U.S. ENVIRONMENTAL PROTECTION AGENCY

TESTING OF CERTAIN HIGH PRODUCTION VOLUME CHEMICALS; SECOND GROUP OF CHEMICALS,

ORAL COMMENTS ON A PROPOSED REGULATION MEETING AND PUBLIC COMMENTS

1201 CONSTITUTION AVENUE, NW HEARING ROOM 1153 EPA EAST WASHINGTON, D.C. 20460 MARCH 31, 2009 8:05 A.M.US EPA MEETING 03/31/09 CCR#16194-1 2

1 U. S. ENVIRONMENTAL PROTECTION AGENCY 2 TESTING OF CERTAIN HIGH PRODUCTION VOLUME CHEMICALS: 3 SECOND GROUP OF CHEMICALS, ORAL COMMENTS ON A PROPOSED 4 REGULATION 5 March 31, 2009 6 DR. WILLIS: All right, good morning, 7 everyone and welcome, thanks for coming to offer 8 comments on the proposed Rule to require testing for 9 certain endpoints on high production volume chemicals. 10 I'd like to start by introducing the EPA staff who are 11 going to be here so that those of you providing 12 comments know actually exactly who you're providing 13 comments to other than the Agency. 14 My name is Jim Willis, I am Director of 15 Chemical Control Division. 16 DR. SHAFFER: My name is John Shaffer, 17 I'm the co-manager of this whole discussion. 18 DR. HALL: My name is Franklin Hall, 19 I'm a chemical engineer in the Economics Exposure 20 Technology Division and I work on the exposure and 21 release elements of these chemicals. 22 DR. GABARDELLA: Paul Gabardella, I'm 23 the co-manager of this high production volume rule, 24 proposed rule and will be seeing this project through 25 to the final stages.US EPA MEETING 03/31/09 CCR#16194-1 3

1 DR. VANRODEN: I'm Victoria VanRoden, 2 also with EPA. 3 DR. CAMPANELLA: There is a sign up 4 sheet, I want to make sure everyone is signed up, I'd 5 like your name, phone number, email or address where 6 you can be contacted, basically that's it, it's our 7 intention is that the Court Reporter here, our 8 intention is to have a transcript of this and the 9 inclusion of hard copy where necessary to that will all 10 be included in the docket, to the public docket and 11 will be used in the final Rulemaking. 12 DR. WILLIS: All right. This meeting was 13 really triggered by our publication of a Proposed HPV 14 II Rule in July of last year, July 4th of last year. 15 The time period for that rule was proposed on October 16 22nd. During that comment period we provided the 17 opportunity for interested parties to present oral 18 comments. 19 And in response to that we received two 20 requests for oral comments, those requests came from 21 People for the Ethical Treatment of Animals and the 22 Chlorinated Paraffins Industry Association so that 23 triggered the need for this public meeting, and as I 24 think all of you know we published in the Federal 25 Register a Notice for this meeting on March 16th ofUS EPA MEETING 03/31/09 CCR#16194-1 4

1 this year. 2 And in response to that we got two 3 further requests to make oral comments from the 4 Physicians Committee for Responsible Medicine and from 5 ARISE, in New Jersey. We also got notice that six or so 6 other individuals plan to attend the meeting although I 7 think if you do your mass balance, they may not have 8 all shown up today. 9 So what I would like to do is take us 10 through those four in the order that they expressed 11 interest and then I'd like to also recall once again 12 Paul Campanella's point that there will be a verbatim 13 transcript of this. 14 Nevertheless, we would like those 15 providing comments to leave their, a brief written 16 statement or a copy of their comments if you would be 17 so kind. So let me then invite the People For The 18 Ethical Treatment of Animals to provide comments. 19 ( WHEREUPON, there was a pause in the proceeding.) 20 MR. KENNEDY: I apologize in advance for 21 my voice. My name is Mark Kennedy and I am Associate 22 General Counsel for the Physicians Committee for 23 Responsible Medicine (PCRM). 24 I make these comments on behalf of both 25 PCRM and People for the Ethical Treatment of Animals inUS EPA MEETING 03/31/09 CCR#16194-1 5

1 support of the written comment jointly submitted by 2 PETA, PCRM, the Alternatives Research Development 3 Foundation, and the American Anti-Vivisection Society. 4 We oppose as improper the issuance of this proposed 5 rule because we believe that EPA has not made two of 6 the findings required under TSCA. 7 First EPA has not found that existing 8 data are insufficient to reasonably determine or 9 predict the effects of exposure to the 19 chemicals 10 covered by the proposed rule. It therefore follows 11 that EPA also could not have found that testing is 12 necessary to develop such data. EPA's decision to 13 issue a test rule without first making these findings 14 will result in unnecessary duplication of testing, 15 needless expenditure of resources, and a substantial 16 and unacceptable increase in the number of animals 17 subjected to testing. 18 Section 4 of the Toxic Substances 19 Control Act require EPA to issue a test rule requiring 20 companies to test certain chemicals that they 21 manufacture when EPA has made the following four Track 22 B findings: 23 1. the chemicals are produced in 24 substantial quantities, 25 2. there is or may be substantial humanUS EPA MEETING 03/31/09 CCR#16194-1 6

1 exposure to the chemicals. 2 3. existing data are insufficient to 3 determine or predict their health and environmental 4 effects and 5 4. testing is necessary to develop such 6 data. In its notice of proposed rulemaking EPA based 7 its finding of data insufficiency solely upon data 8 available from the voluntary HPV Challenge Program, the 9 sources outlined in section 3.1 of the OECD guidelines, 10 and the EPA's HPV Information System. 11 However, EPA did not use its reporting 12 authority under TSCA Section 8 to collect from 13 manufacturers and processors all known data regarding 14 the 19 chemicals covered by the proposed rule. 15 Therefore, EPA cannot validly make a finding regarding 16 insufficiency of data. 17 Because the HPV Challenge Program is 18 discussed at length in the notice and elsewhere, I will 19 not describe it in detail here. The crucial 20 characteristic of the program is that it is voluntary. 21 The only participants in the program are those who 22 choose to provide data, and their participation is 23 limited to the extent to which they are interested in 24 sharing that data. 25 As such there is no guarantee thatUS EPA MEETING 03/31/09 CCR#16194-1 7

1 companies participating in that program have provided 2 all existing data within their possession. Further it 3 goes without saying that the voluntary HPV Challenge 4 Program does not include information possessed by 5 chemical companies that choose not to participate. 6 Therefore the HPV Challenge Program and other voluntary 7 collection programs fail to collect existing data. EPA 8 is well aware of the shortcomings of the HPV Challenge 9 Program. 10 On page 43317 of the notice, EPA states 11 that, quote, "U.S. data needs which remain unmet in the 12 voluntary international efforts may be addressed 13 through TSCA section 4 rulings. This proposed rule 14 addresses the unmet data needs of 19 chemicals." EPA 15 later states on the following page its intent to, 16 quote, "use rulemaking under TCSA to help fill data 17 gaps not addressed as part of the voluntary HPV 18 Challenge Program." 19 Section 8 of TSCA provides a statutory 20 procedure by which EPA could overcome the shortcomings 21 of volunteer data collection programs. Section 8 22 empowers EPA to require chemical manufacturers, 23 processors, and distributors to provide any necessary 24 reports or information needed to evaluate HPV 25 chemicals.US EPA MEETING 03/31/09 CCR#16194-1 8

1 Specifically Section 8(d) allows EPA to 2 mandate reporting by companies, I'm sorry, 8(a), and 3 Section 8(d) allows EPA to compel companies to produce 4 any existing health or safety reports to which they 5 have access. For reasons not explained in the notice 6 EPA has chosen not to use its statutory powers to 7 gather data on the 19 chemicals covered by the proposed 8 rule. 9 Instead EPA, quote, "strongly encourages 10 the submission of", end quote, additional relevant 11 studies and says that it will, quote, "take such 12 measures as are necessary to avoid unnecessary testing 13 in the final rule", end quote. 14 If EPA truly wants to collect data from 15 chemical companies, it makes little sense for it to 16 require companies to test for the data anew when it can 17 simply require them to provide all existing data 18 already in their possession. There are significant 19 reasons why companies may not have voluntarily provided 20 data relevant to the chemicals at issue. 21 First companies that did such testing in 22 the past but do not currently sell or distribute large 23 amounts of these chemicals have no incentive to now 24 produce such data. Further, these companies may have 25 substantial incentives not to produce dataUS EPA MEETING 03/31/09 CCR#16194-1 9

1 voluntarily.. 2 For example, if the data were 3 proprietary and done at a company's expense, there may 4 be some reluctance to share this data for free. More 5 significantly, if the data could be interpreted as 6 showing potential toxicity to humans, there might be 7 significant liability concerns about providing data 8 that might be used in another courtroom, another 9 setting, such as a courtroom, to attempt to show that 10 the company was selling a chemical without appropriate 11 warnings about possible toxic effects. 12 Because it failed to collect existing 13 data, EPA cannot make a valid finding of data 14 insufficiency. Moreover EPA's fourth finding, that 15 testing is necessary for these 19 chemicals consists of 16 just two paragraphs in the notice and is based entirely 17 on its prior invalid finding regarding insufficiency. 18 Because it can't confirm that it has reviewed all 19 existing data, EPA cannot validly find that further 20 testing is necessary. 21 In PCRM v. Johnson, a 2006 case, a 22 federal circuit court discussed the factors required of 23 findings under Track B of TSCA Section 4. First the 24 court noted that EPA must make, quote, "critical 25 science based conclusions", end quote. Here EPA cannotUS EPA MEETING 03/31/09 CCR#16194-1 10

1 claim to have made a critical science based conclusion 2 regarding data insufficiency if it has not first 3 reviewed all existing scientific data. 4 The court also found the use of an, 5 quote, "analytical process for gathering and assessing 6 data to make the necessary determinations for all HPV 7 chemicals", end quote. 8 Here however, EPA has not used its 9 authority to gather and assess data on the chemicals 10 covered by the proposed rule. Next the court focused 11 on whether EPA, quote, "used its own procedures for 12 making the B findings", end quote. Again, here EPA has 13 not used its statutory procedure, TSCA Section 8, for 14 making such findings. 15 Interestingly, in the Johnson case EPA 16 argued that general statements do not constitute 17 factual findings because general statements are neither 18 scientific nor accurate. Yet it seems to have taken 19 the opposite approach here. It is well established that 20 administrative agencies have no power to act beyond the 21 authority conferred upon them by Congress. 22 EPA cannot issue a test rule under TSCA 23 Section 4 without first making certain findings 24 regarding existing data. But EPA cannot make such 25 findings without first using its authority under TSCAUS EPA MEETING 03/31/09 CCR#16194-1 11

1 Section 8 to require manufacturers, processors, and 2 distributors to provide existing data already in their 3 possession. EPA has not done the latter, as such, it 4 cannot do the former. 5 DR. WILLIS: All right. Thank you very 6 much, and next on my list is the Chlorinated Paraffins 7 Industry Association. Can everybody see that okay? 8 Thoughts? Don't write that down, it's how you hack 9 into the system later, right? Yeah, I will, I'm about 10 to pull up a presentation. 11 Andrew Jaques on the list there. 12 Somewhere in here, there we go. 13 DR. JAQUES: Thanks for your patience, 14 I'm sorry, I think my loading of these slides probably 15 is going to take more than this brief testimony will, 16 but my name is Andrew Jaques and I'm with the 17 Chlorinated Paraffins Industry Association. I didn't 18 bring a written copy of what I'm going to say today, I 19 will leave a copy of the slides with you, Jim, and what 20 we say here is identical to the written comments we 21 submitted last fall essentially. 22 CPIA represents producers and users of 23 chlorinated paraffins including the sole producer of 24 the chloro alkene C-12 to C-24 that was included in 25 this test rule. CPIA has been active for many years inUS EPA MEETING 03/31/09 CCR#16194-1 12

1 addressing health and safety and environmental issues 2 related to chlorinated paraffins, including working 3 with EPA Canada, OECD member states, conducting 4 research and sponsoring various international health 5 and environmental activities. 6 I'm just going to talk very briefly 7 about chlorinated hydrocarbon chemistry because I think 8 it's germane to the main point that we want to make in 9 our comments here. Chlorinated paraffins are straight 10 chain hydrocarbons that are generally in the range of 11 C10 to C30 with a typical chlorine content of about 12 thirty to seventy percent, that's by weight so it's 13 not. 14 If there's ten carbons, then there would 15 necessarily be somewhere between six and ten or so 16 chlorines that will get attached to those and those are 17 grouped into three classes of products. Short chain, 18 medium chain and long chain with the carbon ranges that 19 you see here, ten to thirteen for the short, fourteen 20 to seventeen for the medium, and eighteen to thirty for 21 the long chain. 22 The carbon range of these starting 23 hydrocarbon feedstock is really what dictates the 24 carbon range of the finished chlorinated paraffin 25 product and the hydrocarbon feedstocks are reacted withUS EPA MEETING 03/31/09 CCR#16194-1 13

1 chlorine to produce the chlorinated paraffin and the 2 degree of chlorination is essentially what's controlled 3 in that reaction and that can produce different 4 finished characteristics of the final product. Just 5 briefly talking about the difference between alkane and 6 alkenes, the top one is an alkene, there's essentially 7 a decene, one decene for the whole thing, and the 8 bottom is just decane so that would be the simplest of 9 the C10. 10 Once you chlorinate those, this 11 particular example just has five chlorines that have 12 been added onto the chain, you eliminate essentially 13 most of the distinction between the alkane and the 14 alkene starting material, and we anticipate that the 15 studies show that the chlorine will substitute 16 favorably on the side of the double bond such that we 17 don't believe the double bond is remaining after the 18 chlorination occurs. 19 And this is the same conclusion that EPA 20 came to in the 1994 TRI expansion rule which they 21 state, "EPA believes that chlorination of paraffins and 22 a-olefins result in products that do not differ 23 significantly structurally, physically or 24 toxicologically. In terms of the work that's been done 25 so far on the chlorinated paraffins for the HPV andUS EPA MEETING 03/31/09 CCR#16194-1 14

1 OECD SIDS programs, CPI actually sponsored this 2 particular CAS number that's in the test rule in '99 3 when the original rule, I'm sorry, the original 4 voluntary program came out. 5 There was already efforts underway in 6 Europe on chlorinated paraffins primarily led by the UK 7 through...so activities were shifted to the OECD SIDS 8 program, the short and medium chain assessments have 9 already been completed through the OECD SIDS. 10 The long chain is still underway, UK 11 just finished their environmental risk assessment and 12 we're in the process of working with them to finish the 13 final OECD SIDS materials for that category. Once all 14 that's done we anticipate that the medium and long 15 chain will cover this CAS number that's subject to the 16 test rule. 17 While the carbon number range in the CAS 18 number definition is C-12 to 24, the predominant mass 19 is actually about eighty five percent is in the long 20 chain and so that particular category which as I've 21 said is in the process of being finished, we think is 22 going to be particularly germane to this CAS number and 23 the UK assessments. 24 And I think maybe this is one of the 25 reasons why this ended up in the particular test ruleUS EPA MEETING 03/31/09 CCR#16194-1 15

1 used CAS numbers that were common in the EU that didn't 2 include, well, one of them did mention this CAS number 3 although I don't think that was clear in the OECD SIDS 4 information. 5 So, we will work to clarify that. Though 6 in terms of just proposed next steps, and this is 7 really the conclusion of what I want to propose to the 8 agency, we'd like to see the proposed testing on 9 these...this CAS number dropped, we feel that the work 10 that's being done on the chlorinated paraffins 11 categories will adequately cover the OECD SIDS 12 endpoints that have been identified for this CAS 13 number. 14 The CPIA is continuing to work with the 15 UK authorities and the other OECD member states to get 16 the final SIDS category completed for CPs and we 17 anticipate that once all that's competed we will 18 prepare and submit to the Agency as part of the HPV 19 program a final assessment on this CAS number that uses 20 the data from the MCCPs and the LCCPs categories. 21 Thank you very much, and thank you to the EPA for 22 having this hearing. 23 (WHEREUPON, there was a pause in the proceeding.) 24 DR. MANUPPELLO: I brought some 25 handouts with my slides, going through the data weUS EPA MEETING 03/31/09 CCR#16194-1 16

1 found and references for them. My name is Joseph 2 Manuppello, I'm with the People for the Ethical 3 Treatment of Animals. I'd like to thank the EPA for 4 this opportunity to comment on the second HPV test 5 rule. 6 While EPA has taken the lead in 7 commissioning the NRC to develop their toxicity testing 8 in the 21st century report and also in issuing their 9 own strategic plan just last week, we're very concerned 10 that this test rule will add another ten thousand 11 animals to the hundred thousand that have already been 12 killed in the HPV program In so doing, EPA has ignored 13 their own laudable goal expressed in their strategic 14 plan. 15 I lost my first page of notes so I don't 16 know the exact words but basically this is to go from 17 toxicity testing based on whole animal systems to a 18 more in vitro high throughput method using human cells 19 so in addition to ignoring that, EPA has also ignored 20 its first principle that was enumerated in the 1999 21 guidance issued to HPV program participants about 22 animal welfare principles and this advises HPV chemical 23 sponsors to conduct a thoughtful qualitative analysis 24 rather than to use a rote checklist approach. 25 It also makes clear that participantsUS EPA MEETING 03/31/09 CCR#16194-1 17

1 may conclude that there is sufficient data, given the 2 totality of what is known about a chemical, including 3 human experience, that certain endpoints need not be 4 tested. 5 While the Agency specifically agreed to 6 incorporate these animal welfare principles into any 7 subsequent test rules, even a cursory review of 8 existing toxicity data and human experience with the 9 chemicals included in this test rule demonstrates that 10 in many cases, the required tests would add no useful 11 information to what is already known. I need to take a 12 little break, is there any chance I could get some 13 water? I'm just not going to make it through. 14 Thanks a lot. I'll get going. I'll 15 begin by addressing these test requirements 16 individually and present relevant existing data that 17 we've located or obtained and the references for this 18 data are in your handout. I'll go on to describe 19 several approaches for reducing the number of animals 20 killed in mammalian and fish acute toxicity and 21 developmental toxicity testing. 22 And I'll conclude with general comments 23 about the test rule stressing the need to allow an 24 opportunity for public comments after any additional 25 existing data is made available.US EPA MEETING 03/31/09 CCR#16194-1 18

1 Noting that this would also allow any 2 justifications for in vivo genetic toxicity testing or 3 separate repeated dose and reproduction developmental 4 toxicity testing to be made prior to conducting that 5 testing instead of after the fact, so it would allow 6 for the inclusion of chemical category and SAR 7 approaches. I'd like to begin with sorbic acid since it 8 appears to be a special case. 9 We find it especially surprising that 10 the Agency would require testing for sorbic acid, a 11 naturally occurring fatty acid that has been safely 12 used as a preservative and antimicrobial agent in 13 foods, cosmetics and personal care products since the 14 1960s. The proposed test rule would require a 15 reproduction/developmental toxicity screening test that 16 would kill approximately 675 animals. 17 Even more confusing is the fact that 18 this requirement was included in the Agency's first 19 proposed test rule for HPV chemicals but dropped in the 20 final rule and there is no indication as to why it has 21 been included again in this second proposal. 22 Regarding the first test rule, the 23 Ashland Distribution Company or ADC, asked that 24 consideration be given to the results of studies it 25 submitted which indicated a low level of risk toUS EPA MEETING 03/31/09 CCR#16194-1 19

1 reproduction from sorbic acid exposure before 2 conducting another test merely to achieve consistency 3 with current guidelines. 4 The references are included in your 5 handout. The EPA agreed, finding that there was no 6 evidence in the multi-generation reproduction studies 7 to suggest that sorbic acid is a reproductive toxicant 8 and also that there was no evidence in a teratological 9 study conducted by the Food and Drug Research Labs to 10 suggest that sorbic acid is a developmental toxicant. 11 In the final rule the Agency stated clearly that it is 12 not requiring the reproduction/developmental toxicity 13 screening test of sorbic acid in this final rule. 14 We ask why this opinion has changed or 15 whether this requirement has been included again as the 16 result of some oversight. In addition to the studies 17 previously submitted by the ADC, we obtained a report 18 of a three generation reproduction study in rats from 19 the Eastman Chemical Company that was conducted by 20 Bio/Dynamics, Inc. for the Monsanto Company. 21 The authors reported that evaluation of 22 mating, pregnancy and fertility indices; litter 23 survival, offspring viability at parturition, offspring 24 survival, weight and sex distribution data and gross 25 postmortem observation data of offspring did notUS EPA MEETING 03/31/09 CCR#16194-1 20

1 indicate any adverse effects attributable to sorbic 2 acid administration through three successive 3 generations 4 These results are similar to those 5 previously cited by the ADC. Of relevance to humans, 6 Walker observed in a 1990 review that sorbic acid is a 7 naturally occurring fatty acid similar in structure to 8 linoleic and oleic acids and that it is metabolized in 9 mammals as a normal short chain fatty acid similar to 10 hexanoic acid. Guidelines by the International 11 Programme on Chemical Safety suggest that a more 12 limited range of tests might be acceptable for 13 substances which are converted to normal body 14 metabolites. 15 The FDA lists sorbic acid as generally 16 recognized as safe or GRAS as a preservative for direct 17 addition to food. In addition the European Commission 18 Cosmetics Directive has approved the use of sorbic acid 19 without restrictions or warning labels at levels up to 20 0.6 percent. GRAS substances generally have extensive 21 databases demonstrating their lack of toxicity. 22 In its 1999 letter EPA recommends that 23 participants should specifically consider whether the 24 information available makes it unnecessary to proceed 25 with further testing involving animals and whether anyUS EPA MEETING 03/31/09 CCR#16194-1 21

1 additional information obtained would be useful or 2 relevant for GRAS substances. 3 Considering the history of this test 4 requirement, existing data, weight of evidence and GRAS 5 status, it is imperative that EPA reconsider its 6 testing requirements for sorbic acid in the proposed 7 test rule. Moving on to oxalic acid, having recently 8 passed a kidney stone, oxalic acid is something I've 9 had intense personal experience with. 10 Oxalic acid, supposed to pause for 11 laughter there, oxalic acid is listed as requiring a 12 reproduction/developmental toxicity screening test and 13 possibility a fish acute toxicity test. Thanks so 14 much. Uh-oh. 15 That'll do. So oxalic acid is listed as 16 requiring a reproduction/developmental toxicity 17 screening test and possibly a fish acute toxicity test. 18 It seems incomprehensible that additional animal 19 testing would be required for this extremely well 20 characterized toxin. Oxalic acid occurs naturally in 21 foods and its toxicity has been studied extensively as 22 a metabolite of ethylene glycol. 23 The American Conference of Governmental 24 Industrial Hygienists regards oxalic acid as a strong 25 poison and observes that as little as 5 grams haveUS EPA MEETING 03/31/09 CCR#16194-1 22

1 proved fatal when taken internally. Specific data on 2 reproductive and developmental endpoints are numerous. 3 A search of the National Library of Medicine's 4 Developmental and Reproductive Toxicology or DART 5 database returned 23 results. 6 The National Toxicology Program 7 concluded in its Reproduction and Fertility Assessment 8 in CD -1 mice that oxalic acid is a reproductive 9 toxicant even at concentrations that cause few other 10 somatic effects. The NTP reported that at 0.2 percent 11 oxalic acid, the number of litters per pair was reduced 12 by 5 percent , the number of live pups per litter was 13 reduced by 20 percent and the weight of the surviving 14 pups was reduced by nearly 4 percent. 15 Also the percentage of abnormal sperm 16 forms doubled. In their subchronic rat study Goldman et 17 al reported that vaginal smears indicated the existence 18 of prolonged diestrus, persistent vaginal 19 cornification, dense compact ovarian and interstitial 20 tissue with small cells, absence of adipose tissue and 21 depressed follicular development. 22 They also noted that luteal cells 23 contained dark, condensed and shrunken nuclei and that 24 testes tissue appeared compact with seminiferous 25 tubules of small diameter containing immatureUS EPA MEETING 03/31/09 CCR#16194-1 23

1 Sertolicells and spermatogonia with an absence of 2 mitoses. 3 In their study of the effects of 4 ethylene glycol and its metabolites on the development 5 of rat embryos, Klug et al. reported that 1-3 6 millimolar oxalic acid was embryotoxic. 7 In addition to the approximately 675 8 rats that would be killed in a reproductive and 9 developmental toxicity screen, a fish acute toxicity 10 test would likely kill another 120 fish. A search of 11 the ECOTOX database returns four results including a 12 study in bluegills reporting an LC50 of 24 mg/L. 13 The Agency must review these existing 14 data before requiring duplicative studies for this 15 substance. Sulfated and oxidized derivatives of castor 16 oil are listed as each requiring a mammalian acute 17 toxicity test, a combined repeated dose with 18 reproduction/developmental toxicity screen and possibly 19 a fish acute toxicity test. 20 These tests would kill approximately 21 1,350 - 1,600 animals. The castor oil derivatives share 22 a long history of safe use. Castor oil is a natural 23 vegetable oil obtained from the castor bean that is 24 used in pharmaceuticals, food and other industries. 25 The FDA lists castor oil as GRAS forUS EPA MEETING 03/31/09 CCR#16194-1 24

1 over the counter use as a laxative. An extensive 2007 2 safety review of castor oil and its derivatives by the 3 Cosmetic Ingredient Review Expert Panel concluded that 4 these ingredients are safe and that the safety test 5 data on castor oil is broadly applicable to the entire 6 group evaluated. 7 Sulfated castor oil, also known as 8 Turkey red oil, completely disperses in water and, as a 9 result is widely used in cosmetic and personal care 10 products as well as in lubricants and softeners. It is 11 listed by Health Canada as a substance not requiring 12 further work for human health. 13 A 1980 (sic) study reports a mean LC50 14 of 2.2 mg/ L for sulfated castor oil in medaka, which 15 is a aquatic toxicity report. Oxidized castor oil is 16 produced by bubbling air through castor oil at elevated 17 temperatures which causes oxidative polymerization to 18 occur at the double bonds of the fatty acids. 19 In its comments, Vertellus Specialties, 20 Incorporated summarized, among other data, an octanol21 water partition coefficient log value estimated to be 22 17.97 and an LD 50 value for oxidized castor oil of 23 greater than 5 grams per kilogram body weight in rats. 24 Vertellus notes that aquatic toxicity tests would be 25 problematic given the lack of water solubility ofUS EPA MEETING 03/31/09 CCR#16194-1 25

1 oxidized castor oil and expects no effects at 2 saturation. 3 In any case, considering the log Kow 4 value, chronic toxicity testing in Daphnia would be 5 indicated instead of acute toxicity testing in fish. 6 With regard to mammalian toxicity testing, Vertellus 7 observes that given that the oxidation of castor oil 8 results in a polymerized fatty acid triglyceride 9 product, oxidized castor oil should be less 10 bioavailable than the castor oil starting material, 11 which itself is recognized as nontoxic as reported by 12 the NTP, and Vertellus challenges the value of 13 subjecting this chemical to mammalian toxicity 14 endpoints. 15 Given the wealth of human experience 16 with castor oil and its derivatives, it is 17 inconceivable that animal tests would be required. 18 Considering existing data and weight of evidence EPA 19 must consider (sic) its testing requirement for these 20 chemicals. 21 Penta-erythritol tetra-nitrate or PETN, 22 a highly sensitive explosive, is listed as requiring a 23 fish acute toxicity test. A search of the ECOTOX 24 database returns a U.S.Army study reporting acute 25 toxicity for fathead minnows and bluegills thatUS EPA MEETING 03/31/09 CCR#16194-1 26

1 classifies the chemical as not acutely toxic. 2 In addition Dyno Nobel, Incorporated has 3 submitted the results of testing under the first test 4 rule and reports results from water solubility tests 5 suggesting that PETN dissolves very slowly in water to 6 reach a relatively low water solubility limit. Attempts 7 to determine the rate at which PETN degrades in 8 naturally occurring water samples failed to reach 9 solubility limits of PETN determined from previous 10 experiments with pure water. 11 This suggests that breakdown exceeds the 12 rate of solubility. As a result Dyno Nobel concludes 13 that since PETN degrades more rapidly than it 14 dissolves, there is no logical justification for 15 completing any additional aquatic toxicity tests. 16 Dyno Nobel also notes that PETN has not 17 been detected in any environmental water sample to its 18 knowledge. Pyromellitic Dianhydride is listed as 19 requiring a fish acute toxicity test, a mammalian acute 20 toxicity test, and repeated dose toxicity with 21 reproduction and developmental screen. 22 The acid anhydrides have been the 23 subjects of extensive human exposure and case studies 24 with the most common adverse health effects reported 25 being pulmonary edema, immune sensitization andUS EPA MEETING 03/31/09 CCR#16194-1 27

1 irritation of mucous membranes and skin. 2 In addition oral LD50 values of 2.25 to 3 3.5 grams per kilogram body weight have been reported 4 in rats, 2.3 to 2.65 grams per kilogram body weight in 5 mice and 1.6 grams per kilogram body weight in guinea 6 pigs as well as lowest lethal inhalation dose of 150 7 milligrams per cubic meter in rats No embryotoxicity 8 was observed in rats given oral doses of 44 and 220 9 mg/kg body weight. 10 In rats exposed to the oral dose of 44 11 mg/kg body weight, a weak effect on gonad morphology 12 was observed. E. I. Dupont de Nemours and Company 13 submitted comments that included summaries of 14 additional in house data. 15 These include results from an inhalation 16 toxicity study reporting an Approximate Lethal 17 Concentration or ALC of 3 mg/L in rats and from an 18 acute oral toxicity study reporting an ALD of 5,000 19 milligrams per kilogram in rats. 20 In addition Dupont argues that 21 trimellitic anhydride or TMA is an appropriate analog 22 for PMDA, and reports a No Observed Effects 23 Concentration of 896 milligrams per liter in fish, 792 24 milligrams per liter in invertebrates and 739 25 milligrams per liter in algae.US EPA MEETING 03/31/09 CCR#16194-1 28

1 Further Dupont understands that PMDA has 2 been preregistered under REACH and expects that a SIEF 3 consortia will be organized to share data on this 4 chemical. At a minimum, rather than risk duplicating 5 animal studies, EPA should await the results from this 6 SIEF before establishing requirements for this chemical 7 in its final rule. 8 This chemical, also known as Ionox 220, 9 is listed as possibly requiring a fish acute toxicity 10 test. It is included in comments submitted by 11 Albemarle Corporation in which Albemarle notes that it 12 previously reported to EPA an octanol water partition 13 coefficient log value grater than 6.5. 14 In addition a study conducted by Shell 15 Oil Company reports a value of 7.4 Since these values 16 are greater than 4.2, the aquatic toxicity endpoint 17 should be filled by a chronic test on Daphnia. Also the 18 report submitted by Shell Oil includes data on acute 19 toxicity to steelhead trout and chronic toxicity to 20 fathead minnows. 21 There may also be data available from 22 Exxon Mobil as their MSDS for 10W-30 motor oil states 23 that this chemical is not expected to be harmful to 24 aquatic organisms based on available data. Diethyl25 phosphoro-chloro-thioate or DECTP is listed asUS EPA MEETING 03/31/09 CCR#16194-1 29

1 requiring a fish acute toxicity test and a 2 reproduction/developmental toxicity test. 3 In its submitted comments Albemarle 4 Corporation reports that its production of this 5 chemical ceased subsequent to the 2006 IUR and that no 6 future production of this chemical is anticipated. As a 7 result Albemarle suggests that the Agency's findings of 8 substantial production and human exposure should be 9 reevaluated. 10 In the event that additional production 11 of DECTP exists, we note that in 1981 Chemical Hazard 12 Information Profile Draft Report for DECTP by the EPA's 13 Office of Toxic Substances lists median lethal doses 14 ranging from 810 mg/kg body weight in guinea pigs to 15 1340 mg/kg body weight in rats. 16 The study upon which this was apparently 17 based, an investigation of the toxicological 18 characteristics of thiophosphoric acid esters by 19 Kukatov, also reports an LD 50 of 910 milligrams per 20 kilogram in mice. 21 The EPA report notes structural 22 similarities with dimethyl-chloro-thio- phosphate and 23 we urge the Agency to consider any existing data on 24 this chemical as a possible analog. Sodium gluco25 heptonate is listed as requiring a mammalian acuteUS EPA MEETING 03/31/09 CCR#16194-1 30

1 toxicity test, a combined repeated dose with 2 reproduction/developmental toxicity screen and possibly 3 a fish acute toxicity test. 4 The FDA's Priority based Assessment of 5 Food Additives or PAFA database lists sodium 6 glucopheptonate as a secondary direct food additive 7 permitted in food for human consumption and as an 8 indirect food additive. 9 Further, the PAFA database includes that 10 or indicates that fully up to date toxicology 11 information has been sought. As noted previously with 12 regard to GRAS substances, EPA has recommended that 13 consideration be given as to whether information 14 already available makes it unnecessary to proceed with 15 further testing involving animals and whether any 16 additional information obtained would be useful or 17 relevant. 18 It seems likely that the FDA has 19 toxicology information that addresses at least some of 20 the endpoints sought in this test rule and we urge the 21 Agency to investigate whether this is the case. C. I. 22 Leuco Sulphur Black 1 is listed as requiring a 23 mammalian acute toxicity test and possibly a fish acute 24 toxicity test. 25 A European Chemicals Bureau, IUCLIDUS EPA MEETING 03/31/09 CCR#16194-1 31

1 Dataset, summarizes data from 1986 studies of acute 2 toxicity in mammals and fish conducted for Sandoz 3 Products. These report an LD50 of greater than 2 grams 4 per kilogram body weight in rats and an LC50 of 401 5 milligrams per liter in salmon trout. 6 Again the Agency must review these 7 studies and reconsider its requirements for this 8 chemical. Diethyltoluenediamine or DETDA is listed as 9 requiring a fish acute toxicity test and a combined 10 repeated dose with developmental screen, repeated dose 11 with reproduction/developmental screen. We note that an 12 MSDS from Bayer MaterialScience reports an LC 50 value 13 of 194 mg/l in goldfish. 14 The EPA lists Albemarle Corporation as a 15 tentative ICCA sponsor for this chemical. Albemarle 16 submitted written comments on DETDA including an ECOSAR 17 estimated 96 hour fish LC 50 of 37.9 milligrams per 18 liter. 19 Albemarle also notes that DETDA has been 20 tested in multiple repeated dose studies including two 21 year carcinogenicity tests by several exposure routes. 22 Neither the male nor female reproductive tracts were 23 identified as target organs in these studies which 24 Albemarle has previously forwarded to the EPA. 25 Albemarle also includes occupationalUS EPA MEETING 03/31/09 CCR#16194-1 32

1 exposure data and handling recommendations and 2 concludes that additional testing for reproductive 3 endpoints is not indicated. 4 Just a few more. Hydrocarbons, C 5 greater than 4 is listed as requiring a mammalian acute 6 toxicity test, a combined repeated dose with 7 reproduction/ developmental toxicity screen and 8 possibly a fish acute toxicity test. 9 Aquatic toxicity data for this mixture 10 would be expected to fall within a narrow range of 11 values regardless of chemical class or carbon number 12 because the toxic mode of action for neutral organic 13 hydrocarbons is known to be non-polar narcosis. 14 As thoroughly discussed in The American 15 Petroleum Institute's test plan for the Gasoline 16 Category, this mechanism of short term toxicity for 17 these chemicals is disruption of biological membrane 18 function, and any differences between toxicities can be 19 explained by differences between the target tissue 20 partitioning behaviors of the individual constituents. 21 The existing fish toxicity database for 22 hydrophobic neutral chemicals supports a critical body 23 residue, the internal concentration that causes 24 mortality, of between 2 and 8 millimole per kilogram 25 body weight for fish.US EPA MEETING 03/31/09 CCR#16194-1 33

1 Also given a compositional analysis of a 2 mixture of hydrocarbons, the acute toxicity can be 3 calculated and toxicity QSARS may be used to provide 4 LL50 estimates for hydrocarbons where acute toxicity 5 data are not available, since these are well 6 established for hydrocarbons. 7 We urge the Agency to consider such an 8 approach for this mixture. For acetaldehyde I'd like to 9 summarize comments submitted by the Acetaldehyde 10 Working Group or AWG of the Vinyl Acetate Council. 11 These were extensive comments. 12 AWG notes first that acetaldehyde was 13 originally designated as being sponsored in another 14 program and considering that the International Agency 15 for Research on Cancer, IARC, and the international, or 16 the IPCS as already mentioned are evaluating 17 acetaldehyde. 18 It was not recognized that acetaldehyde 19 was in fact an orphan chemical. Acetaldehyde has been 20 reviewed numerous times by regulatory agencies 21 including the EPA, the IPCS, and IARC and it has been 22 labeled as GRAS for use as a flavor additive and 23 adjuvant. 24 AWG observes that the Agency's exposure 25 findings presented for acetaldehyde do not recognizeUS EPA MEETING 03/31/09 CCR#16194-1 34

1 that acetaldehyde is a normal human metabolite and that 2 endogenously produced acetaldehyde levels are likely to 3 be higher than those from exogenous sources. 4 As previously noted for sorbic acid, 5 guidelines by the IPCS suggest that a more limited 6 range of tests might be acceptable for normal body 7 metabolites. AWG also notes that acetaldehyde exposure 8 from industrial sources is limited by regulatory 9 controls already in place. It may also be a closed 10 system intermediate as defined by the OECD/SIDS 11 guidelines and as such reproductive toxicity data 12 should not be required. 13 AWG evaluated the Agency's findings for 14 human exposure by looking at actual concentrations of 15 acetaldehyde from environmental monitoring and computer 16 (sic) product modeling and then comparing these levels 17 to human biomonitoring data. 18 It was found that exposure from 19 environmental sources appears to be significantly less 20 than from acetaldehyde naturally produced in the body. 21 AWG also observes that there is already a significant 22 toxicology data base for acetaldehyde. 23 AWG reviewed the available data and 24 provided robust summaries for several unpublished 25 studies as well as a specially commissioned review ofUS EPA MEETING 03/31/09 CCR#16194-1 35

1 developmental and reproductive toxicity data. The in 2 vivo developmental and reproductive toxicity data 3 indicate no significant developmental or reproductive 4 organ effects from oral or inhalation exposure to 5 acetaldehyde. 6 Due to its strong irritation to mucous 7 membranes, acetaldehyde exposure by inhalation is 8 unlikely to result in sufficiently high maternal blood 9 concentrations to result in an adverse effect on 10 developing embryos. 11 Also a 1997 expert panel review of 12 acetaldehyde by Toxicology Excellence for Risk 13 Assessment concluded that systemic toxicity, including 14 any effects on a fetus, are not likely to be of concern 15 following inhalation exposure because its exposure is 16 likely to be limited by respiratory tract and ocular 17 irritation. 18 AWG also notes that a new IUCLID dossier 19 for acetaldehyde will be developed under REACH by 20 December 2010. This should address the EPA's data 21 requirements. A new reproduction/developmental toxicity 22 screening test will not add any new information to the 23 data set already available on acetaldehyde. 24 AWG concludes, and we agree, that to 25 require an additional screening level toxicity study onUS EPA MEETING 03/31/09 CCR#16194-1 36

1 acetaldehyde would be inconsistent with EPA's stated 2 goal to maximize the use of existing and scientifically 3 adequate data to minimize further testing. 4 Moving on from the specific chemicals, 5 I'm at the end of my slides, as a general observation 6 about the test that would be required under this 7 proposed rule, we note that basic information on 8 physical/chemical properties and environmental fate are 9 apparently lacking for many of these chemicals. 10 For example, the test rule would require 11 testing for all physical/chemical endpoints for five 12 chemicals or groups, while testing for one to four of 13 these endpoints would be required for another five 14 chemicals. 15 It is senseless to conduct health 16 effects in ecotoxicity testing until such basic 17 information is known, since in some cases a chemical's 18 physical/chemical and environmental fate properties 19 will preclude the need for further testing. 20 This is the backbone of an intelligent 21 testing strategy such as the OSIRIS initiative, 22 Optimized Strategies for Risk Assessment of Industrial 23 Chemicals through Integration of Non-Test and Test 24 information, the goal of which is to significantly 25 increase the use of non-testing information toUS EPA MEETING 03/31/09 CCR#16194-1 37

1 regulatory decision making under REACH and thus to 2 minimize the need for animal testing. 3 At this point, I'd like to outline a 4 number of approaches for reducing the number of animals 5 killed in toxicity testing, beginning with mammalian 6 acute toxicity testing. The acute toxicity test 7 inflicts suffering so extreme that by design many of 8 the animals who are exposed to the test chemicals are 9 poisoned to death. 10 Under the proposed rule, mammalian 11 toxicity testing would be required for seven chemicals. 12 Alternative approaches exist that either refine 13 existing methods, allowing more information to be 14 obtained from them, or replace acute toxicity testing 15 with non- animal methods. 16 Last year, for example, the 17 International Council on Harmonization proposed 18 removing the acute toxicity testing requirement from 19 its guidelines in favor of obtaining this data from 20 available repeated dose studies. 21 This followed the report of a coalition 22 of European pharmaceutical companies that regulatory 23 decisions are almost never based on the results of 24 acute toxicity tests. ECVAM, the European Center for 25 the Validation of Alternative Methods, reported that itUS EPA MEETING 03/31/09 CCR#16194-1 38

1 was able to correctly classify a majority of chemicals 2 using this approach. 3 Another approach for chemicals tested by 4 the inhalation route of exposure is based on the 5 observation that a chemical's water solubility and 6 vapor pressure represent the effective dose to which 7 fish or mammals would be exposed, respectively. As a 8 result, acute mammalian inhalation toxicity can be 9 predicted using available acute fish toxicity data and 10 vice versa. 11 The International QSAR Foundation has 12 preliminary data showing very good correlations, and is 13 using this concept to build a QSAR model. These 14 approaches are examples of the kind of thoughtful 15 toxicology that the Agency and chemical manufacturers 16 should be applying to the testing of HPV chemicals. 17 Also recent efforts to validate the in 18 vitro 3T3 Neutral Red Uptake or NRU cytotoxicity assay 19 as a replacement for the in vivo acute toxicity test 20 indicate that it correctly discriminates non-toxic 21 chemicals -- those with an LD 50 greater than 2 grams 22 per kilogram body weight from more toxic ones and shows 23 a good correlation with mammalian LD 50 data at both 24 extremes of the toxicity spectrum. 25 This suggests using the 3T3 NRU assay asUS EPA MEETING 03/31/09 CCR#16194-1 39

1 a first tier, particularly for those substances that 2 are already suspected to be at the extremes of 3 toxicity. If the in vitro predictions corroborate the 4 expectations from preliminary evidence, then no 5 additional animal testing need be conducted for such 6 substances. This would result in an immediate reduction 7 in the number of animals used. 8 We urge the Agency to reconsider 9 allowing this approach, particularly for pyromellitic 10 dianhydride, CI Leuco Sulphur Black 1 and the castor 11 oil derivatives since at least preliminary data exist 12 indicating that these chemicals are nontoxic. 13 The same is likely true of sodium 14 glucoheptonate which is permitted as a food additive by 15 the FDA. In addition ECVAM is currently conducting a 16 definitive validation study of the 3T3 NRU assay, the 17 results of which are expected later this year. 18 At a minimum the Agency should await the 19 results of this validation effort before finalizing 20 acute toxicity requirements for these chemicals. Moving 21 on to aquatic toxicity testing, based on the OECD's 22 Test Guideline 203, each fish acute toxicity test will 23 kill approximately 120 animals. 24 Under the proposed rule, fish toxicity 25 testing would be required for as many as twelveUS EPA MEETING 03/31/09 CCR#16194-1 40

1 chemicals. As a general observation fish toxicity 2 testing is intended to predict the potential for 3 economic loss and ecological damage resulting from fish 4 death on a large scale. 5 If a chemical is toxic to the food on 6 which fish subsist, fish populations would be affected 7 even without direct toxicity to fish. As a result, 8 toxicity to aquatic plants and invertebrates should 9 generally be characterized prior to consideration of 10 acute toxicity testing on fish. 11 In addition in silico and in vitro 12 methods exist that can replace in vivo fish testing and 13 another alternative approach can greatly reduce the 14 number of fish killed. 15 The Agency's guidance document entitled 16 The Use of Structure-Activity Relationship in the High 17 Production Volume Chemicals Challenges Program notes 18 that if a QSAR model is available, then it may be used 19 and identifies ECOSAR as an available model to estimate 20 aquatic toxicity. 21 Toxicity screening of HPV chemicals is 22 an ideal application of such QSAR tools and the Agency 23 and chemical sponsors should make every effort to use 24 them. 25 An in vitro approach to fish toxicityUS EPA MEETING 03/31/09 CCR#16194-1 41

1 testing is the validated DarT test which uses 2 fertilized zebrafish eggs as a replacement for living 3 fish. Since the eggs do not hatch, the DarT test is a 4 non-animal test method. 5 Following a 48 hour exposure assessed 6 endpoints are comparable to lethality in vivo. These 7 include incomplete gastrulation and somite development, 8 absence of a heartbeat and coagulation of eggs. 9 The reliability and relevance of this 10 test have been confirmed through an international multi 11 laboratory validation study coordinated by the German 12 Environmental Protection Agency. 13 Predictions of acute toxicity from the 14 DarT test correlated very well with in vivo reference 15 data. This in vitro test has been accepted in Germany 16 as a replacement for the use of fish in the assessment 17 of wastewater effluent and has since been nominated for 18 development into an OECD test guideline. 19 It is clearly suitable for immediate use 20 as a replacement for the use of fish in providing 21 screening level hazard data. If a fish acute toxicity 22 test is still perceived to be required, the fish acute 23 threshold or step down test can reduce the number of 24 fish killed by 50 to 70 percent. 25 Since fish are less sensitive than algaeUS EPA MEETING 03/31/09 CCR#16194-1 42

1 or Daphnia in acute aquatic toxicity tests roughly 85 2 percent of the time, an upper threshold concentration 3 or UTC is set at the lowest EC 50 value observed in the 4 algae and Daphnia tests. An acute toxicity is carried 5 out at the UTC with five fish each in the test and 6 control groups. 7 If no toxicity is observed, no further 8 tests are carried out and the LC 50 is reported as 9 greater than the UTC value. If toxicity is observed, a 10 second test is performed at a step down concentration 11 using a dilution factor of 3.2 which is based on a 12 semi-logarithmic concentration series. 13 The testing continues to lower 14 concentrations until no toxicity is observed. The LC50 15 value is obtained using all of the test data by 16 applying the binomial method of interpolation. An 17 additional refinement can be obtained by terminating 18 the test after 24 hours of exposure if lethality or 19 serious morbidity are observed in two out of the five 20 fish. 21 When no replacement for the acute fish 22 toxicity test is perceived to be applicable, we 23 strongly urge the use of this new testing strategy. 24 With regard to developmental toxicity testing, we note 25 that an embryonic stem cell test or EST has beenUS EPA MEETING 03/31/09 CCR#16194-1 43

1 validated by ECVAM as a test for embryotoxicity, a 2 critical developmental toxicity endpoint. 3 The test uses rodent derived stem cells 4 which survive in culture indefinitely and are capable 5 of differentiation. Embryoxtoxicity is determined by 6 the concentration of the test chemical required to 7 inhibit differentiation by 50 percent, together with 8 growth inhibition by 50 percent relative to controls. 9 This method is suited for immediate use 10 at the screening level and would reduce the number of 11 animals killed since chemicals that test positive for 12 embryoxtoxicity in the EST could be classified as 13 probable developmental toxicants without further 14 testing. 15 I'd like to say a few words about in 16 vitro genetic toxicity testing and combined repeated 17 dose reproduction/developmental toxicity testing that 18 will lead to some general comments about this test 19 rule. The proposed rule states that persons who would 20 be required to conduct testing for chromosomal damage 21 are encouraged to use in vitro genetic toxicity 22 testing. 23 It seems to us that a rule must 24 stipulate the Agency's requirements not just encourage 25 actions by regulated entities. Further, a subjectUS EPA MEETING 03/31/09 CCR#16194-1 44

1 person who uses one of the in vivo methods instead of 2 the in vitro method would be required to submit to EPA 3 a rationale for conducting that alternative test in the 4 final study report. 5 Similarly a person who uses separate 6 repeated dose and reproduction/ developmental toxicity 7 tests instead of the combined protocol would be 8 required to submit to EPA a rationale for conducting 9 these alternative tests in the final study reports. If 10 a company's rationale is flawed, there will have been 11 no opportunity to spare animals from these tests. 12 We call upon the Agency to amend the 13 proposed rule to mandate the use of internationally 14 accepted in vitro genetic toxicity screening tests and 15 the combined protocol. 16 In addition, companies proposing to use 17 in vivo genetic toxicity testing or separate repeated 18 dose and reproduction/developmental toxicity tests 19 should be required to submit a compelling justification 20 for an exemption prior to the testing being conducted, 21 and opportunity for public comment should be made 22 available prior to the Agency's final decision. 23 In response to similar comments on the 24 first proposed test rule, the Agency noted that it 25 anticipates that test sponsors will generally choose toUS EPA MEETING 03/31/09 CCR#16194-1 45

1 conduct the less costly and less resource intensive in 2 vitro and combined tests unless there are sound 3 scientific reasons not to do so. 4 In our retrospective analysis of all 5 test plans submitted to the HPV Challenge Program, 6 however, we found that 21 percent of in vivo 7 chromosomal aberration tests originally proposed were 8 subsequently replaced by the in vitro test in revised 9 test plans. 10 This saved the lives of more than 500 11 animals. Likewise, 35 percent of individual repeated 12 dose reproduction and developmental toxicity tests were 13 subsequently replaced by the combined protocol and this 14 saved the lives of more than 16,000 animals. 15 In many cases these revisions resulted 16 at least in part from the involvement of animal 17 protection organizations. The Agency suggests that 18 publication of study plans in order to provide an 19 opportunity for public comment on the inclusion of any 20 alternative tests could cause a significant delay in 21 the initiation of testing. 22 Considering that the Agency took more 23 than four years just to respond to public comments on 24 the first proposed test rule and more than five years 25 to publish a final rule, a 120 day public commentUS EPA MEETING 03/31/09 CCR#16194-1 46

1 period seems hardly significant. The Agency's sudden 2 concern for efficiency is not an acceptable reason for 3 allowing test sponsors to justify the use of in vivo 4 methods after the fact. 5 Another reason for the publication of 6 study plans along with an opportunity for public 7 comment would be to allow the evaluation of existing 8 data that is not yet publicly available. 9 In its response to comments on the first 10 test rule, the Agency claimed that its "designation in 11 the proposed test rule of the tests and test methods to 12 be required for each chemical is in essence the test 13 plan for each chemical." 14 Elsewhere in its response, however, the 15 Agency agreed that publicly available data bases do not 16 provide access to all existing data on particular 17 chemicals and stated its hope that the test rule would 18 "cause manufacturers to release any in house testing 19 results and other existing data of which they are 20 aware." 21 If it is in part the purpose of the 22 proposed test rule to make this data available during 23 the public comment period or after, how is the public 24 to comment on their adequacy and whether or not 25 additional testing is called for?US EPA MEETING 03/31/09 CCR#16194-1 47

1 The Agency must allow for public comment 2 after any in-house testing results or other existing 3 data are made available in a test plan as part of this 4 proposed rule. This would also provide test sponsors 5 with the opportunity to consider the use of categories 6 or analogs and SAR analyses. 7 Notably these approaches have once again 8 been excluded from the current proposal, although 9 comments suggesting procedures for their inclusion were 10 received in response to the first test rule from 11 diverse organizations including the Synthetic Organic 12 Chemical Manufacturers Association, the American 13 Chemistry Council, and several animal protection 14 organizations. 15 The Agency states that these approaches 16 would require "time consuming and intensive procedural 17 steps such as multi-phase rulemaking without a 18 corresponding benefit." 19 However, throughout the HPV Challenge 20 Program, category and SAR approaches have resulted in 21 considerable benefit by reducing testing required and 22 consequently the number of animals killed in that 23 testing. 24 In our retrospective analysis we show 25 that nearly a third of all test plans submitted to theUS EPA MEETING 03/31/09 CCR#16194-1 48

1 HPV Challenge Program in which animal tests were 2 proposed were for categories of chemicals. These 3 opportunities for read-across from already 4 characterized category members are likely to have 5 spared the lives of tens of thousands of animals. 6 Likewise, ECOSAR data was used to fulfill the fish 7 acute toxicity endpoint in approximately 10 percent of 8 these test plans. 9 In conclusion, the Agency has once again 10 failed to consider the totality of what is known about 11 each chemical, including human experience, before 12 concluding that all endpoints need to be tested. The 13 inclusion of such familiar substances as acetaldehyde, 14 sorbic acid, oxalic acid and castor oil derivatives is 15 evidence that this primary principle has been grossly 16 ignored. 17 Also the Agency must allow for public 18 comment after any in-house testing results or other 19 existing data are made available in a test plan as a 20 result of this proposal. We also urge the Agency to 21 take this opportunity to reconsider the alternatives to 22 mammalian acute toxicity testing, fish acute testing, 23 toxicity testing and developmental toxicity testing 24 detailed earlier. 25 Finally, and most urgently, the AgencyUS EPA MEETING 03/31/09 CCR#16194-1 49

1 must thoroughly evaluate the existing data we have 2 cited for many of the chemicals included in this 3 proposed test rule. We appeal to the Agency and to 4 chemical companies themselves to carefully evaluate all 5 available data to avoid conducting duplicative animal 6 tests. Thank you. 7 DR. WILLIS: Thank you, next on my list 8 is ARISE from New Jersey.. 9 MR. CHAIFETZ: Good morning, my name is 10 Stuart Chaifetz, I'm program director for ARISE. On 11 February 14th, 2008 the National Institutes of Health 12 and the Environmental Protection Agency held a press 13 conference announcing a new collaborative effort to use 14 state of the art technology to test for chemical 15 toxicity These pioneering procedures, which include 16 using robotics and human cell cultures have brought us 17 to the dawn of a new era in scientific experimentation 18 and toxicity safety testing. 19 The EPA rules we are here today to 20 discuss, however, drag us back into the darkness for 21 exposing animals to lethal doses of chemicals is not a 22 thing of the 21st Century. Toxicity testing using 23 animals is, quote, "clearly quite expensive, it is time 24 consuming, it uses animals in large numbers and it 25 doesn't always predict which chemicals would be harmfulUS EPA MEETING 03/31/09 CCR#16194-1 50

1 to humans. 2 These are the words of Dr. Francis 3 Collins, the then Director of the National Human Genome 4 Research Institute, speaking at the NIH/EPA 5 teleconference on the 14th of last year. Dr. Collins 6 continued, quote. "There are differences between 7 species. 8 We are not rats and we are not even 9 other primates," end quote. Speaking directly to the 10 point of the NIH/EPA joint venture that would act as a 11 replacement for animal testing, Dr. Collins said, 12 quote, "And so the desire here is to try to see if we 13 could do better." 14 Samuel Wilson, former director of the 15 NIH National Institute of Environmental Health 16 Sciences, was also at the NIH/EPA press conference and 17 he echoed Dr. Collins' statements. As quoted in 18 Scientific American, February 15th, 2008 Wilson said, 19 quote, " this sort of high throughput testing will 20 enable researchers to generate more data relevant to 21 humans and at the same time reduce the amount of animal 22 experimentation." 23 The cross species extrapolation from 24 animals to humans is "not always as precise as it 25 should be," Wilson said. This collaboration is aUS EPA MEETING 03/31/09 CCR#16194-1 51

1 milestone because it gives us the ability to apply a 2 new generation of approaches to determining toxicities. 3 Robert Kavlock, Director of the National Center for 4 Computational Toxicology at EPA was quoted in the same 5 article and joined his colleagues in expressing the 6 inherent flaws with animal toxicity testing by saying, 7 quote,:"that it is also expensive, inefficient and is 8 not always an accurate indicator of how a substance 9 will affect humans." 10 The NIH/EPA are not alone in seeking a 11 more advantageous method to test for toxicity. Another 12 ground breaking technological advancement are called 13 "biochips", the MetaChip (Metabolizing Enzyme 14 Toxicology Assay Chip) and the DataChip, (Data Analysis 15 Toxicology Assay Chip), which were created by 16 researchers at Rensselaer Polytechnic Institute, the 17 University of California at Berkeley and Solidus 18 Biosciences, Inc. 19 Both chips are glass slides with the 20 MetaChip containing human enzymes while the DataChip 21 contains cell cultures. 22 As was reported in the National 23 Institute of Environmental Health Sciences News of 24 March 2008: Quote, "When the two slides are 25 sandwiched together and incubated, they mimic theUS EPA MEETING 03/31/09 CCR#16194-1 52

1 body's reactions to compounds. 2 If the cells stop growing, appear sick 3 or die, it's an indication that a toxin is present". 4 End quote. The headline for the story on biochips in 5 Scientific American, December 21st, 2007 read, quote, 6 "Biochips promise to deliver better drug and chemical 7 testing, cutting costs and nixing the need for most 8 animal testing." Dr. Collins set the correct ethical 9 and scientific tone when he said that the desire is to, 10 quote, "do better", yet the rules we are discussing 11 today fail this. They do not do better. 12 These animal tests will be expensive. 13 They will take a great deal of time. They will destroy 14 the lives of thousands of animals, and they will not 15 produce the best hazard assessments for human health 16 and the environment. 17 In science, we must always press 18 forward, pushing the frontiers of our knowledge and our 19 ethics to new heights, topping each crowning moment 20 with the race to the next summit. 21 With so much technology within our 22 grasp, is it not better to apply this superior 23 technology to the testing of HPV chemicals rather than 24 waste so much time, money and life? Our argument, in 25 its most direct and uncomplicated expression, is thatUS EPA MEETING 03/31/09 CCR#16194-1 53

1 we do it better. Thank you very much. 2 DR. CAMPANELLA: I think that brings us 3 to a close the comment period. 4 Are there any other comments from the 5 audience that anybody wants to make? 6 If not I want to thank you all for 7 coming, I think I've heard some interesting and very 8 useful analysis today. I thought the, I thought the, a 9 lot of the points made by Mr. Manuppello were very good 10 and will cause us to consider very seriously what he 11 said as we go forward to develop a final rule. 12 We're going to revisit a lot of these 13 points and incorporate them into our thinking. I think 14 it's useful for us to hear these comments and I don't 15 mean the written ones, but also the oral ones because I 16 think they add a new dimension to the analysis that we 17 have to do to make wise decisions about these 18 chemicals. 19 So I thank you all for coming, I know it 20 was a good opportunity for you to come, also it was a, 21 sort of a burden to come and present, but we appreciate 22 that and so I thank you again. 23 We will be producing a transcript of the 24 meeting, which will be entered into the public docket 25 and that will available for your perusal whenever. IUS EPA MEETING 03/31/09 CCR#16194-1 54

1 think you'll probably have, I'm not sure what the 2 delivery date of that would be, do you have any, any 3 idea when that would be ready? 4 COURT REPORTER: Seven to ten days. 5 DR. CAMPANELLA: Seven to ten days. 6 Okay, thank you then we'll conclude this. 7 (WHEREUPON, the PUBLIC MEETING was concluded at 8 9:19 a.m.) 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25US EPA MEETING 03/31/09 CCR#16194-1 55

1 CAPTION 2 The foregoing matter was taken on the date, and at the 3 time and place set out on the Title page hereof. 4 It was requested that the matter be taken by the 5 reporter and that the same be reduced to typewritten 6 form. 7 Further, as relates to depositions, it was agreed by 8 and between counsel and the parties that the reading 9 and signing of the transcript, be and the same is 10 hereby waived. 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25US EPA MEETING 03/31/09 CCR#16194-1 56

1 CERTIFICATE OF REPORTER 2 COMMONWEALTH OF VIRGINIA 3 AT LARGE: 4 I do hereby certify that the witness in the foregoing 5 transcript was taken on the date, and at the time and 6 place set out on the Title page hereof by me after 7 first being duly sworn to testify the truth, the whole 8 truth, and nothing but the truth; and that the said 9 matter was recorded stenographically and mechanically 10 by me and then reduced to typewritten form under my 11 direction, and constitutes a true record of the 12 transcript as taken, all to the best of my skill and 13 ability. 14 I further certify that the inspection, reading and 15 signing of said deposition were waived by counsel for 16 the respective parties and by the witness. 17 I certify that I am not a relative or employee of 18 either counsel, and that I am in no way interested 19 financially, directly or indirectly, in this action. 20 21 22 23 24 CHARLES DAVID HOFFMAN, COURT REPORTER / NOTARY 25 SUBMITTED ON MARCH 31, 2009US EPA MEETING 03/31/09 CCR#16194-1 57 0 0.2 22:10 0.6 20:20

1 1 5:23 22:8 30:22 39:10 1,350 23:21 1,600 23:21 1.6 27:5 10 48:7 10W-30 28:22 120 23:10 39:23 45:25 1-3 23:5 1340 29:15 14th 49:11 50:5 150 27:6 15th 50:18 16,000 45:14 16th 3:25 17.97 24:22 19 5:9 6:14 7:14 8:7 9:15 194 31:13 1960s 18:14 1980 24:13 1981 29:11 1986 31:1 1990 20:6 1994 13:20 1997 35:11 1999 16:20 20:22

2 2 5:25 31:3 32:24 38:21 2.2 24:14 2.25 27:2 2.3 27:4 2.65 27:4 20 22:13 2006 9:21 29:5 2007 24:1 52:5 2008 49:11 50:18 51:24 2009 2:5 2010 35:20 203 39:22 21 45:6 21st 16:8 49:22 52:5 220 27:8 28:8 22nd3:16 23 22:5 24 14:18 23:12 42:18

3 3 6:2 27:17 3.1 6:9 3.2 42:11 3.5 27:3 31 2:5 35 45:11 37.9 31:17 3T3 38:18 38:25 39:16

4 4 5:18 6:5 7:13 9:23 10:23 22:14 32:5 4.2 28:16 401 31:4 43317 7:10 44 27:8 27:10 48 41:5 4th 3:14

5 5 21:25 22:12 24:23 5,000 27:18 50 24:22 29:19 31:12 31:17 38:21 38:23 41:24 42:3 42:8 43:7 43:8 500 45:10

6 6.5 28:13 675 18:16 23:7

7 7.4 28:15 70 41:24 739 27:24 792 27:23US EPA MEETING 03/31/09 CCR#16194-1 58 8 8 6:12 7:19 7:21 10:13 11:1 32:24 8(a 8:2 8(d8:1 8:3 810 29:14 85 42:1 896 27:23

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