mammalian toxicity

for castor oil, oxidized , and is not requiring that testing for castor oil, oxidized, in this final rule. While castor oil, sulfated, sodium salt, is listed in a Health Canada d ocument in a table entitled “Substances not requiring further work for human health at this time,” (Health Canada , 2006) , Health Canada notes that it “will track these substances for an y new information that might warrant subsequent action (e.g., assessment)” (Health Canada, 2007). Since EPA did not locate an y adequate aquatic or mammalian data on castor oil, sulfated, sodium salt or castor oil, oxidized, (except, as noted, acute mammalian toxicity data for castor oil, oxidized), the test rule for both subs tances is appropriate. Comment. Vertellus commented that aquatic toxicity tests on oxidized castor oil would be problematic due to the extreme insolubility of this material. Response . EPA agrees and therefore is not requiring this testing . Comment. Vertellus also commented on bacterial reverse mutation, chromosomal aberration, mammalian repeated - dose, reproduction and developmental toxicity testing of oxidized castor oil . Vertellus indicates that the NTP report on castor oil results should reflect th e worst case toxicity scenario . Oxidized castor oil should be even less biologicall y active and bioavailable; therefore, they believe this testing is unnecessary . Response . As indicated in an earlier response on castor oil, oxidized, it is unclear how and to what degree the toxicity

of castor oil would be modified by oxidation . Again, the best way to determine the effect of oxidation on castor oil toxicity is through testing of the substance itself.20

Comment . Vertellus submitted comments on oxidized castor oil (CAS No. 68187 - 84 - 8) . Vertellus commented that testing for melting point is not applicable, since oxidized castor oil is a liquid at room temperature. Response . The melting point ideally is identical with the solidification or freezing point . Therefore, a measured freezing point would in this case meet the obligation to report the melting point. Since ASTM E - 324 - 99 (capillary tube) does not specifically include instructions for determining freezing point, EPA is instead requiring OECD 102 (melt ing point/melting range) which includes guidance for determining that endpoint . Comment . Vertellus commented that for boiling point, they expect oxidized castor oil, like castor oil, to decompose on heating, which complicates determining this endpoint. Response . If the substance will be decomposed upon heating, then the decomposition temperature would in this case meet the obligation to report the boiling point. Comment . Vertellus commented that u sing EPA’s EPIWIN, vapor pressure for oxidized castor oil is estimated to be 2.0 x 10 - 31 mm Hg at 25 o C which, given the viscosity of various oxidized castor oils, appears to be valid, and that OECD guidance indicates that the need for testing for this endpoint is therefore unnecessary. Response . EPA agrees . A measured value of this endpoint is a proposed testing requirement for HPV chemicals . However, if an estimated value is much smaller than the cut off value (i.e., 1x 10 - 8 mm Hg), then the estimated value must be reported/stated as <1x 10 - 8 mm Hg f or this endpoint. Comment . Vertellus commented that Method C would be indicated according to the proposed rule, but that the n - Octanol/Water Coefficient ( log Kow) is estimated to be 17.97 using EPA’s EPIWIN modeling software and OECD guidance indicates that log Kow may not work for surfactants, polymers, inorganics, and organometallics . Therefore Vertellus questions the feasibility of this testing requirement. Response . EPA agrees . Although a measured value for log Kow is a proposed testing requirement for HPV chemicals , an estimated value is also acceptable if the value is expected to be higher than 8 . In addition, if the tested substance has a surfactancy propert y, as is the case for castor oil, sulfated, sodium salt, the testing of this endpoint is no t feasible. Therefore, EPA is not requiring this testing endpoint in the final rule for either of these chemical substances . Comment . Vertellus commented that EPA’s EPIWIN model estimates a water solubility of 2.5 x 10 - 16 mg/ L at 25 o C and that the HVP2 NPRM states that no testing is required where solubility is estimated at < 0.01 mg/L. Response . EPA agrees, with a correction to Vertellus’ comment . Although a measured value for water solubility is a proposed testing requirement for HPV ch emicals, if the estimated value is expected to be equal to, or smaller than, 0.001 mg/L (i.e., ≤ 0.001 mg/L ; but not <0.01 mg/L as indicated in the comment for this endpoint), no testing is required . An estimated value is acceptable only under this c ondition, and must be reported as < 0.001mg/L for this endpoint.21

Special Note . Although EPA did not receive comments specific to the endpoints of log Kow or w ater s olubility for castor oil, sulfated, sodium salt; because of its surfactant nature and sim ilarity in structure to castor oil, oxidized, EPA cannot make the §4(a)(1)(A)(iii) finding that testing is necessary to develop data for these endpoints, and therefore is not requiring testing of those endpoint s for that chemical substance. However, becaus e of its chemical surfactancy properties , EPA is still requiring aquatic toxicity

testing for castor oil, sulfated, sodium salt . 8 . Benzenediamine, ar,ar - diethyl - ar -methyl (CAS No. 68479- 98- 1). Comment. AWOs commented that aquatic toxicity data are available for benzenediamine, ar,ar diethyl - ar - methyl in goldfish (Bay er MaterialScience LLC, 2007) . For this reason, AWOs believe that EPA must review these data and reconsider its requirements for this substance in the proposed test rule. Response . EPA disagrees . The document referenced by AWOs is a material safet y data sheet (MSDS) for the product BAYTEC 505, which is the substance in question . The current version of this document (Ba ye r MaterialScience LLC, 20 08) contains some information on the toxicity of benzenediamine, ar,ar - diethyl - ar - methyl (referred to in the document as diethyltoluenediamine, or DETDA) . Although the MSDS provides an LC 50 value for acute toxicity to fish, it does not provide study detail s that are needed to evaluate the reliability of the study

from which this value was derived . For this reason, data obtained from the MSDSs are considered to be insufficient . Given the absence of adequate data, EPA is requiring aquatic toxicity testing on benzenediamine, ar,ar - diethyl - ar - methyl. Comment . Albemarle Corporation (Albemarle) commented that a melting point value was available for benzenediamine, ar,ar - diethyl - ar - methyl and provided the value of 104.64 °C (MPBPWI N v 1 .42) . Response . A measured value for this endpoint is required for HPV chemicals . The melting point value provided by

Albemarle using MPBPWI N v 1 .42 was an estimated value. Therefore, a measured value is still needed. Comment . Albemarle provided boiling point values of 3 28.81 °C and 308 °C. Response . A measured value of this endpoint is required for HPV chemical s . The value of 328.81°C was an estimated value. The value of 308°C was a measured value and is the preferred value . Although this value was determined in a non - G LP study in Albemarle’s laboratory , it is consistent with the boiling point value estimated b y MPBW IN v1.42 . EPA finds these data acceptable and no further testing on this endpoint is needed. Comment . Albemarle provided estimated water solubility values of 695.3 mg/L, 461 .9 mg/L and 151.6 mg/L. Response . A measured value of this endpoint is required for HPV chemicals. According to the proposed test rules for this endpoint, if the estimated value is expected to be equal to, or smaller than, 0.001 mg/L, no testing is required . However, an estimated value is acceptable only under this condition and there were three different estimated water solubility values provided in Albemarle's comments.22

These three estimated values all fell into the > 10 mg/L - 5,000 m g/ L data range as stated in the proposed rule for the water solubility . Therefore, the Method A, B, C, or D must be used to obtain a measured value for this endpoint. Comment . Albemarle provided an estimated vapor pressure value of 0.000132 mm Hg. Response . A measured value for this endpoint is required for HPV chemicals. The vapor pressure value provided was an estimated value and was greater than the cut - off value of 1x 10 - 8 mm Hg that would negate the need for the required measured value . Therefo re, a measured value is still needed. Comment . Albemarle provided an estimated log K ow value of 2.23 and a corresponding BCF of 10.46. Response . A measured value of this endpoint is required for HPV chemicals. The log K ow value provided was an estimated value . Therefore, a measured value is still needed. Comment. Albemarle commented that, based on estimates obtained using the ECOSAR program of EPI Suite, benzenediamine, ar,ar - diethyl - ar - methyl (also known as DETDA) may be toxic to fish, daphnia and aquatic plants on an acute basis and to daphnia on a chronic basis; therefore, since these effects are adequatel y characterized b y EP IS uite, actual testing of DETDA is not indicated. Response . Although ECOSAR modeling is a useful tool in predicting the toxici ty of substances, it does not provide an adequate substitute for actual testing . The test rule requires that actual testing be performed on DETDA because no adequate measured data exist for aquatic toxicity endpoints for this substance . Therefore, aquatic toxicity testing continues to be required for DETDA. Comment. Albemarle commented that DETDA has been tested in Ames, DNA repair, in vitro cell point mutation, in vitro cell transformation, in vivo rodent dominant lethal, and in vivo mouse micronucleus tests . Certain of these tests were conducted according to OPPTS/OECD guidelines and GLPs; others were performed prior to the adoption of formal guidelines . Copies of these studies (listed in Table 3) have been previously forwarded to EPA . Additional testin g is not indicated. Response . EPA disagrees that additional testing is not indicated on DETDA . Albemarle submitted a table (Table 3 in their letter) representing previously submitted documents representing studies conducted on DETDA . Only one of those doc uments represents a genetic toxicity study (Lonza Inc., 1983) . While EPA does have this study available, the study is not adequate for the gene mutation endpoint as no information was provided b y the sponsor as to the purity of the test substance. EPA does not have the other genetic toxici ty studies that Albemarle referred to , but did not provide in their comment, nor could these studies be located elsewhere . A bacterial reverse mutation test and a test for chromosomal damage, as indicated by Table 3 in the test rule document, is still required. Comment. Albemarle also commented that DETDA has been tested in multiple repeated - dose studies including a 28 - day

oral range - finding study , a 21 - day dermal repeated - dose study , a 90 - day repeated dose study , a 28 - d ay

repeated - dose study

with a reversibility

component, and two - ye ar carcinogenicity23

tests (including gavage, dietary and subcutaneous injection) . Neither the male nor female reproductive tracts were identified as target organs . These studies (listed in Ta ble 3 of Albemarle’s comments ) have been previousl y forwarded to the agency . Additional testing for reproductive endpoints is not indicated given the results of the multiple repeated - dose studies and also the available industrial hygiene monitoring data. Response . Even with the male and female reproductive tracts not identified as target organs in previously

conducted repeated - dose studies on DETDA, this information alone is not adequate to obviate the need for reproductive and developmental toxicity testi ng . Had developmental toxicity testing been performed on DETDA and all negative results obtained for developmental endpoints, that information, along with negative toxicity results for male and female reproductive tracts in repeated dose studies of adequ ate length, may have eliminated the need for further reproductive toxicity testing . However, no developmental testing has been conducted on DETDA . The available industrial h ygi ene monitoring data are not utilized in making a determination regarding the nee d for reproductive and developmental testing . Therefore, EPA continues to require a combined repeated - dose toxicity study with the reproductive/developmental toxicity screening test for DETDA. 9. Alkenes, C12 -24, chloro (CAS No. 68527 - 02 - 6). Comment. EPA received comments from AWOs and the Chlorinated Paraffins Industry Association (CPIA) on alkenes, C12 - 24, chloro . AWOs commented that proposed aquatic, acute mammalian and mutagenicity

testing are available with IUCLID data sheets for this CAS number . AWO s also commented that this chemical mixture is another good candidate for SAR or category data fulfillment . CPIA stated that testing conducted on similar classes of chlorinated paraffins (CPs) and data currently being developed under the OECD and SIDS program and ICCA HPV Initiatives should satisfy the proposed testing requirements. Response . An International Uniform Chemical Information Database (IUCLID) document is available for CAS No. 68527 - 02 - 6 (European Chemicals Bureau, 2000b). The IUCLID document, however, does not contain sufficient information to evaluate the adequacy of the data presented for aquatic and acute mammalian toxicity or mutagenicity . It should be noted that the only aquatic data contained in the IUCLID document is on the acute toxicity to fish endpoint . Moreover, the data in the IUCLID document for the aquatic, acute mammalian and mutagenicity endpoints were collected on chemicals that have different CAS numbers from that of alkenes, C12 - 24, chloro. Since the IUCLID document supplies references for the studies provided, EPA conducted a further evaluation of the studies contained in the document . Upon evaluation of the information from these references (ECOTOX; Zeiger et al. 1987; Birtley et al. 1980; NTP 1986), EPA agrees that the sub stances used for testing (CAS No. 63449 - 39 - 8 for aquatic and mutagenicity testing; CAS No. 85535 - 85 - 9 for acute oral toxicity testing in rats) are appropriate as supporting chemicals for alkenes, C12 - 24, chloro . Moreover, the data supplied for acute mammal ian toxicity and mutagenicity

testing are adequate to support these endpoints . The NTP 1986 document supplies adequate data on repeated - dose toxicity testing of CAS No. 63449 - 39 - 8 as a supporting chemical . Therefore, upon further consideration, EPA has det ermined that no further testing is required on alkenes, C12 - 24, chloro for the acute mammalian, repeated - dose, and mutagenicity endpoints. Reproductive and developmental testing is still required, as is chromosomal aberrations testing.24

The situation for aquatic toxicity testing is more complex . The IUCLID document for CAS No. 63449 - 3 9 - 8 (European Chemicals Bureau, 2000e) indicates that this substance is not water soluble, and reports a measured log K ow of > 6 . The proposed test rule indicates that a s ubstance requiring aquatic toxicity testing that has a measured log K ow of ≥ 4.2 belongs to Test Group 2 . Inthis case, the substance is required to have chronic toxicity to Daphnia testing, as well as toxicity to aquatic plants testing . The IUCLID document for CAS No. 63449 - 29 - 8 indicates that this substance has been subjected to chronic Daphnia testing . However, these data appear to be inadequate to fulfill the test rule, as no analy

tical monitoring was conducted during the study , other information on methods used was not provided, and the study description specifies that an emulsifier was used, without providing information on what the emulsifier was . Therefore, EPA continues to require chronic Daphnia testing for alkenes, C12 - 24, chloro . Moreover, toxici ty to aquatic plants testing is still required because no data are available for this endpoint . Comment. EPA received comments from the Chlorinated Paraffins Industry Association (CPIA) on alkenes, C12 - 24, chloro. CPIA commented that while the subject c hemical in the HPV2 proposed rule is a chloroalkene, EPA previously concluded that chlorinated alkanes and alkenes should be treated as similar products since the chlorination process eliminates any unsaturated double bonds in the alkene feedstock (see EPA statements in November 30, 1994, final TRI rule). While this chlorinated paraffin spans all three main product classes, it is predominantly a mixture of long - chain isomers, and relevant data will be from the long - chain product profile currentl y under deve lopment. CPIA intends to submit a specific profile for this compound after completion of the long - chain product Dossier pursuant to the ICCA program, and CPIA commits to submit to EPA the necessary robust summaries earl y next year. For all these reasons, C PIA believes that EPA should not pursue a final HPV test rule on CAS No. 68527 - 02 - 6. Response. The review that EPA conducted for the se substances under TRI in 1994 is not relevant to the review EPA must conduct to meet its requirements for this substance under TSCA section 4. T he substances that CPIA refers to in their comments are, under TSCA, different chemical substances. EPA agrees that analog data may sometimes be appropriate. H owever, EPA evaluates the appropriateness of using substitute data from an “analog substance” on a case - by - case, test - by - test basis, and in the case of the testing above; EPA has accept ed analog data for certain of the proposed testing endpoints. However, for othe r testing endpoints, EPA does not agree that the surrogate chemicals are acceptable analogs. Furthermore, while CPIA indicated they are sponsoring this substance under the ICCA program, as of this time EPA has not received these data . Upon receipt, EPA wil l evaluate the data for adequacy , and if adequate, EPA will accept them as meeting the corresponding testing requirements in the rule . In summary , EPA is not finalizing the acute mammalian, repeated - dose, and in vitro mutagenicity

tests proposed for alk enes, C12 - 24, chloro . EPA continue s to require testing on the following endpoints of the proposed test rule: ph ysical/chemical properties (all), biodegradation, aquatic toxicity

testing ( C1, Test Group 2), in vitro chromosomal aberrations, and reproductiv e and developmental toxicity . For an y t esting that CPIA does not sponsor before publication of the final rule, any testing performed must meet the requirements specified in the rule.25

10 . Hydrocarbons, C>4 (CAS No. 68647 - 60- 9). Comment. EPA received a comment from AWOs on hydrocarbons, C>4, that the proposed fish acute toxicity test is unnecessary

since it is known that hydrocarbons kill fish via non - polar narcosis. Response . Although it is expected that hydrocarbons can be lethal to fis h because of their non - polar nature, the purpose of the acute toxicity test is to determine the actual LC 50 of the compound . Without testing, vital information on the lethality of h ydrocarbons, C>4, would not be available . Therefore, EPA requires acute tox icity to fish testing on h ydrocarbons, C>4. 11 . Phenol, 4,4’

-methylenebis[2,6

-bis]1,1 - dimethylethyl) - (CAS No. 118- 82 - 1). Comment. EPA received comments from Albemarle on proposed aquatic toxicity testing (Category C1) for phenol, 4,4’ - methylenebis[2,6 - b is]1,1 - dimethylethyl) - . Albemarle asked what aquatic toxicity testing under C1 is required for this compound, Test Group 1 or Test Group 2, given the submitted Log Kow values . The log K ow was submitted by Albemarle Corp. previously (White 2005); the log K o w was > 6.5 . A study

report conducted by

Shell using an HPL C method gave a log Kow value of 7.4 at pH 6.9 . Albemarle assumes that these studies were acceptable and the Test Group 2 (chronic toxicity testing) covers the endpoints proposed to be tested based on the log K ow . Regarding the toxicity to plants, Albemarle Corp. references Mattock, S.D. and A.E. Girling, “Ionox 220: acute toxicity ( Salmo gairdneri, Daphnia magna and Selanastrum capricornutum ) and N - Octanol/Water Partition Coefficient” (Shell Oil, NTI S document ID 88 - 920003444, 1988) as fulfilling this requirement . Response . EPA agrees in part . As indicated on Table 3 of the proposed rule 40 CFR Part 799, §799.5087, when aquatic toxicity testing is required, a test group which specifies the tests to be performed is determined by the test substance’s measured log K ow , as obtained under Test Category A, or using an existing log Kow . Albemarle is correct in determining that Test Group 2 is required for testing phenol, 4,4’ - methylenebis[2,6 - bis]1,1 - dimethylethyl) - , based on the log Kow s that Albemarle reports in their comment . Test Group 2 requires that chronic tox icity to Daphnia and toxicity

to plants (algae) testing be performed . However, Albemarle’s assumption that these tests were performed, or performed adequatel y, appears to be incorrect . The referenced study conducted by

Shell Oil (Mattock and Girling , 1988) describes onl y acute, but not chronic, testing on Daphnia with I onox 220 (Ionox 220 is a trade name for phenol, 4,4 - methylenebis[2,6 - bis]1,1 - dimethylethyl) - ) . Although this same study reported testing of Ionox 220 in algae, EPA considers this testi ng to be in adequate . The authors of the study indicated that the test substance appeared to be out of solution at certain concentrations . This observation is not unexpected, since this substance has an extremely low water solubility (estimated log K ow of 8 .99; estimated water solubility of 0.0001707 mg/L) . The highest concentration tested was 1000 mg/L . The authors reported that no toxicity to algae was observed . Therefore, the 96 - hour EC 50 was reported as > 1000 mg/L . No analy

tical monitoring of the test substance concentration was performed during testing and no description was provided for how the test substance was solubilized . Therefore, EPA is requiring that aquatic toxicity testing be performed on phenol, 4,4’ - methylenebis[2,6 - bis]1,1 - dimethylethyl) - under Test Group 2 . Both tests in this test group are required . Comment. AWOs commented that acute toxicity to fish testing is requested for phenol, 4,4 - methylenebis[2,6 - bis]1,1 - dimethylethyl) - , and indicates that EPA should not include this require ment,26

based on data submitted by Shell Oil Company

to EPA on 06/09/1992, which includes acute toxicity to steelhead trout and chronic toxicity to fathead minnows (EPA TSCATS Database 2008) . Response . The comment was in error, as EPA is not requesting acute toxicity to fish testing for phenol, 4,4 - methylenebis[2,6 - bis]1,1 - dimethylethyl) - in the proposed test rule . Rather, EPA is requiring chronic Daphnia testing and toxicity to aquatic plants testing for this chemical . Comment. AWOs comment ed that Ex xonMobil may have data available for 10W - 30 motor oil, of which phenol, 4,4’ - methylenebis[2,6 - bis]1,1 - dimethylethyl) - is one of two ingredients . Mobil states that based on available data, the substance is not expected to be harmful to aquatic organisms (Ex xonMobil, MSDS, 2007). Response . EPA disagrees with the comment . The current material safet y data sheet (MSDS) of ExxonMobil for Mobil 1 High Mileage 10W - 30 (ExxonMobil, 2009) indicates that phenol, 4,4’ - methylenebis[2,6 - bis]1,1 - dimethylethyl) - is one of at least two ingredients in the product, and also indicates that Mobil 1 High Mileage 10W - 30 is not expected to be harmful to aquatic organisms . However, the MSDS provides no information on the amount of each ingredient in the product, nor does it provide a basis for the expectation that the product would not be harmful to aquatic organisms . Since the product is a mixture, further information on the composition of Mobil 1 High Mileage 10W 30 would be needed to determine if it is an acceptable analog for ph enol, 4,4’ - methylenebis[2,6 - bis]1,1 - dimethylethyl) - . Aquatic toxicity data on the product would also be needed for EPA to determine if adequate aquatic toxicity data exist for fulfillment of the proposed test rule . 12 . Phosphorochloridothioic acid, O,O- diethyl ester (CAS No. 2524- 04- 1). Comment . AWOs commented that aquatic toxicity testing is not needed for phosphorochloridothioic acid, O,O - diethyl ester because it is a chemical intermediate that is insoluble in water. Response . EPA disagrees . Phosphorochloridothioic acid, O,O - diethyl ester can be expected to hydrol yz e quickl y in water to produce two tautomeric forms of O,O - diethyl phosphorothionate (also known as dieth yl thiophosphoric acid, or DETP; CAS No. 2465 - 65 - 8) and hydrochloric acid (HCl ) . One tautomeric form of DETP contains a P=S bond and the other form contains a P=O bond . These tautomers exist in equilibrium . The parent chemical, as well as both tautomers of DETP, are predicted by EPI Suite modeling to be highl y soluble. The water sol ubilities predicted by EPI Suite are 468, 1008, and 24,050 mg/L for the parent compound, the P=S tautomer of DETP and the P=O tautomer of DETP, respectivel y . EPI Suite also predicted log Kow values of 2.37, 2.09, and 0.48 for the same three chemicals, resp ectivel y . Since the predicted log K ow values are < 4.2 for the parent compound as well as for both tautomers of DETP, testing should be conducted in accordance with the requirement of Test Group 1, as indicated in Table 2 of the proposed test rule . Pri or to aquatic toxicity

testing, a h ydroly sis test is recommended to determine the half - life of the parent chemical and to confirm the h ydrol ys is products . Depending upon the half - life for the parent chemical, testing of either phosphorochloridothioic acid, O,O - diethyl ester or its degradation products is recommended as described in OECD 23 (Guidance Document on Aquatic Toxicity Testing of Difficult Substances and Mixtures, Section 3.5: Substances that degrade in the test sy stem) .27

It should be noted that HCl produced by the h ydrolysis reaction could significantly lower the pH of the test solution . For example, at a concentration of 10 mg/L, if the parent chemical h ydrol yz ed completely , the HCl produced would be predicted to lower the pH of a neutral soluti on to approximately

4.3 . Therefore, both degradation products (HCl and DETP) would be expected to have detrimental effects on aquatic organisms. In further support of the solubility of phosphorochloridothioic acid, O,O - diethyl ester and its hydrol ys is pr oducts is information from the IUCLID d ataset for phosphorochloridothioic acid, O,O diethyl ester, as well as values for the P=S tautomer of DETP provided by ECOSAR, both of which suggest potential moderate toxicity of the parent compound and its hydrol ysi s products . An L C 50 of 62 mg/L for 24 - h acute fish toxicity testing conducted on guppies (Poecilia reticulata ) is reported in the IUC LID Dataset . Aquatic toxicity values estimated by

ECOSAR for phosphorochloridothioic acid, O,O - diethyl ester are as follows : 96 - h L C 50 for fish = ~8 mg/L; 48 - h LC 50 for Daphnia = ~6 mg/L ; 96 - h EC 50 for green algae = ~4 mg/L . Aquatic toxicity values estimated by

ECOSAR for the P=S tautomer of DETP are as follows: 96 - h L C 50 for fish = ~11 mg/L, 48 - h LC 50 for Daphnia = ~8 mg/L, and 96 - h EC 50 for green algae = ~5 mg/L . Therefore, EPA continues to require testing of the parent substance or degradation products for acute toxicity to fish and Daphnia and toxicity to algae. In regards to its use as a chemical intermediate, this claim w ould need to be substantiated by a potential test sponsor (i.e., manufacturer or importer). Comment. EPA received comments from Albemarle on phosphorochloridothioic acid, O,O - diethyl ester (CAS No. 2524 - 04 - 1) . Albemarle reported production of this chemical in 2005 in the 2006 IUR report . Production of this chemical has since ceased and no further production is anticipated by Albemarle . The findings of “substantial production” and “substantial human exposure” should be re evaluated b y EPA. Response . EPA has examined this issue . Albemarle is not the only producer of this chemical and existing production data indicate that this chemical is still an HPV chemical . However, a company that does not manufacture or process the chemical nor intends to do so within the time period specified in 40 CFR 799.5087(b) of this rule , will not be responsible for conducting the testing . In the proposal (Ref. 60, p. 43326) to this final rule, EPA stated that certain of the chemicals for whic h mammalian toxicity-- repeated dose/reproduction/developmental toxicity testing is required may

be used solely

as "closed s ys tem intermediates," and if that were the case, such chemicals may be eligible for a reduced testing battery

which substitutes a dev elopmental toxicity study for the SIDS requirement to address repeated dose, reproduction, and developmental toxicity . EPA requested persons who believe their chemical is used solel y as a closed s ys tem intermediate to submit appropriate information along w ith their comments which substantiate this belief . EPA received no such claims from a chemical manufacturer of this substance . BI BLIOGRAPHY Acetaldeh yd e Working Group of the Vin yl Acetate Council (AWG) . Comments on EPA’s Proposed Test Rule for Testing of Certain High Production Volume Chemicals, Second Group of Chemicals, submitted to the TSCA Public Docket Office, EPA, October 22, 2008.28

Albemarle Corporation (Albemarle) . Comments on EPA’s Proposed Test Rule for Testing of Certain High Production Volum e Chemicals, Second Group of Chemicals, submitted to the TSCA Public Docket Office, EPA, October 21, 2008. American Chemistry

Council (ACC) . Comments on EPA’s Proposed Test Rule for Testing of Certain High Production Volume Chemicals, Second Group of Chem icals, submitted to the TSCA Public Docket Office, EPA, October 22, 2008. Anon . Castor oil is contraindicated in pregnant or menstruating women . American Formulary Service, Volumes Iand II . Washington, D.C.: American Society of Hospital Pharmacists . To 1 984, p.56:12. Anon . Final report on the safet y assessment of sorbic acids and potassium sorbate . Journal of the American College of Toxicology . 7(6): 837 - 880 . 1988. Anon . Final report on the safet y assessment of Ricinus communis (Castor) seed oil, hydrog enated castor oil, gl yc eryl ricinoleate, gl yceryl ricinoleate SE, ricinoleic acid, potassium ricinoleate, sodium ricinoleate, zinc ricinoleate, cetyl ricinoleate, eth yl ricinoleate, gl ycol ricinoleate, isoprop yl ricinoleate, methyl ricino leate, and octyld odecyl ricinoleate . International Journal of Toxicology . 26(Supplement 3): 31 - 77 . 2007. Ba ye r MaterialScience LLC . BAYTEC 505 Material Safety Data Sheet . 2008 . 8 p. Bentley , R.E., Sleight, B.H., and Macek, K.J . Preliminary evaluation of the acute toxicity of desensitized primer compounds and primer waste effluents to representative aquatic organisms . US Army Med. Res. Dev. Command, Washington, D.C. (U.S.NTI S AD - !026125) . 35 p . Birtley , R.D.N., Conning, D.M., Daniel, J.W., Ferguson, D.M., Longstaf f, E. and Swan A.A.B . The toxicological effects of chlorinated paraffins in mammals . Toxicology and Applied Pharmacology . 54: 514 - 525 . 1980. Brannen, K.C., Panzica - Kelley , J.M., Charlap, J.H., and Augustine - Rauch, K.A . Zebrafish: A nonmammalian model of developmental toxicology . In: Developmental Toxicology , Third Edition . D.K. Hansen and B. Abbott., eds . NY: Informa Healthcare . 2009, pp. 215 - 241. Buesen, R., Genschow, E., Slawik, B., Visan, A., Sppielmann, H., Luch, A., and Seiler, A . Embryonic stem c ell test remastered: Comparison between the validated EST and the new molecular FACS - EST for assessing developmental toxicity in vitro . Toxicological Sciences 108(2): 389 - 400 . 2009. Buzzell, J.C., Young, R.H.F, and Ryckm an, D.W . Behavior of organic chemi cals in the aquatic environment . Part II . Behavior in dilute sy stems . Environ. Sanitary Engineering Labs . Washington University , St. Louis, MO . 1968 . 81 p. Chapin, R.E. and Sloan R.A. 1997 . Reproductive assessment by continuous breeding: Evolving study design and summaries of ninety studies. Environmental Health Perspectives 105 (Suppl. 1): 199 - 395. Chlorinated Paraffins Industry Association (CPIA) . Comments on EPA’s Proposed Test Rule for Testing of Certain High Production Volume Chemicals, Second Grou p of Chemicals, submitted to the TSCA Public Docket Office, EPA, October 22, 2008.29

Demaree, G.E., Sjogren, D.W., McCashland, B.W. and Cosgrove, E.P . Preliminary studies on the effect of feeding sorbic acid upon the growth, reproduction and cellular metabo lism of albino rats . Journal of the American Pharmaceutical Association 44: 619 - 621 . 1955. Dy no Nobel, Inc. (Dy

no Nobel) . Comments on EPA’s Proposed Test Rule for Testing of Certain High Production Volume Chemicals, Second Group of Chemicals, submitted to the TSCA Public Docket Office, EPA, October 15, 2008. Ellis, M.M . Detection and measurement of stream pollution . In : Bull. Bur. Fish. No. 22 . U.S. Department of Commerce, Washington, D.C.: 365 - 437 . 1937. EPA. 1992. Risk Assessment Forum. Framework for Ecological Risk Assessment. EPA/630/R - 92 - 001. February

1992. EPA 1996 . Office of Prevent, Pesticides, and Toxic Substances (OPPTS) . Ecological Effects Test Guidelines . OPPTS 850.1000 . Special Considerations for Conducting Aquatic Laboratory Studies ‘‘Public Draft.” EPA 1999 . Office of Prevent, Pesticides, and Toxic Substances (OPPTS) . Letter from Susan H. Wayland, Deputy

Assistant Administrator, to participants in the voluntary HPV Challenge Program . October 14, 1999 . Available online at: http://www.epa.gov/chemrtk/ceoltr2.htm . EPA 2004a . Request for assistance in reviewing four studies for TSCA section 4 test rule . Memorandum from Maria Szilagyi, OPPT, Risk Assessment Division (RAD) to Donald Rodi er, High Production Volume Chemical Branch (HPVCB), RAD . October 5, 2004 . (Ref. 74 in the TSCA section 4 final test rule entitled “Testing of Certain High Production Volume Chemicals.”) EPA 2004b . TETRATOX test . Memorandum from Donald Rodier, RAD, to Greg Schweer, CITB CCD . November 1, 2004. EPA 2006 . OPPT . Final test rule for the Testing of Certain High Production Volume Chemicals . Federal Register (71 FR 13708, March 16, 2006 ) ( FRL

– 7335

–2) . EPA 2008 a . OPPT . Proposed Test Rule for the Testing of Certain High Production Volume Chemicals; Second Group of Chemicals . Federal Register (73 FR 43314, July 24, 2008) (FRL - 8373 - 9). EPA 2008b . Letter from Elizabeth Resek , Office of Science Coordination and Policy , EPA, to Samuel H. Wilson, Ph.D., NIEHS, on August 28, 2008 . http://iccvam.niehs/nih.gov/methods/acutetox/transmitFeb08/EPA - Response.pdf European Chemicals Bureau . 2000a . European Commission . IUC LID Data Set for Acetaldeh yde (CAS No. 75 - 07 - 0) . European Chemicals Bureau . 2000b . European Commission . IUC LID Data Set for Alkenes, C12 - 24, chloro (CAS No. 68527 - 02 - 6) .30

Europe an Chemicals Bureau . 2000c . European Commission . IUC LID Data Set for Ethanol (CAS No. 64 - 17 - 5). European Chemicals Bureau . 2000d . European Commission . IUC LID Data Set for C.I . L euco Sulphur Black I (CAS No. 66241 - 11 - 0). European Chemicals Bureau . 2000e . European Commission . IUC LID Data Set for Paraffin waxes and hydrocarbon waxes, chloro (CAS No. 63449 - 39 - 8). ExxonMobil Corporation . Material Safet y Data Sheet . Mobil 1 High Mileage 10W - 30 . 2009 . 8 p. Food and Drug Administration (FDA) . Code of Federal Regulations Title 21, Chapter 1, Subchapter B, Part 176 . In direct food additives: Paper and paperboard components . April 1, 2008. Food and Drug Research Labs . Teratologic evaluation of FDA 73 - 4 (potassium sorbate: Sorbistat) in mice and rats . Prepared un der DHEW Contract No: FDA 223 - 74 - 2176 . NTIS No. PB - 245520 . Waverly , NY. 1975. Garry , D., Figueroa, R., Guillaume, J., Cucco, V . Use of castor oil in pregnancies at term . Alternative Therapies in Health and Medicine . 6(1): 77 - 79 . 2000. Gaunt, I.F., Butterworth, K.R., and Gangolli, S.D . Long - term toxicity of sorbic acid in the rat . Food and Cosmetics Toxicology . 13: 31 - 45. 1975. Genschow, E., Spielman, H., Scolz, G., Seiler, A., Brown, N., Piersma, A., Brady, M., Celemann, N., Huuskonen, H., Paillard, F., et al . The ECVAM international validation study on in vitro tembryotoxicity

tests . Results of the definitive phase and evaluation of prediction models . Alternatives to Laboratory Animals . 30: 151 - 176 . 2002. Gosselin, R.E., Hodge, H.C., Smith, R.P., and G leason, M.N . Clinical toxicology of commercial products . 4 th Edition . Baltimore: Williams and Wilkins . 1976, p.II - 152. Health Canada. Results of the Health - Related Components of Categorization of the Domestic Substances L ist under CEPA 1999. July 27, 200 6. ( www.hc - sc.gc.ca/ewh semt/contaminants/existsub/categor/_result_substance/not_req - ne_aucune - 03 - eng.php ). Health Canada. Integrated Framework for the Health - Related Components of Categorization of the Domestic Substances List Under CEPA 1999: Questions and Answers. December 14, 2007. ( http://www.hc - sc.gc.ca/ewh - semt/contaminants/existsub/categor/question - 5 - eng.php ) . He& Answers Hutchinson, T.H. et al . A strategy to reduce the numbers of fish use d in acute ecotoxicity testing of pharmaceuticals . Environmental and Toxicological Chemistry . 22: 3031 - 3036 . 2003. Ishidate, M., Jr., Sofuni, T., Yoshikawa, K., Hay ashi, M., Nohmi, T., Sawada, M. and Matsuoka, A. 1984. Primary

mutagenicity

screening of food additives currentl y used in Japan. Food Chemistry and Toxicology

22: 623 - 636.31

Jerama, S., et al . A strategy to reduce the use of fish in acute ecotoxicity testing of new chemical substances notified in the European Union . Regulatory Toxicology and Pharmacology . 42: 218 - 224 . 2005. JSOnline 2008 . Article discusses sodium glucoheptonate in the workplace . Published in the Milwaukee - Wisconsin Journal Sentinel, August 24, 2008 . Available online at www.jsonline.com/news/milwaukee/32597744.html. Kinsner, A . et al . ECVAM ongoing activities to meet the cosmetics 2009 deadline related to acute oral toxicity . Presented at the 15 th International Congress on In Vitro toxicology, Stockholm, Sweden: September 25 - 288, 2008, p. 191. Larsen, J., Schultz, T.W., Rasmussen, L ., Hooftman, R., and Pauli, W . Progress in an ecotoxicological standard protocol with protozoa: Results from a pilot ring test with Tetrahymena pyriformis . Chemosphere . 35(5): 1023 - 1041 . 1997. LeBlanc, G.A. Intersp ecies relationships in acute toxicity of chemicals to aquatic organisms. Environmental Toxicology and Chemistry . 3: 47

– 60. 1984. National Institute of Environmental Health Sciences (NIEHS) 1997 . [cited in supporting documentation section of HPV1 final rule

— alread y in HPV1 docket] . Lonza, Inc. Salmonella/mammalian - microsome mutagenicity test with P 5183. Report from Research Consulting Company , Ltd., Project 019620. 1983 . Mattock, S.D., and Girling, A.E . Ionox 220: Acute toxicity ( Salmo gairdneri , Daph nia magna and Selanastrum capricornutum ) and N - octanol/water partition coefficient (Shell Oil, NTI S document ID 88 - 920003444). 1988 . Available through TSCATS. May er, F.L., Jr., and Ellersieck, M.R . Manual of acute toxicity : Interpretation and database f or 410 chemicals and 66 species of freshwater animals . U.S. Department of Interiors, Resource Publication No. 160, U.S. Fish and Wildlife Service, Washington, D.C . 1986 . 505 p. Mackay , D. et al . A ph ys icochemical foundation for baseline toxicity . Submitte d for publication, Personal Communication, 2008. National Toxicology

Program (NTP) . Oxalic acid (CAS No. 144 - 62 - 7) . Reproduction and fertility assessment in CD - 1 mice when administered in drinking water . Abstract, NTP Report No. RACB84064 . September 1985. NTP, National Institutes of Health, U.S. Department of Health and Human Services . Toxicity studies of castor oil in F344/N rats and B6C3F 1 mice [dosed feed studies] . Technical Report Series, NTP Tox 12, March 1992. NTP . National Institutes of Health, U.S. Department of Health and Human Services . Toxicology and carcinogenesis studies of chlorinated paraffins (C 23 , 43% chlorine) (CAS No. 63449 - 39 - 8) in F344/N rats and B6C3F 1 mice (gavage studies) . Technical Report Series No. NTP TR 305. May 1986 .32

Peopl e for the Ethical Treatment of Animals (PETA) . Comments on EPA’s Proposed Test Rule for Testing of Certain High Production Volume Chemicals, Second Group of Chemicals, submitted to the TSCA Public Docket Office, EPA, October 22, 2008. Phy sicians Committee for Responsible Medicine (PCRM) . Comments on EPA’s Proposed Test Rule for Testing of Certain High Production Volume Chemicals, Second Group of Chemicals, submitted to the TSCA Public Docket Office, EPA, June 4, 2008. Riley , R.G., Zachara, J.M., and Wobbe r, F.J . Chemical contaminants on DOE lands and selection of contaminant mixtures for subsurface science research . U.S. Department of Energy . U.S. Department of Commerce, NITS Document No. DE92 014826 . April 1992. Shtenberg, A.I., and Ignat’ev, A.D . Toxico logical evaluation of some combinations of food preservatives . Food and Cosmetics Toxicology . 8: 369 - 380. 1970. Sprince, H., Parker, C.M., Smith, G.G., and Gonzales, L .J . Protection against acetaldeh yd e toxicity in the rat b y L - cy steine, thiamin and L - 2 - methylthiazolidine - 4 - carbox yl ic acid . Inflammation Research . 4(2): 125 - 130. 1974. SRC. Sy racuse Research Corporation. 2010a. EPI Suite Estimation result (p rintouts) for Ethanedioic acid; [CASRN: 144 - 62 - 7] June 30, 2010 SRC. Sy racuse Research Corporation . 2010b. EPISuite Estimation result (printouts) for D - gluco heptonic acid, monosodium salt, (2.xi.) - ; [CASRN:31138 - 65 - 5]. June 30, 2010. Tonogai, Y., Ogawa, S., Ito, Y., and Iwaida, M . Actual survey on TLM (median tolerance limit) values of environment al pollutants, especiall y on amines, nitriles, aromatic nitrogen compounds . The Journal of Toxicological Sciences 7(3): 193 - 203 . 1982 . Veith, G., et al . A baseline model for the inhalation toxicity from nonspecific chemical interactions in mammals . Submi tted for publication, Personal Communication, 2008. Vertellus Specialities, Inc . (Vertellus) . Comments on EPA’s Proposed Test Rule for Testing of Certain High Production Volume Chemicals, Second Group of Chemicals, submitted to the TSCA Public Docket Offi ce, EPA, October 22, 2008. Walker, R., Toxicology

of sorbic acid and sorbates . Food Additives and Contaminants . 7(5): 671 - 66 . 1990. Zeiger, E., Anderson, B., Haworth, S., Lawlor, T., Mortelmans, K. and Speck, W . Salmonella mutagenicity

tests: III . Results from the testing of 255 chemicals . Environmental Mutagenesis . 9, Supplement 9: 1 - 100 . 1987.33 APPENDIX CHECKLIST FOR OTHER SOURCES OF DATA ON HPV CHEMICALS PubMed - Bibliographic database that contains references to journal articles in th e life sciences with a concentration on biomedicine TOXNET - National L ibrary of Medicine databases on toxicology , hazardous chemicals, environmental health, and toxic releases; includes:  TOXLINE with BIOSI S and NTI S;  Development and Reproductive Toxicology File (DART);  Chemical Carcinogenesis Research Information Sy stem (CCRI S) - Carcinogenicit y and mutagenicity

test results for over 8000 chemicals);  Hazardous Substances Data Bank (HSDB) - Comprehensive, peer - revie wed toxicology data for about 5000 chemicals;  Genetic Toxicology Data Bank (GENE - TOX) - Peer - reviewed genetic toxicology test data for over 3000 chemicals. TSCATS - Unpublished technical reports submitted by industry to the EPA Registry of toxic effects of chemical substances (RTECs) Environmental Fate Database (EFDB) ECOTOX - EPA’s peer - reviewed ecotoxicology database EPA’s Integrated Risk Information Sy stem (IRIS) website USEPA - TRI(Toxics Release Inventory Chemicals website ) USEPA - Ambient Water Quality Criteria website (Both Human Health and Aquatic L ife) USEPA - Drinking Water Standards website USEPA - OPP (Office of Pesticide Programs) websites Agency for Toxic Substances and Disease Registry (ATSDR) website National Toxicology

Program (NTP) website International Program on Chemical Safet y Concise International Chemical Assessment Documents (IPCS INCHEM or CICADs) European Chemical Substances Information Sy stem (ESI S) - source of IUCLID Datasets34

NLM d atabases (ChemID to locate available data sources including Medline/PubMed, Toxline, HSDB, ATSDR, EPA SRS, etc.), STN/CAS online databases (Registry file for locators, ChemAbs for toxicology

data, RTECS, Merck, etc.) and Science Direct