  
		







      Testing of Certain High Production Volume Chemicals-     Second Group of Chemicals; Final Rule

			Response to Public Comments










										

						             					








           Prepared by 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, 2010










                               Table 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 toxicity test method									       6
      3. Aquatic toxicity test method									       7 
      4. Genetic toxicity test method									       9
       5. Reproductive and developmental toxicity screening						       9

D. Animal Welfare Considerations									     10 

E. Chemical Specific Comments									     10

      1. Acetaldehyde (CAS No. 75-07-0)								     10
      2. 1,3-Propanediol, 2,2-bis[(nitrooxy)methyl]-, dinitrate(ester) (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)			     17
      6. C.I. Leuco Sulphur Black 1 (CAS No. 66241-11-0)						     17
      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)						     23
     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-diethyl ester (CAS No. 2524-04-1)			     26

Bibliography				  							                 27

Appendix                                                                                                                                                 33



     A. Introduction

	This document contains a summary of the comments received by 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: 

         * The Acetaldehyde Working Group (AWG) of the Vinyl Acetate Council, 
         * Albemarle Corporation (Albemarle), 
         * American Chemistry Council (ACC),  
         * Chlorinated Paraffins Industry Association (CPIA), 
         * Dyno Nobel, Inc. (Dyno Nobel), and 
         * Vertellus Specialties, Inc (Vertellus). 
      
	EPA also received comments from a number of Animal Welfare Organizations (AWOs).  Many AWOs submitted comments under the letterhead of People for the Ethical Treatment of Animals (PETA), and contained comments on behalf of PETA, the Physicians Committee for Responsible Medicine (PCRM), the Alternatives 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 Society 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 Inventory 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 is 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 affected chemical companies) should carefully examine all publicly available chemical 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 EPISuite site and OECD on its QSAR site before conducting any animal testing. It was further suggested that there be a better attempt at pooling available knowledge by grouping chemicals into categories to characterize hazard and minimize animal testing.

Response. In the voluntary HPV program, sponsors were provided with the opportunity to use all tools available, including Quantitative Structure Activity Relationship (QSAR) models, EPISuite, and any other sources of information that would obviate the need for further testing of a compound of interest. Persons 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 and 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 consideration under a category or SAR approach, and that practicable measures are available at the time to modify the testing requirement, EPA would take such measures as are necessary to avoid unnecessary testing. However, no data were brought forward by a sponsor or commenter 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 recommended and utilized before any new in vivo testing is sponsored. AWOs also commented that existing test data may be sufficient to adequately evaluate a particular hazard or risk without additional testing in some instances. AWOs recommended that ongoing work on developing weight-of-evidence approaches by 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 (continually considered) and employed wherever 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 physical chemical property 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 physical properties 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 chemical's environmental fate is generally not necessary prior to assessing its toxicity. It is agreed that highly reactive chemicals that undergo instantaneous destruction upon exposure to the environment should not be tested for toxicity. However, reactivity of this nature is generally well known to those who manufacture, transport, use or otherwise handle the chemical in question. In addition, the reactivity 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 property testing has been conducted. 


Comment. AWOs commented that the proposed rule does not make sufficient use of category approaches, quantitative structure-activity relationships, weight-of-evidence approaches or integrated testing strategies as compared to the (voluntary) HPV Challenge Program.

Response. EPA disagrees. EPA welcomes the use of all of the above-stated approaches in determining the need for additional testing. Persons 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 substantiating this belief. However, no data were brought forward by 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. In the case of variable mixtures, such as those that may be observed 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 relying on one representative version of the complex mixture.


Comment. AWOs commented that the proposed rule response-to-comment period (120 days) 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 to the chemicals which they manufacture (or process) only. EPA anticipates that these data will be readily 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 consideration. 


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 necessary (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.
      
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 widely accepted globally, and, the HPV program is satisfying OECD screening 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 enforceability 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. Accordingly, in order to comply with this test rule, testing must be conducted in accordance with the specified mandatory and enforceable requirements in the ASTM or TSCA 799 series guidelines. EPA's 799 series guidelines, however, have been harmonized with the OECD guidelines. ASTM standards, like the TSCA guidelines, are internationally accepted 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 test 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 cytotox 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 definitive validation of this hypothesis with thousands of chemicals, with data expected in early 2009. AWOs suggested that EPA wait for these results in order to avoid unnecessary in vivo oral acute toxicity testing. In addition, an emerging method to estimate toxicity for exposures via the "inhalation route" (Veith, G. et al., 2008; Mackay, D. et al., 2008) should also be pursued.

Response. While EPA generally agrees that, for a variety of reasons, test methods which minimize the use of live animals are desirable, 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 cytotoxicity assay, EPA agrees with the conclusion of a 2006 ICCVAM Test Method Evaluation Report (ICCVAM/NTP 2006); namely, that data from the 3T3 NRU cytotoxicity assay may be used in a weight-of-evidence approach, where appropriate, for determining starting doses for in vivo acute oral systemic toxicity studies (EPA 2008b). EPA also agrees with ICCVAM's conclusion that these in vitro test methods are not sufficiently accurate to replace animals for regulatory labeling and hazard classification purposes (EPA 2008b). 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 ICCVAM report, 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 systemic toxicity tests, were based on validation studies conducted on only 72 chemicals.  EPA agrees that an evaluation of thousands of chemicals using the 3T3 NRU cytotoxicity 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 evaluate as of this writing. In the meantime, EPA continues to allow the use of many approaches, including SAR approaches and any other information to determine which industrial chemicals are most likely to be toxic. 

	3. Aquatic toxicity test method.

Comment. Albemarle disagrees 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 EPISuite software/PBT Profiler). Albemarle further commented that, as a practical matter, either acute and/or range-finding tests would generally need to be performed in order to properly select test concentrations for a chronic study. Thus, proceeding immediately into chronic studies based on log Kow is generally not possible. 

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 many 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 in providing guidance for test concentrations for the chronic study. If conducting an additional acute or range-finding study 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 Kow 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/EPISuite 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. Log Kow has been used as an indicator of bioconcentration potential in part because a bioconcentration factor (BCF) is frequently not available for HPV chemicals. To better refine bioconcentration potential when log Kow would suggest concern, valid fish bioconcentration studies are preferred by EPA. In the absence of measured values, the EPA EPISuite system is used to estimate bioconcentration potential. OPPTS P2 Framework/EPISuite software/PBT Profiler is also consistent in predicting that, in general, bioconcentration increases with increasing log Kow values. In addition, the model predictions from EPISuite 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 first be conducted on aquatic plants and invertebrates, as toxicity to these organisms (fish food supply) might obviate the need for fish toxicity testing.

Response. EPA disagrees. The 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 ecosystem. In addition, it is possible that a chemical substance may be much more toxic to fish than to aquatic plants or invertebrates. Therefore, it 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 OECD 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 possible 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 adequately validated, the Agency will continue to recommend approved guidelines studies and not studies under development, which may in fact not be adequately predictive. The acute fish toxicity test conducted in vivo will continue to be required. 

	Acute aquatic toxicity testing determines an LC50; 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 hours of exposure when lethality and /or serious morbidity are observed in two out of five fish (as described by AWOs). This does not appear to be a viable alternative to determining the correct LC50.


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 phylum from that of fish (LeBlanc 1984). Extrapolating from such a wide phylogenetic gap would introduce considerable uncertainty 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 not enable EPA to extrapolate to chronic effects; nor do they permit EPA to identify toxicity caused by metabolic activation or other mechanisms (EPA 2004b). 



	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 endpoints. In the 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 toxicity 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. In cases where an HPV chemical requires genetic mutation or chromosomal aberrations 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.

Comment. 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 combination 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 validated 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 probable 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 by the ECVAM has since been shown to have some significant drawbacks. The main drawbacks, from EPA's perspective, are the test's reliance on a morphological endpoint (contracting cardiomyocytes) and the training and validation required to ensure that personnel can reliably obtain repeat assessments for this endpoint. The 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 authors 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 readily hydrolyze 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 hydrolyze into only 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 hydrolysis products, it is not always clear how the hydrolysis products may interact as separate entities mixed together in vivo (i.e., one hydrolysis product may enhance the absorption of another hydrolysis product). A substance may be well-characterized as an individual entity when given by the oral route, but that result does not necessarily predict its toxicity when combined with another well-characterized, or not well-characterized, hydrolysis 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, routinely evaluates confounding factors such as these to eliminate unnecessary in vivo testing. 


Comment. AWOs indicated that mammalian and/or ecotoxicity testing with highly 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 all of those endpoints. Whether EPA decides to forego testing on any 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 company 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 highly volatile with greater than 93% of its TRI releases to air. EPA's AirData database includes acetaldehyde atmospheric measurements from 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 stations in 2006 ranged from 0.16 to 5.58 ppb, with 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 within this low ppb range of concentrations.

Response. EPA does not agree. The AirData monitoring data for acetaldehyde appear to be ambient air samples, with a good representation of urban areas that should have been tested, since those are the places where acetaldehyde 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 acetaldehyde has low potential 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 also 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 by AWG is misleading. While there is information on 4 products (3 adhesives and 1 roofing product), only 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 acetaldehyde 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 acetaldehyde 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 comments are used, the outputs 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 by AWG, that "... it does not appear that use of consumer products will generate any significant additional acetaldehyde exposure, especially given the short duration and periodic nature of these exposures in comparison to the constant daily exposure to ambient air."  The acetaldehyde 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 acetaldehyde is also contained in other types of products (SRD http://www.epa.gov/opptintr/exposure/pubs/srd.htm).


Comment. AWG commented that its member companies have collectively 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 acetaldehyde in this rule. EPA's exposure findings fail to recognize that acetaldehyde is a normal human metabolite and that endogenously produced levels are likely to be higher than those from exogenous sources; i.e., more acetaldehyde may be provided in normal metabolism than from the environment. Further, exposure to acetaldehyde 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 systems 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 itself exclude a requirement for the chemical to be tested for its potential toxicity to humans. Indeed, many chemicals considered essential for human health (e.g., metals such as copper and manganese; vitamins) can be toxic to humans at sufficiently high levels of exposure. While EPA agrees that endogenous levels of acetaldehyde may in some cases be higher than would be expected through environmental exposures due to industrially produced acetaldehyde, environmental exposures will add to the burden of acetaldehyde produced through metabolism, and testing is necessary to assess whether these additional levels may be of concern.
   
   In regards to acetaldehyde being primarily a chemical intermediate in closed systems, as noted in the proposed rule, a chemical which is used solely as "closed system 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 persons who believe their chemical is used solely as a closed system 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 EC50s have 4 values available (4.7-48 mg/L), and that one study, Randall and Knopp (1980) which was considered 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 address the proposed testing endpoint. AWG also suggested that EPA should take into account acetaldehyde'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 performed in the required way; i.e., the test must be performed such that an EC50 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 representative organism for toxicity to aquatic plants. The daphnia studies, as well, are lacking adequate details of testing, including the study by Randall and Knopp (1980). EPA agrees that acetaldehyde should have a short residence time in natural surface waters and that its lack of persistence should help mitigate risk to the aquatic environment. However, knowledge of toxic effects is also needed to evaluate potential risk (EPA, 1992). Therefore, EPA continues to require acute daphnia and aquatic plant toxicity testing for acetaldehyde.


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 acetaldehyde.

Response. AWG provided two robust summaries of oral developmental studies on acetaldehyde. The two summaries 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 study in which a single dose was used, no teratogenic 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 study, no differences in mortality, body 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 increased 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 acceptable to EPA for the determination of reproductive toxicity. The studies should have at least needed to approach the limit dose of acetaldehyde by the oral route from days 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 only females dosed thereafter (through pregnancy and nursing period). Because the studies provided as robust summaries by AWG include no indication that males were dosed 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 required.


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 acetaldehyde. For these reasons, AWOs believed that the screening-level data for acetaldehyde are clearly 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 acetaldehyde. A review of these studies however indicates that none of them adequately cover developmental and reproductive effects. While there are data that show acetaldehyde producing significant developmental effects in rats, these data were collected by administering acetaldehyde 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 large assemblage of data does exist for the reproductive and developmental toxicity of ethanol, and acetaldehyde is a major metabolite of ethanol, a comparison of LC50 data from ethanol and acetaldehyde indicates that acetaldehyde 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 acetaldehyde is required by the oral route. Moreover, because of the 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).
      
Comment. Dyno Nobel submitted comments on 1,3-propanediol, 2,2-bis[(nitrooxy)methyl]-, dinitrate(ester); also referred to as pentaerythritol tetranitrate or PETN. Dyno Nobel indicates that this particular substance is a highly sensitive explosive and that it 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 pathways  -  Inherent biodegradation; Toxicity to plants (Algae); and Reproduction/Developmental Toxicity Screening Test. Due to the chemical's explosive properties, a great deal of difficulty was encountered in having the test performed. Such testing was finally completed in early 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. Dyno Nobel indicates that results from the water solubility tests suggest that PETN dissolves very slowly 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 of solubility. Therefore, Dyno Nobel respectfully submits that since degradation rates exceed water solubility rates, there is no logical justification for completing any 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 Kow of < 4.2, it belongs to Test Group 1. Substances in Test Group 1 are required to have acute aquatic toxicity 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 with analytical 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 with 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 by Dyno Nobel. Even if Dyno Nobel is correct in its assertion that the test material degrades so fast that the required initial nominal levels cannot be achieved (which EPA cannot evaluate without access to the full test report) loss of identity of the parent material does not provide any information on possible degradation products, the toxicity of which may be of concern. 

	Furthermore, 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 LC50 for PETN may be lower than its maximum attainable concentration (HPVIS, CAS No. 55-63-0). Therefore, EPA 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 reason, 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 by EPA to be invalid due to questionable methodology. The study protocol 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, sodium hydroxide and atomized aluminum. These processing procedures yielded 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 appropriate 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-hexadienoic 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 sorbic acid is a naturally-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 generally 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 by AWOs, as well as three other studies (Walker 1990; Food and Drug Research Labs 1975; Anon 1988) 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 developmental 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 toxicity 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).



	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 study report was 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 adequacy (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 requested 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-generation study protocol was developed by 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 reproductive 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 reproductive 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 systems 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 presented in a table were for those that did not produce chromosomal aberrations "at the highest non-cytotoxic dose used in the experiment." No information was provided on the chromosomal aberrations potential of concentrations higher than the highest non-cytotoxic concentration tested. The OECD 473 guideline indicates that "where cytotoxicity 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 cytotoxicity.  The Ishidate et al. paper reports only the results of a "maximum dose" of ethanedioic acid tested; i.e., 0.125 mg/ml, a dose which was quite low and apparently not cytotoxic.  Thus, the study reported in the Ishidate et al. paper does not provide 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 on 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 water solubility and octanol-water partition coefficients need to be determined for this chemical substance prior to conducting acute fish toxicity testing. According to EPIWIN, the log Kow is -8.23 and the water solubility is 220,000 mg/L (SRC, 2010a). As such, the compound is estimated 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 glucoheptonate in the test rule. AWOs recommended that the physicochemical 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 safely used in the preparation of steam that will contact food.  However, the food safety evaluation inherent in this permitted use (which itself is limited per the terms of section 173.310(b)) does not necessarily extend to the potential hazard of workplace exposure levels or environmental contamination levels. Sodium glucopheptonate is a chelating agent routinely 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 no health effects data exist on this chemical. According to the EPISuite estimation method, sodium glucoheptonate is expected to be completely water soluble; as such, the generation of physicochemical 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 fish that report an LD50 of greater than 2000 mg/kg-bw in rats and an LC50 of 401 mg/L in salmon trout, respectively, 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 rainbow (or steelhead) trout (Salmo gairdneri) with the LD50 and LC50 reported by 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 IUCLID data set; therefore, the adequacy of these studies to address the endpoints under consideration cannot be determined by EPA. Although a study need not conform exactly to the current OECD guidelines to be considered adequate to fill a required endpoint 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 days that animals were observed after dosing. In general, for an acute oral study to be considered adequate, animals must be observed for at least 14 days after dosing.  The description of the acute study in rainbow trout is missing essential details on the results of analytical monitoring of the dosed water; i.e., dose levels in the water, oxygen 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 LC50 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 generally recognized as safe (GRAS) for over-the-counter use as a laxative. Moreover, 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 any adequate mammalian or aquatic toxicity data on castor oil, sulfated, sodium salt; but has received adequate acute mammalian toxicity data for castor oil, oxidized. In addition, EPA agrees that aquatic toxicity testing for castor oil, oxidized would not provide useful results, and is not requiring that testing for this substance. However, while EPA 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, castor oil, sodium salt is a surfactant.  Water solubility, per se, is less a consideration for aquatic toxicity testing of this substance. As noted in an EPA guidance document, since surfactants 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.

	In regards to mammalian toxicity, it is unclear how 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, 1992). It is also true that castor oil has been designated as generally recognized as safe by 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 been collected in humans, while less information is available for laboratory animals.  These data on humans are of limited use. Dosing of humans during pregnancy is limited and generally anecdotal, while dosing in animals would be regimented and, when conducted correctly, 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 any 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 many 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 from 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 document 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 any new information that might warrant subsequent action (e.g., assessment)" (Health Canada, 2007). Since EPA did not locate any 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 substances 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 the worst case toxicity scenario. Oxidized castor oil should be even less biologically 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.


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 (melting 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 using 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 for 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 property, as is the case for castor oil, sulfated, sodium salt, the testing of this endpoint is not 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 chemicals, 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 condition, and must be reported as < 0.001mg/L for this endpoint.


Special Note.  Although EPA did not receive comments specific to the endpoints of log Kow or water solubility for castor oil, sulfated, sodium salt; because of its surfactant nature and similarity 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 endpoints for that chemical substance. However, because 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 (Bayer 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 safety data sheet (MSDS) for the product BAYTEC 505, which is the substance in question. The current version of this document (Bayer MaterialScience LLC, 2008) 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 LC50 value for acute toxicity to fish, it does not provide study details 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 (MPBPWIN v 1 .42).

Response. A measured value for this endpoint is required for HPV chemicals. The melting point value provided by Albemarle using MPBPWIN v 1 .42 was an estimated value. Therefore, a measured value is still needed.


Comment. Albemarle provided boiling point values of 328.81 °C and 308 °C.

Response. A measured value of this endpoint is required for HPV chemicals. 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-GLP study in Albemarle's laboratory, it is consistent with the boiling point value estimated by MPBWIN 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. These three estimated values all fell into the >10 mg/L - 5,000 mg/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. Therefore, a measured value is still needed.


Comment. Albemarle provided an estimated log Kow 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 Kow 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 EPISuite, 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 adequately characterized by EPISuite, actual testing of DETDA is not indicated.

Response. Although ECOSAR modeling is a useful tool in predicting the toxicity 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 testing 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 documents 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 by the sponsor as to the purity of the test substance. EPA does not have the other genetic toxicity 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-day repeated-dose study with a reversibility component, and two- year carcinogenicity tests (including gavage, dietary and subcutaneous injection). Neither the male nor female reproductive tracts were identified as target organs. These studies (listed in Table 3 of Albemarle's comments) have been previously 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 testing.   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 adequate length, may have eliminated the need for further reproductive toxicity testing. However, no developmental testing has been conducted on DETDA. The available industrial hygiene monitoring data are not utilized in making a determination regarding the need 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. AWOs 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 substances 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 mammalian 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 determined 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. 
   
	The situation for aquatic toxicity testing is more complex. The IUCLID document for CAS No. 63449-39-8 (European Chemicals Bureau, 2000e) indicates that this substance is not water soluble, and reports a measured log Kow of > 6. The proposed test rule indicates that a substance requiring aquatic toxicity testing that has a measured log Kow of >= 4.2 belongs to Test Group 2. In this 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 analytical 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, toxicity 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 chemical 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 currently under development. 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 early next year. For all these reasons, CPIA believes that EPA should not pursue a final HPV test rule on CAS No. 68527-02-6.

Response.  The review that EPA conducted for these 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. The substances that CPIA refers to in their comments are, under TSCA, different chemical substances. EPA agrees that analog data may sometimes be appropriate. However, 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 accepted analog data for certain of the proposed testing endpoints. However, for other 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 will 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 alkenes, C12-24, chloro. EPA continues to require testing on the following endpoints of the proposed test rule:  physical/chemical properties (all), biodegradation, aquatic toxicity testing (C1, Test Group 2), in vitro chromosomal aberrations, and reproductive and developmental toxicity. For any testing that CPIA does not sponsor before publication of the final rule, any testing performed must meet the requirements specified in the rule.




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 fish because of their non-polar nature, the purpose of the acute toxicity test is to determine the actual LC50 of the compound. Without testing, vital information on the lethality of hydrocarbons, C>4, would not be available. Therefore, EPA requires acute toxicity to fish testing on hydrocarbons, 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-bis]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 Kow was submitted by Albemarle Corp. previously (White 2005); the log Kow was > 6.5. A study report conducted by Shell using an HPLC 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 Kow. 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, NTIS 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 Kow, 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 Kows that Albemarle reports in their comment. Test Group 2 requires that chronic toxicity to Daphnia and toxicity to plants (algae) testing be performed. 
 
	However, Albemarle's assumption that these tests were performed, or performed adequately, appears to be incorrect. The referenced study conducted by Shell Oil (Mattock and Girling, 1988) describes only acute, but not chronic, testing on Daphnia with Ionox 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 testing to be inadequate. 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 Kow 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 EC50 was reported as > 1000 mg/L. No analytical 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 requirement, 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 commented that ExxonMobil 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 (ExxonMobil, MSDS, 2007).

Response. EPA disagrees with the comment. The current material safety 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 phenol, 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 hydrolyze quickly in water to produce two tautomeric forms of O,O-diethyl phosphorothionate (also known as diethylthiophosphoric 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 highly soluble. The water solubilities 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, respectively. EPI Suite also predicted log Kow values of 2.37, 2.09, and 0.48 for the same three chemicals, respectively. Since the predicted log Kow 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.  

	Prior to aquatic toxicity testing, a hydrolysis test is recommended to determine the half-life of the parent chemical and to confirm the hydrolysis 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 system). 

	It should be noted that HCl produced by the hydrolysis reaction could significantly lower the pH of the test solution. For example, at a concentration of 10 mg/L, if the parent chemical hydrolyzed completely, the HCl produced would be predicted to lower the pH of a neutral solution 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 hydrolysis products is information from the IUCLID dataset 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 hydrolysis products. An LC50 of 62 mg/L for 24-h acute fish toxicity testing conducted on guppies (Poecilia reticulata) is reported in the IUCLID Dataset. Aquatic toxicity values estimated by ECOSAR for phosphorochloridothioic acid, O,O-diethyl ester are as follows: 96-h LC50 for fish = ~8 mg/L; 48-h LC50 for Daphnia = ~6 mg/L; 96-h EC50 for green algae = ~4 mg/L. Aquatic toxicity values estimated by ECOSAR for the P=S tautomer of DETP are as follows: 96-h LC50 for fish = ~11 mg/L, 48-h LC50 for Daphnia = ~8 mg/L, and 96-h EC50 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 would 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 by 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 which mammalian toxicity--repeated dose/reproduction/developmental toxicity testing is required may be used solely as "closed system intermediates," and if that were the case, such chemicals 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 persons who believe their chemical is used solely as a closed system intermediate to submit appropriate information along with their comments which substantiate this belief. EPA received no such claims from a chemical manufacturer of this substance. 


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                                   APPENDIX 
                                       
             CHECKLIST FOR OTHER SOURCES OF DATA ON HPV CHEMICALS
PubMed - Bibliographic database that contains references to journal articles in the life sciences with a concentration on biomedicine 

TOXNET - National Library of Medicine databases on toxicology, hazardous chemicals, environmental health, and toxic releases; includes: 
*    TOXLINE with BIOSIS and NTIS; 
*    Development and Reproductive Toxicology File (DART); 
*    Chemical Carcinogenesis Research Information System (CCRIS) - Carcinogenicity and mutagenicity test results for over 8000 chemicals); 
*    Hazardous Substances Data Bank (HSDB) - Comprehensive, peer-reviewed 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 System (IRIS) website 

USEPA - TRI (Toxics Release Inventory Chemicals website) 

USEPA - Ambient Water Quality Criteria website (Both Human Health and Aquatic Life)

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 Safety Concise International Chemical Assessment Documents (IPCS INCHEM or CICADs) 

 European Chemical Substances Information System (ESIS) - source of IUCLID Datasets 

NLM databases (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 

