LABORATORY TESTING OF CHEMICALS FOR ENDOCRINE DISRUPTION
POTENTIAL–ANALYSIS OF MARKET FACTORS

October 14, 2009

Final

Economics and Policy Analysis Branch Economics, Exposure, and Technology Division

Office of Pollution Prevention and Toxics

U.S. Environmental Protection Agency Washington, D.C. 20460CONTRIBUTORS

The analyst responsible for completion of this report was Lynne Blake-Hedges. Analytical and draft preparation support was provided by Eastern Resear ch Group, Inc. of Lexington, Massachusetts under

EPA Contract No. EP-W-05-014.

## TABLE OF CONTENTS

1.0 INTRODUCTION .........................................................................................................................1

1.1 B ACKGROUND

............................................................................................................................... 2

1.1.1 EDSP Generated Demand for Endocrine Disruptor Testing Services .......................................3

2.0 SUPPLY OF ENDOCRINE DISRUPTOR TESTING SERVICES ..........................................5

2.1 L ABORATORIES C APABLE OF T IER 1 S CREENING .........................................................................5

2.2 I NDUSTRY C APACITY FOR T IER 1 S CREENING ..............................................................................7

2.3 P OTENTIAL FOR E NTRY INTO THE M ARKET /E XPANSION FOR E NDOCRINE D ISRUPTOR T ESTING 8

3.0 ISSUES THAT COULD IMPACT ENDOCR INE DISRUPTOR TESTING DEMAND AND

SUPPLY

............................................................................................................................... .........11

3.1 F OOD AND D RUG A DMINISTRATION R EQUIREMENTS ................................................................11

3.2 E UROPEAN R EQUIREMENTS ........................................................................................................13

3.2.1 Registration, Evaluation, and Authorisation of Chemicals .....................................................13

3.2.2 Pesticide Restrictions ..............................................................................................................14

3.3 O THER U.S. E NVIRONMENTAL P ROTECTION A GENCY I NITIATIVES ...........................................14

3.3.3 Toxic Substances Control Act .................................................................................................14

3.3.4 Federal Insecticide, Fungicide, and Rodenticide Act ..............................................................15

4.0 LABORATORY CAPACITY CONCLUSIONS .......................................................................16

5.0 COST ESTIMATES FOR CONDUCTING TIER 1 ASSAYS ................................................18

5.1 M ETHODOLOGY ..........................................................................................................................18

5.2 A SSAY C OSTS .............................................................................................................................19

5.2.1 Assumptions ............................................................................................................................19

5.2.2 Cost Data

............................................................................................................................... ..20

5.2.3 Limitations ..............................................................................................................................2 2

5.3 A DDITIONAL C OSTS ....................................................................................................................22

5.3.4 Analytical Methods and Validation .........................................................................................23

5.3.5 Preliminary Analytical Work ..................................................................................................24

5.3.6 Additional Cost Summary .......................................................................................................24

5.3.7 Chemicals

............................................................................................................................... .25

5.4 D ISCOUNTS

............................................................................................................................... ..25

5.5 C OST S UMMARY .........................................................................................................................26

APPENDIX A LABORATORIES CAPABLE OF TIER 1 SCREENING ...............................A-1

APPENDIX B EXAMPLE COST AND CAPACITY QUESTIONS ........................................ B-1

APPENDIX C POTENTIAL CHEMICALS TO BE TESTED AS PART OF EDSP .............C-1

## 1.0 INTRODUCTION

In recent years, some scientists have proposed that certain chemicals might be disrupting the endocrine system of humans and animal wildlife. A variety of chemicals have been found to disrupt the endocrine systems of animals in laboratory studies, and compelling evidence shows that endocrine systems of certain fish and wildlife have been affected by ch emical contaminants, resulting in developmental and reproductive problems. The 1996 Food Quality Protecti on Act, which amended the Federal Food, Drug, and Cosmetic Act (FFDCA), directed the U.S. E nvironmental Protection Agency (EPA) to develop a screening and testing program, using appropriate validat ed test systems and other scientifically relevant information, to determine whether certain substan ces may have hormonal effects in humans. Also in 1996, amendments to the Safe Dri nking Water Act authorized EPA to screen substances that may be found in sources of drinking water for endocrine disr uption potential. To meet its regulatory obligations, EPA initiated the Endocrine Disruptor Screening Prog ram (EDSP) that developed a Tier 1 battery of in

vitro and in vivo screening assays and Tier 2 in vivo tests to examine pesticide chemicals and environmental contaminants for their potential to a ffect the endocrine systems of humans and wildlife. 1

Due to the potential number of chemicals requiri ng examination and number of screening and testing assays to be requested, EPA wishes to know whether sufficient laboratory capacity is available to satisfy the demand for chemical screening and testing request ed by the EDSP. The purpose of this report is to provide a snapshot of the relevant laboratory capacity from a segment of the chemical testing industry in the United States, as well as overseas. This report prov ides neither comprehensive coverage of the entire industry nor does it represent a statistical sample of the industry. Rather, the intent is to provide insight into the testing industry’s likely response to the EDSP test orders and infer, based on limited industry contacts, whether sufficient capacity exists for complying with the test orders.

Another purpose of this report is to provide update d cost estimates for the Tier 1 EDSP screening assays. In 2009, EPA provided the Office of Management and Budget (OMB) with estimates of the cost of Tier 1 screening in support of an Information Collection Re quest (hereafter referred to as the ICR estimates). 2 In that submission EPA relied upon cost data from an industry-sponsored survey conducted by Applied Pharmacology and Toxicology, Inc. in 2003, 3 with the data updated to 2008 dollars and adjusted by EPA to reflect (a) Agency costs of having the validati on tests conducted and (b) changes made to the Tier 1 protocols. The protocols have completed validation and are now closer to what will be required under

Tier 1 test orders. Since the ICR estimates were based upon the unvalidated and preliminary test protocols, EPA sought laboratory review of the most recent versions of the assay protocols and input on the costs of performing the tests. The cost information provided in this report is the result of consultations

with a limited number of laboratori es conducted during May and June 2009.

In this report, the term “chemical testing industry” applies broadly to any organization, in the United States and abroad, that has the capab ility to use standard laboratory methods to determine the effects that a particular chemical may have on humans or th e environment. These may include contract research organizations (CROs) conducting toxicology chemical testing; in-house testing laboratories operated by chemical companies or others (who may also do work for hire), as well as laboratories maintained and

1 Additional information about the development of the program can be located at www.epa.gov/endo

. 2 Attachment F to EPA ICR #2249.01 dated April 3, 2009. The Federal Register notice “Agency Information Collection Activities; Submission to OMB for Review an d Approval; Comment Request; Tier 1 Screening of Certain Chemicals Under the Endocrine Disruptor Screening Program (EDSP); EPA ICR No. 2249.01” was published on April 15, 2009.

3 Applied Pharmacology and Toxicology, Inc. Cost Estimate Survey: Endocrine Screening Assays . May 23, 2003.
Available at http://www.apt-pharmatox.com/pdf/2003EDSP-CostReport.final.pdf

1operated by academic or other institutions. The majority of organizations contacted for and discussed in this report, however, are U.S.-based CROs.

1.1 B ACKGROUND

EPA developed a two-tiered approach to gather information needed to identify endocrine-active substances. Tier 1 screening uses a battery of assays to identify substances with the potential to interact with the estrogen, androgen, or thyroid hormone sy stems. Chemicals identified as having such potential following Tier 1 screening proceed to Tier 2. Tier 2 testing is intended to identify and establish a doseresponse relationship for any adverse effects that migh t result from the interactions identified through the Tier 1 assays.

Section 408(p) of the FFDCA requires EPA to use validat ed test systems and other scientifically relevant information in the EDSP . Even though Tier 1 screening assays were developed and validated individually, EPA plans to use them in the context of a battery of complementary assays. An individual assay may serve to strengthen the weight of evidence in a determination 4 or provide coverage of mechanisms of actions not addressed by other assays in the battery. Table 1 displays the Tier 1 assays, all of which have completed the validation process. 5

Table 1. EDSP Tier 1 Screening Assays Proposed by EPA Assay

In vitro Rat uterine cytosol estrogen receptor binding (Rat ER binding) Rat prostate cytosol androgen r eceptor binding (Rat AR binding) Human placental or recombinant aromatase (Human aromatase) Human cell line (H295R) steroidogenesis (Human steroidogenesis) Human estrogen receptor- α transcriptional activation (Human ER transcriptional)

In vivo rat tests Uterotrophic (rat) Hershberger (rat) Pubertal female (rat) Pubertal male (rat) In vivo tests of aquatic species Amphibian metamorphosis (frog) Fish short-term reproduction

Chemicals that go through Tier 1 screening and are found to have the potential to interact with the estrogen, androgen, or thyroid hormone systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests ar e necessary based on available data from Tier 1. Tier 2 testing is designed to identify any adverse endocri ne-related effects caused by the test chemical and establish a quantitative relationship between dose and e ndocrine effect. Table 2 presents the Tier 2 assays,

as well as their validation status as of June 2009. Si nce most of Tier 2 assays are still under development, the remainder of this report is focused on Tier 1 assays.

4 For example, EPA could determine that positive results in an ER binding assay, in conjunction with positive results in the uterotropic and pubertal female assays, provide a consistent signal for estrogenicity.

5 Additional information about the assays can be located at www.epa.gov/endo/pubs/assayvalidation

.

2Table 2. EDSP Tier 2 Testing Assays Proposed by EPA Assay Validation Status as of June 2009

In vivo Amphibian development, reproduc tion Pre-validation in progress Avian 2-generation Validation in progress Fish lifecycle Pre-validation in progress Invertebrate lifecycle Pre-validation in progress Mammalian 2-generation reproductive toxicity test Validated

1.1.1 EDSP Generated Demand for Endocrine Disruptor Testing Services

The universe of chemicals identified as potential candidates for the EDSP include:

 Pesticides;

 Commercial chemicals;

 Cosmetic ingredients;

 Food additives;

 Nutritional supplements; and

 Certain mixtures.

EPA proposed a strategy for prioritizing chemicals fo r initial chemical selection for Tier 1 screening in

the Federal Register in December 2002. 6 The approach focused initially on pesticide-related chemicals that EPA is required to screen, including pestic ide active ingredients and high production volume chemicals that are also inert pes ticide chemicals. Upon review of co mments received in response to the proposed approach, EPA published a final approach for the initial selection of chemicals in the Federal Register in September 2005 and a draft list of initial substances in June 2007. 7

, 8 In April 2009, the Agency published the final list of 67 substances to undergo screening based upon exposure potential. 9

This chemical list was included with EPA’s April 2009 submission to OMB for review of an ICR. 10 The ICR describes the process for collecting Tier 1 screeni ng data for the first group of chemicals. Based on the ICR, EPA estimates it will issue test orders to 390 manufacturers, importers, and pesticide registrants

6 EPA, “Endocrine Disruptor Screening Program, Prop osed Chemical Selection Approach for Initial Round of Screening; Request for Comment,” Federal Register, December 30, 2002; Available at www.epa.gov/endo/pubs/12-02-frnotice.pdf

. 7 EPA, “Endocrine Disruptor Screening Program; Chemi cal Selection Approach for Initial Round of Screening,” Federal Register , September 27, 2005; Available at www.epa.gov/fedrgstr/EPA-TOX/2005/September/Day27/t19260.pdf

. 8 EPA, “Draft List of Initial Pesticide Active Ingredient s and Pesticide Inerts to be Considered for Screening under the Federal Food, Drug, and Cosmetic Act,” Federal Register , June 18, 2007; Available at www.epa.gov/endo/pubs/draft_list_frn_061807.pdf

. 9 EPA, “Final List of Initial Pesticide Active Ingredients and Pesticide Inert Ingredients to be Screened under the Federal Food, Drug, and Cosmetic Act,” Federal Register , April 15, 2009; Available at http://www.epa.gov/endo/pubs/final_list_frn_041509.pdf

10 EPA, “Agency Information Collection Activities; Submission to OMB for Review and Approval; Comment Request; Tier 1 Screening of Certain Chemicals Under the Endocrine Disruptor Screening Program (EDSP); EPA ICR No. 2249.01, OMB Control No. 2070–New,” Federal Register , April 15, 2009. Available at http://www.epa.gov/endo/pubs/icr_frn_041509.pdf.

3of the 67 chemicals. EPA expects most of the recipi ents to respond by selecting one of the three courses of action, described in the I CR, to comply with the order: 11

1. Agree to individually generate new data;

2. Participate in a consortium to generate new data; or

3. Submit or cite existing data.

Based on its experience with the pesticide registra tion program and testing requirements under the Toxic Substances Control Act, EPA assumes new testing will be undertaken largely by consortia representing manufacturers, importers, and pesticide registrants of individual chemicals or groups of chemicals to avoid duplication of effort and reduce costs. This expectation was shared by two CROs and one in-house laboratory likely to be asked to conduct testing, who were contacted for this report. 12 An unknown number of test order recipients may already have co nducted testing, and therefore, will submit existing data. Given the uncertainty about the extent of consortia-forming and the amount of test data that may already exist, this report assumes two scenarios rega rding the volume of new test requests generated by

the EDSP test orders. In its ICR documentation th e Agency assumed only one set of data on average would be generated for the 67 chemicals. Since the focus of this report is on available laboratory capacity, EPA also explored a high volume scenario in which two sets of data, on average, would be generated per chemical, or a total of 134 data sets. While expected to be an overestimate, this assumption may mimic capacity demands placed on the laboratories for other testing that may use similar capabilities

EPA anticipates requiring recipients of the test orders to follow this schedule:

 90 days: submission of initial response describi ng how the company will respond to the test order;

 12 months: submission of a progress report; and

 24 months: final submission of data.

Assuming that the EPA issues the test orders in the Fall of 2009, the majority of EDSP-generated Tier 1 screening from the initial list of chemicals will occur in 2010 and 2011.

Additional chemicals will be selected for screening in the future; however, EPA has not yet determined how it will prioritize the next set of chemicals. 13 Therefore, further endocrine disruptor testing rounds are expected, but the likely timeline has not been determined. This report focuses on EDSP-related testing of

the initial 67 chemicals over the 2010-2011 timeframe.

11 Personal communication with Molly Rodgers, Environm ental Scientist, Eastern Re search Group—Contractor supporting EDSP. April 6, 2009.

12 Personal communication with David Geter, Toxicology Specialist, Dow Chemical Company. May 14, 2009; personal communication with Kevin Causey, Manager, ILS. May 26, 2009; and personal communication with Jon Rhodes, Director of Chemical Serv ices, ABC Laboratories. May 28, 2009.

13 In the U.S. House of Representatives’ version of the fiscal year 2010 appropriations bill for EPA (H.R. 2996), the Agency is required to publish within one year a second list of no less than 100 chemicals for EDSP screening that includes drinking water contaminants, such as halogenated organic chemicals, dioxins, flame retardants, plastics, pharmaceutical s, and personal care products.

4

## 2.0 SUPPLY OF ENDOCRINE DI SRUPTOR TESTING SERVICES

Since a comprehensive list of laboratories capable of conducting endocrine disruptor testing is not readily available from the industry, one goal of this report is to identify a subset of those laboratories that may be capable of conducting the testing needed to supp ort the EDSP data requirements. This section was prepared using published information about the chemi cal testing industry, discussions with EPA and other experts familiar with the industry, and information collected first hand from laboratories exhibiting at the Society of Toxicology’s ToxExpo in March of 2009 in Baltimore, Maryland. Additionally, laboratories interviewed for Section 5 regarding testing costs were asked about their capacity.

The information provided here, including the list of laboratories provided in Appendix A, should not be construed as a comprehensive survey of the chemical testing industry. Data collection was limited by resources available and compliance with the Paperwork Reduction Act. 14 This section, therefore, is designed to help EPA better understand the potential number of laboratories with these capabilities and their capacity for conducting EDSP Tier 1 screening. The section is broken into three subsections:

1. Total number of laboratories with endoc rine disruptor testing experience;

2. Estimate of the number of tests that can be completed; and

3. Discussion of factors in laboratories’ decision to expand or enter the endocrine disruptor testing market.

2.1 L ABORATORIES C APABLE OF T IER 1 S CREENING

EPA has compiled a list of 32 laboratories believed to be capable of providing endocrine disruptor testing services (see Appendix A) 15 . Two of these are in-house laboratories that support testing for their corporate parent only, although one of them indicated a willingness to perform testing for third parties. 16
Table 3 summarizes the testing capabilities of these la boratories by indicating the number of laboratories

that are able to conduct each of the Tier 1 screeni ng assays. The majority of laboratories specialize in certain categories of tests, with only 4 of the 32 able to cover the entire Tier 1 battery of assays, which consists of 11 separate screens. More than 70 pe rcent of the laboratories can complete all four in vivo rodent screens, and approximately half have capabilities to conduct the in vitro screens.

The in vitro human aromatase and steroidogenesis assays and in vivo fish and amphibian assays are conducted by the fewest number of laboratories: 11, 11, 12, and 10, respectively. More detailed information on individual laboratories and their ability to perform endocrine disruptor testing is found in Appendix A.

While EPA may accept test data conducted in deve loping countries under the provision that it meets EPA’s good laboratory practice (GLP) standards, tw o laboratories located in non-developed countries (i.e., Brazil, India) identified during discussions with ToxExpo exhibitors have not been included in the total capacity calculations in Table 4 further below. Additionally, none of the laboratories described

14 The Paperwork Reduction Act prohibits federal agenci es from making the same information request of more than nine non-federal entities without approval from OMB.

15 Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does not constitute or imply its endorsemen t, recommendation, or favoring by the United States

Government.

16 Dow Chemical Company only performs in-house testing, while Bayer CropScience indicated that they would be willing to perform testing for third parties.

5below as having the potential to enter the market are included in the total capacity reported in Tables 3

and 4.

Table 3. Count of Laboratories with Capabilities for Tier 1 Screening*

Number of Laboratories

Location

Assays U.S. Other Developed

Country NonDeveloped

Country Total

In vitro Rat ER binding 13 2 0 15 Rat AR binding 13 2 0 15

Human aromatase 10 1 0 11 Human steroidogenesis 10 1 0 11 Human ER transcriptional 12 2 0 14

In vivo rodent tests Uterotrophic (rat) 17 4 2 23 Hershberger (rat) 17 4 2 23 Pubertal female (rat) 17 4 2 23 Pubertal male (rat) 17 4 2 23 In vivo tests of aquatic species Amphibian metamorphosis 6 3 1 10 Fish reproduction 7 4 1 12
* Based on a subset of 32 laboratories believed to have endocrine disruptor testing capabilities (includes both in-house and CRO laboratories). Does not include laboratories who indicated they could potentially conduct these tests. This table does not represent total industry capabilities.

Eleven laboratories that do not currently perform endoc rine disruptor testing suggested they could enter the endocrine disruptor testing market due to their experience in related areas. 17 These laboratories already perform toxicology tests, including, in some cases, in vivo rodent or aquatic species testing, and thus are in good position in terms of trained personne l and equipment to perform these types of endocrine disruptor tests. Several laboratories suggested that it would take approximately one to three months to obtain the necessary animals, ensure they are prep ared for the test, and train their employees on the protocol(s) before they could begin testing. Laboratories’ ability to adapt to demand is further examined

in Section 2.3.

In addition to the 11 laboratories discussed in the previous paragraph, EPA also identified two laboratories that previously offered in vitro rat endocrine disruptor testing services, but no longer do. WIL Research Laboratories participated in EPA’s validation of in vitro Tier 1 assays under the EDSP, but no longer performs this type of testing due to low demand. Another laboratory, Harlan Labs, indicated it had not received a test request in the past two years so had shifted resources to other business areas. Harlan indicated, however, that it could re-enter the endocrine disruptor testing market with three to six months of preparation if justified by an increase in testing demand.

17 These laboratories are: Banyan Biomarkers, BASi, Bi oQual, Caliper Life Sciences, Center for Environmental and Human Toxicology (University of Florida, College of Veterinary Medecine), CorDynamics, Certichem, Irisys, Lifecyte, RADIL (University of Missouri), and Wuxi AppTech.

62.2 I NDUSTRY C APACITY FOR T IER 1 S CREENING

In addition to understanding the numbe r of the laboratories that offer toxicology testing services, the Agency is also interested in understanding whether these laboratories have the capacity to handle the additional testing demand that woul d be generated by the EDSP, over the timeframe envisioned for the program (see Section 1.1.1). Since the proposed in vitro screening assays can typically be performed in a matter of days and generally allow for the use of automated equipment, laboratories can handle a high throughput of samples and capacity is not expected to be a constraint. Two laboratories commented that they prefer running in vitro tests on multiple chemicals at a time as this minimizes the level of effort for each chemical since there are significant economies of scale in performing this work. 18 Many small and large laboratories indicated they could perform “hundreds” or “thousands” of the in vitro endocrine disruptor assays each year. 19 The minimum number of assays that could be completed in a single laboratory per year was estimated to be 10, and that was reported by a small laboratory associated with a University. Overall, given the nature of the testi ng and opportunities for automation, EPA feels confident that a majority of the laboratories could complete the five in vitro assays for 100 chemicals annually. As calculated in Table 4, even using a conservative est imate of 10 chemicals per laboratory per year, EPA believes that at least 110 chemicals could be tested. This is almost twice the number required under EPA’s high volume estimates (i.e., 134 data sets over a two year period is 67 chemicals each year). This analysis is primarily based on testing capacity iden tified in the United States, but also includes four laboratories located in other developed nations (i.e., Europe, Japan, Canada).

Table 4. Estimated Annual Capacity for EDSP Tier 1 Assays
Capacity (Tests

Conducted Per Year) Total Annual Capacity** Annual Demand

Under EDSP Assays Number of

Labs* Low High Low High ICR High ER & AR binding (rat) 15 150 825 ER transcriptional (human) 14 140 770 Steroidogenesis and aromatase (human) 11 110 605

In vivo rat assays 21 10 100

210 1,155

In vivo amphibian metamorphosis 9 19 171

In vivo fish reproduction 11 20 220 34 67

* The number of laboratories with capacity to conduct each type of testing is derived from Table 3, excluding laboratories located in developing countries. ** EPA’s low estimate is obtained by multiplying the number of laboratories by the minimum number of tests that can be conducted per year, as reported by interviewees. The high estimate assumes half of the laboratories could conduct testing at the higher volume, and the other half perform the low estimate, which EPA believes to be conservative. It was beyond the scope of this report to conduct a detailed survey, but EPA expects the true capacity among these laboratories to lie between the low and high end points. For in vivo aquatic testing (amphibian metamorphosis and fish short-term reproduction) EPA multi plied the average capacity (b ased on data from more than half of the laboratories) by the numb er of laboratories with such capabilities.

18 Personal communication with David Geter, Toxicology Specialist, Dow Chemical Company. May 14, 2009; and personal communication with Alexander Lyubimov, Director, University of Illinois at Chicago, Toxicology Research Lab. June 9, 2009.

19 EPA identified laboratories as small if the parent company had less than 100 employees.

7Estimated capacities for the in vivo rat assays tended to range from 10 to 20 chemicals per year for

smaller laboratories to sometimes in excess of 100 chemic als per year for larger laboratories. Again, if EPA assumes a conservative estimate of 10 chemicals pe r year can be completed per laboratory, current capacity would accommodate 210 chemicals for in vivo rat screening, compared to a high volume estimate of 67 chemicals to be tested annually u nder the EDSP. EPA believes the actual capacity for in

vivo screening to be much larger than the low estimat ion, indicating that the incremental increase in testing demand generated by EDSP will be met with sufficient capacity.

Historically, EPA has identified fewer laborator ies with aquatic chemical testing capabilities. 20 Given this concern, EPA collected detailed information about cap acity from 7 of the 12 laboratories with capabilities for conducting one or two of the aquatic screening assays. The number of chemicals that could be tested among these laboratories ranged from a low of 4 to as many as 30 per year. No capacity differential was identified between small and large laboratories. One la boratory that performs the entire battery of Tier 1 assays explained that these aquatic screens required significantly more time and resources compared with other endocrine disruptor assays that they conduct. 21 The equipment involved, set-up costs, and time to expand capacity make it less attractive for laboratories to undertake this type of testing. The average annual capacity among these laboratories was 19 chemicals for the amphibian assay and 20 for the fish assay. As calculated in Table 4, even with the smal ler number of laboratories capable of completing the aquatic in vivo testing, EPA believes capacity is sufficient.

EPA believes that sufficient capacity exists for endocri ne disruptor testing of aquatic species based on the analysis done in Table 4; however, a few laboratori es expressed concern that there is insufficient capacity.

Three in vivo aquatic testing laboratories suggested EPA’s tw o year timeframe to complete the testing is

not feasible. 22

, 23

, 24 One of these laboratories suggested that EPA needs to account for a three to six month lag before industry would issue test requests because of time needed to coordinate consortia. Additionally this laboratory has noticed that compani es often delay issuing test requests to benefit f others’ experience with the new testing requireme nts. However, the major reason voiced by these laboratories is their assumption that only they and po tentially one other laboratory have the capabilities to perform this type of testing. Given that these thr ee laboratories also reported lower average capacity (11 chemicals per year compared to an average of 19 to 20 chemicals per year for all laboratories with these capabilities), their concern about capacity is understood. As seen in Tables 3 and 4, however, there additional capacity these laboratories may not be awar e of, which can reconcile the difference of opinion

between these three laboratories an rom

is

d EPA.

2.3 P OTENTIAL FOR E NTRY INTO THE M ARKET /E XPANSION FOR E NDOCRINE D ISRUPTOR
T ESTING

In developing this report, EPA also sought to be tter understand how laboratories will respond to testing demand precipitated by the EDSP. Laboratories interv iewed for the report uniformly stated that the promise of demand alone would not lead them to increase capacity or expand into new areas. While no one laboratory could exactly define “sufficient” ma rket demand that would cause them to consider

20 Eastern Research Group, Analysis of Laboratory Capacity to S upport U.S. EPA Chemical Testing Program

Initiatives. U.S. EPA, Office of Pollution Prevention and Toxics, Economic Analysis and Policy Branch. EPA contract 68-W6-02-077. August 30, 2004.

21 Personal communication with David Geter, Toxicology Specialist at the Dow Chemical. May 14, 2009.

22 Personal communication with David Palmer, Director of Business Services, Wildlife International, Ltd. May 21,

2009.

23 Personal communication with Ron Biever, Chief Scie ntific Officer, Springborn Smithers. May 26, 2009.

24 Personal communication with Jon Rhodes, Director of Chemical Services, ABC. May 28, 2009.

8expansion, the common theme among laboratories is an observed backlog of several months in current testing demand, along with a strong forecast that the high demand would continue for several years.

As indicated in Section 2.1, a number of exhibitors at ToxExpo who are not currently offering endocrine disruptor testing felt that their expertise would allow them to branch into this area. At the same time, they indicated that their business planning would require more than a few short-term requests to generate real interest in developing these capabilities. Many labor atories noted the importance of a multiple year contract with either a government agency, private industry, or a group of manufacturers.

In general, laboratories report that they do not hire in anticipation of testing. Several noted their practice of accumulating “several months worth” of work in b acklog before hiring, to avoid later layoffs if the

demand increase turns out to be short lived. Laborat ories also indicated that the depressed and volatile state of the current economy contributes to their sense of caution with respect to hiring. These statements are consistent with findings from 2004 when EPA queried laboratories about their capacity in anticipation of EPA’s High Production Volume (HPV) Challenge and the European Union’s Registration, Evaluation, Authorization and Restriction of Chemical substances (REACH) testing programs. 25 While laboratories remarked on their ability to quickly move into new areas of testing, they also noted that entry into a new, albeit related, field would involve shifting of pers onnel and incremental costs, and that they would proceed with capacity expansion cautiously.

Four laboratories that currently offer aquatic endoc rine disruptor testing services discussed expansion specific to EPA’s EDSP. None of the laboratories i ndicated they would consider expansion based on the initial set of 67 chemicals. One laboratory described the first group of 67 chemicals as a “blip”, but if EPA rolled out a much larger list of chemicals to be tested, they would consider expansion. 26 One other laboratory stated that they would look to expand capac ity if EPA required supplemental rounds of testing of the magnitude of approximately 1,000 chemicals. 27 A third laboratory echoed these sentiments stating they would look to double or triple capacity if EP A required expanded their testing requirement to a “much larger” list of chemicals. 28 The fourth laboratory indicated it would only expand if it secured a contract from a group of manufacturers. 29 Previously, this laboratory had invested in equipment to increase capacity for work that had not materialized.

Laboratories with endocrine disruptor testing experience discussed their company’s commitment to crosstraining employees to help with lulls that inevitabl y occur within a specific testing area. Many CROs indicated they intentionally hire employees with dive rse skill sets and experience in order to increase their areas of expertise, allow for greater flexibility in the services they offer, and improve their ability to adapt to changing market conditions. 30 One example cited was the recent hire of a Ph.D with expertise related to amphibians. This employee was selected to meet current demand for their services and strengthen th laboratory’s knowledge of amphibian testing. Although not hired because of EPA’s EDSP Tier 1 screening, the employee’s experience with amphibi ans had factored into their hiring decision. e

25 Eastern Research Group, Analysis of Laboratory Capacity to S upport U.S. EPA Chemical Testing Program

Initiatives. Office of Pollution Prevention and Toxics. EPA contract 68-W6-02-077. August 30, 2004.

26 Personal communication with David Palmer, Director of Business Services, Wildlife International. May 21,

2009.

27 Personal communication with Ron Biever, Chief Scientific Officer, Springborn. May 26, 2009.

28 Personal communication with Doug Fort, Manager, Fort Environmental Labs. June 4, 2009.

29 Personal communication with Irv Schultz, Manager, Battelle. June 8, 2009.

30 Personal communication with Kevin Causey, Manager, ILS. March 17, 2009; personal communication with Robert Foster, Senior Scientific Advisor, NOTOX. March 17, 2009; personal communication with Timothy Ward, Regulatory Affairs Specialist, ABC Laboratories. March 17, 2009.

9Based on discussions with laboratories and given the prediction of sufficient capacity to conduct the initial round of Tier 1 assays, EPA concludes that labor atories are unlikely to expand their capacity or add new capabilities based on projected EDSP test data demand.

10

## 3.0 ISSUES THAT COULD IMPACT ENDOCRINE DISRUPTOR

TESTING DEMAND AND SUPPLY

When considering the supply of laboratory capacity fo r conducting endocrine disruptor testing, it is also important to understand other issues that may impact industry capacity such as competing demand for its

services or other market factors. This section reviews some of these factors to provide additional context to the information provided in Section 2. EPA be lieves that sufficient laboratory capacity should be available to meet the initial testing demand generate d by the EDSP. That conclusion was based, however, on only the incremental demand represented by the EDSP, without consideration of other sources of industry demand. The following sections explore whethe r other testing initiatives including those of the U.S. Food and Drug Administration (FDA), EPA, and the European Union, could impact with industry’s ability to meet incremental EDSP testing demand. The section also explores how the recent economic

decline has affected demand in these other areas.

3.1 F OOD AND D RUG A DMINISTRATION R EQUIREMENTS

CROs involved in toxicological testing reported that testing associated with FDA and other pharmaceutical-related requirements represents the largest share of their business base. As a result, decisions related to physical space, equipment, a nd human resources are strongly linked to FDA testing program requirements. Under the authority of the FFDCA, FDA requires toxicology testing of pharmaceuticals and food additives. Some of this testi ng is similar to that required under the EDSP or requires similar capabilities. Since laboratories generall y indicated there were no concerns with expansion

of Tier 1 in vitro testing capacity (see Section 2.2), this s ubsection considers the extent to which FDAdriven testing overlaps with in vivo Tier 1 assays.

Commonly required in vivo tests by the FDA in the area of human pharmaceuticals include: 31

 Toxicokinetics and pharmacokinetics in rodents and/or other species

 Single-dose studies in rodents, and occasionally dogs and primates

 Subacute (14-28 day), subchronic (90 day) and/or chronic (90+ day) studies in rodents, dogs, and occasionally primates

 Reproduction segment I––fertility studies in rodents

 Reproduction segment II––prenatal developmental toxicity in rodents and rabbits

 Reproduction segment III––postnatal development in rodents

 Mutagenicity and genot oxicity studies of at least two varieties

 Carcinogenicity studies in rats and transgenic mice

 Immunotoxicity in rodents

 Triggered specialized studies (e.g., phototoxicity and pyrogenicity)

While the vast majority of CROs with in vivo capabilities noted that they are currently operating below their capacity, several laboratori es did note that pharmaceutical in vivo tests requiring rodents (particularly the chronic tests taking over 90 days) could potentially compete for personnel and space with endocrine disruptor in vivo rat screening assays. Many of the EDSP in vivo tests take at least 21 days to complete and require multiple tanks or cages per chemical. Nonetheless, because of large demand from the pharmaceutical sector for in vivo rodent testing, CROs capacity is large. As shown in Table 3, more than 70 percent of the laboratories that were iden tified through the development of this report offer in vivo

31 The Humane Society of the United States and Proc ter & Gamble, “FDA,” December 6, 2007. Available at: www.alttox.org/ttrc/us/regulator y-research-agencies/fda.html

11rodent testing services. Laboratories do not anticipate any capacity issues for conducting EDSP’s in vivo
rodent tests.

When asked to identify any areas of EDSP testing that could present capacity or bottleneck issues in a hypothetical situation of increased demand generated from FDA, the most common areas cited were amphibian metamorphosis and fish short-term reproduction assays. One laboratory explained that the fish Early Life Stage (ELS) studies often required by FDA would directly compete with the fish short-term reproduction endocrine disruptor assay. 32 The factors limiting capacity expansion to meet any increased demand are primarily related to equipment, particularly the diluters used in the testing. Facility space may also be a factor, but to a lesser extent. For context, the laboratory estimated that each additional fish endocrine disruptor assay would displace one and half ELS studies in terms of capacity.

In light of the recent economic slowdown, laborator ies are reporting a general decline in demand for testing from pharmaceutical and biotechnology companies. Among exhibitors at the ToxExpo, those that rely most heavily on FDA-driven testing requests described their situation using terms such as “barely afloat” or “taking it off the chin.”

One laboratory whose workload has historically been evenly split between the pharmaceutical and chemical industry reported a major decline in de mand from pharmaceutical clients. Demand from the chemical sector, on the other hand, has remained strong. As a result, this laboratory has shifted staff in the

short term to accommodate more industrial chemical toxicology work. Doing so has been minimally disruptive as a result of their cross-training of empl oyees and use of similar equipment and skill sets in both types of testing. Somewhat ironically, this same firm made a shift in the opposite direction seven years ago, when it faced a decline in chemical tes ting tied to consolidation inthe chemical and agrichemical industries. In the present environment, they are seeing consolidation in the pharmaceutical and biotech markets in 2009, with many large pharmaceuti cal companies buying out biotech companies. This is leading to fewer testing requests because of a decline in new products being brought to market.

A few laboratories noted that biotech and pharmaceuti cal companies have laid off employees to try to save money, which has led to more outsourcing of t esting previously conducted in-house. According to market researchers at Frost and Sullivan, the greatest growth potential for CROs is in the early stage work for biotechnology and pharmaceutical development. 33 This type of work includ es toxicology studies that until recently had been conducted by in-house labor atories. The significance of this phenomenon could

not be ascertained but some CROs described it as a tre nd that has temporarily helped counteract the loss in demand linked to the struggling economy.

In conclusion, CROs that depend on testing request s from pharmaceutical and biotech companies have surplus testing capacity. Several of these laborator ies expressed interest in better understanding the potential testing needs generated from the EDSP to he lp fill the decline in FDA-driven work, which utilizes similar equipment and trained personnel. Alth ough the observation is based on anecdotal evidence from a small number of CROs, it may be indicative of some flexibility in the testing industry to adjust capabilities in response to changes in testing demand.

32 Personal communication with Jon Rhodes, Director of Chemical Services, ABC Laboratories. May 28, 2009.

33 Dubin, Cindy. “CRO Trends & Drivers,” Specialty Pharma , 9(4), April 2009.

123.2 E UROPEAN R EQUIREMENTS

3.2.1 Registration, Evaluation, and Authorisation of Chemicals

In 2007, the European Union’s legislation to create the Registration, Evaluation, and Authorisation of Chemicals (REACH) program went into effect. REACH requires the registration of chemicals, including the submission of test data to demonstrate the regist rant’s evaluation of the chemical’s risks. Under the program, substances produced or imported in annual qua ntities of 1,000 metric tons (2.2 million pounds) or more would need to be registered by November 30, 2010; substances produced or imported at annual quantities of 100 to 1,000 metric tons (220,000 to 2.2 million pounds) w ould need to be registered by May 31, 2013; and substances produced or imported at annual quantities of 1 to 100 tons (2,200 to 220,000 pounds) would need to be registered by May 31, 2018. 34

The testing requirements for chemicals under REACH vary based on the production volume of the chemical (i.e., less test data are required for lo wer production volume chemicals) and the suspected toxicity of the chemical. 35 Some of the basic information requirements for REACH include:

 Substance identity;

 Physicochemical properties;

 Mammalian toxicity;

 Ecotoxicity;

 Environmental fate, including abiotic and biotic degradation; and

 Information on manufacture and use(s) as well as risk management measures.

Much of the test data requested relies on the Orga nisation for Economic Cooperation and Development’s (OECD’s) Screening Information Data Set (SIDS) batteries. While REACH does not specifically require the same testing as the EDSP, several of the SIDS testing areas are similar to those in EDSP. Thus, there is potential for REACH testing to compete with endocri ne disruptor testing in terms of laboratory space, equipment, and human resources. At the time of the ToxExpo (mid-March 2009), however, CROs stated that they had little or no testing scheduled related to REACH. Testing laboratories in Europe, as well as Asia, are uncertain about REACH’s impact on the market. None of the laboratories indicated that they have expanded in anticipation of REACH; however , a couple of European laboratories had been consulting with chemical companies about how to approach the REACH requirements.

The expected workload to be generated by REACH va ried dramatically from laboratory to laboratory. A few CROs expect chemical companies to complete th e testing using in-house laboratories, form consortia to minimize duplicative efforts, or submit data that has already been generated. At the other end of the spectrum, one laboratory representative expressed concer n that companies were procrastinating until the deadline and that demand would suddenly materialize as deadlines approach. Some believe or fear that affected companies will delay their testing to lear n from the experiences of other companies on how to respond to the requirements. One laboratory in par ticular expressed concern about a possible influx of

34 Any manufacturer or importer that did not pre-register a chemical with the European Chemical Agency prior to the 2008 deadline is required to submit the registration immediately if they wish to continue its manufacture or import.

35 Foster, Bob. “REACH Registration and Evaluation.” NOTOX BV. Presented at SOCMA Corporate Excellence Conference. May 18, 2008.

13testing requests in the second half of 2010 that w ould overwhelm European testing capacity, pushing overflow requests to Asia and the United States. 36

A recent article written by a REACH consultant al so expressed concern that CROs will become a bottleneck in meeting the REACH deadline. 37 Using the environmental testing on pharmaceutical products created by the European Medicines Agency in 2007 as an example, the author stated that the required increase in laboratory capacity in Europe an d the United States lagged by two years before it met the 10 percent increase in market demand for testing services. The primary reason cited for the delay was the time needed to put qualified staff in place.

3.2.2 Pesticide Restrictions

In January 2009, the European Parliament adopted a new regulation that will ban certain pesticides from use in food production unless industry provides test data demonstrating them as safe. Many of these pesticides have been identified as having the potential to disrupt the endocrine system. 38 Although the regulation still requires approval from the Agriculture Council for formal endorsement by the member States, the regulation is expected to become effective in late 2010. Thus, industry may conduct endocrine disruptor testing for banned pesticides in order to a llow their continued use. This new regulation has the potential to increase demand for endocrine disruptor tes ting services, however, the level of this demand is

unknown.

3.3 O THER U.S. E NVIRONMENTAL P ROTECTION A GENCY I NITIATIVES

3.3.3 Toxic Substances Control Act

Working under authorities and requirements of the Toxic Substances Control Act (TSCA), EPA gathers and reviews data, assesses risk, and regulates chemic als in commerce. Under Section 4 of TSCA, EPA can require companies to conduct testing on selected ch emicals for which data are needed to evaluate potential health or environmental hazards. Over the l ast several years, the Agen cy has worked to ensure the availability of data on High Production Volume (HPV) chemicals by asking for manufacturers to commit voluntarily to provide testing information. 39 TSCA initiatives, including the voluntary HPV Challenge, use the OECD’s SIDS batteries as the basic set of test data. The SIDS dossiers cover five main categories of data: general information (e.g., use patterns, volume), physical-chemical properties, environmental fate and transport, ecotoxity, and t oxicity. Data to be summarized for human toxicity include studies assessing acute toxicity, subchroni c toxicity, genotoxicity, and developmental and reproductive toxicity.

The HPV Challenge Program led to the sponsoring of more than 2,200 HPV chemicals; however, most of the information from these sponsored chemicals came from data that companies already had, or was derived using structure-activity relationship (SAR) modeling to predict the characteristics of a compound

36 Personal communication with K.S. Rao, Head of Corporate Development, Advinus Therapeutics. March 18,

2009.

37 Erler, Steffen. Technical Director, Smithers REACH Services. “Dr Reach - Who are you?,” Chemical Watch

, May 2009. Available at http://chemicalwatch.com/2223.

38 Pesticide Residues Committee, Summary Impact Assessment: Proposal for a Regulation of the European Parliament and of the Council Concerning the Placing of Plant Protection Products on the Market, January
2009. Available at www.pesticides.gov.uk/prc_home.asp?id=1980#author isation_regulation_and_sustainable_use_directive

39 An HPV chemical is one that is produced or imported in the United States in quantities of 1 million pounds or

more per year.

14based on its structural similarity to other compounds with existing data. The widespread use of existing data and SAR-based approaches to meet the HPV Challenge requirements resulted in substantially less new business for the chemical testing industry than was expected.

Based on the low volume of new testing demand coming out of the HPV Challenge program and available capacity to perform testing in the industry, t esting related to Section 4 rules and programs is not expected to compete with EPA’s endocrine disrupt or testing initiative. One lasting impact of the industry’s experience with HPV, however, may be a reluctance to expand laboratory capacity to accommodate similar types of initiatives. A few of th e CROs explained that the condition of the economy combined with the past disappointment with initiatives such as the HPV Challenge has led them to adopt a “wait and see” approach to any demand in crease associated with new testing initiatives.

3.3.4 Federal Insecticide, Fungicide, and Rodenticide Act

EPA has authority to regulate pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act. Before registering a new pesticide or new use for a registered pesticide, EPA requires more than 100 different scientific studies and tests from applicants in order to make a determination that proper use of the pesticide will cause no harm to human health and will pose no unreasonable risks to the

environment. 40 One CRO expects laboratories to be contracted for EDSP testing of agri-chemicals as a follow on to their work supporting the chemical’s initial registration. 41

One laboratory suggested that the fish short-te rm reproduction assay required under the EDSP could compete for resources with any 260-day fish full lifecycle studies required by EPA for pesticide registration. 42 Both tests require similar equipment, labor atory space, and personnel, but the fish full lifecycle test is equivalent to nearly ten fish EDSP assays in terms of resource intensity. Thus, if a laboratory received one or two unexpected requests to perform this test, it might not have capacity to perform the EDSP fish assay. According to the same la boratory, however, requests for fish full lifecycle

studies are rare.

40 Office of Pesticide Programs, “Regulating Pestic ides,” U.S. EPA. June 9, 2009. Available at www.epa.gov/pesticides/regulating.

41 Personal communication with Kevin Causey, Manager, ILS. May 26, 2009

42 Personal communication with Ron Biever, Chief Scie ntific Officer, Springborn Smithers. May 26, 2009.

15

## 4.0 LABORATORY CAPACITY CONCLUSIONS

This report presents the results of EPA’s efforts to an alyze the chemical testing industry and evaluate its current capacity to conduct testing using EPA’s EDSP Ti er 1 screening assays. Although part of this task involved efforts to identify specific laboratories, including international and domestic CROs, readers are cautioned that this report and its conclusions are base d on information from only a subset of the industry. It was beyond the scope of this effort to c onduct a comprehensive survey of all laboratories.

Within these limits, EPA identified 32 laboratories that offer endocrine disruptor testing services and concluded that these laboratories represent sufficient capacity to complete the testing demand generated by the EDSP under EPA’s high volume scenario (i.e., tw o data sets are generated for each chemical). Since EPA believes that on average only one data set will be generated per chemical, this conclusion appears justified.

Some areas of testing may be more constrained than others. While there is sufficient capacity to complete

the in vivo fish and amphibian screens, there appears to be less excess capacity in these areas than in others required under the EDSP. Seve ral laboratories that conduct this type of testing expressed concern about being able to complete the testing in a two-year window. These laboratories may underestimate U.S. capacity for in vivo fish and amphibian screening, identifying only four laboratories qualified to undertake the aquatic toxicology work compared with the numbers confirmed by EPA (i.e., seven laboratories for fish related testing and six laboratories for amphibians). Additionally, EPA has identified additional capacity for these tests in Canada and Europe.

Some laboratories that provide toxicology testing to meet FDA requirements indicate that they could enter the market for endocrine testing with approximately three months preparation time. Those laboratories with the necessary equipment and staff, and who may have excess capacity due to reduced test requests from pharmaceutical clients, would be most likely to en ter the market for EDSP testing. It is important to note, however, that these laboratories consistently ex pressed hesitation to undertake the costs of moving into a new field without a long term guarantee of work.

Similarly, laboratories already providing endocrine disruptor testing services would expand only after sustaining a backlog of test requests for several m onths and concluding that the higher level of demand will continue. From discussions with laboratories, none indicated that entry of an initial 67 chemicals into the program would cause them to expand capacity to accommodate additional testing during the two year testing timeframe. Few laboratories engage in specula tive expansion in anticipation of increased future testing driven by EPA or European chemical testing initiatives. Some of this reluctance may be a result of past experience waiting for EPA-driven testing de mand that never materia lized. Several aquatic toxicology laboratories did suggest, however, that if EPA required a larger number of chemicals to be screened under EDSP (which one laboratory suggested woul d need to be on the order of 1,000 chemicals) they would consider doubling or tripling their current capacity.

EPA also investigated whether other chemical testing initiatives, such as the European Union’s REACH or forthcoming pesticide regulation, along with ot her EPA programs, could create any spike in demand for CRO testing services. One consultant has estimated there to be insufficient testing capacity in place to meet the 2010 REACH deadline. Based on discussions with CROs, however, EPA was unable to determine the impact of REACH on endocrine disruptor testing capacity.

16Potential new restrictions on pesticides in Europe ma y require industry to undertake endocrine disruptor testing to develop data to support exempting chemic als from the ban. The resulting volume of testing work, however, is unknown at this time. Overall, EPA believes there is sufficient capacity to accommodate additional testing needs assuming that a ma jority of the REACH-related demand would not compete with the specialized skills required of the ED SP assays. Further, the cap acity totals presented in this report represent an unknown subset of all laborator ies. In particular, EPA believes there is additional European capacity available that is not accounted for in this report.

17

## 5.0 COST ESTIMATES FOR COND UCTING TIER 1 ASSAYS

5.1 M ETHODOLOGY

The number of laboratories that could be solicited for cost information was restricted by the Paperwork Reduction Act, which prohibits federal agencies from making the same information request of more than nine entities, and the project’s resource limitations. EPA felt its data quality objectives for the project could be met if the testing assays were divided in to three different groups based upon the type of testing—Group A: in vitro , Group B: in vivo rat toxicology, and Group C: in vivo aquatic toxicology. EPA deemed the questions for each group of laborator ies to be sufficiently different, which would allow up to nine laboratories in each group to be asked questi ons regarding the costs of testing for the particular protocols that the different groups would be able to conduct. The screening assays were divided into the three groups as shown in Table 5. The table identifies the version date of the protocol provided to the

laboratories.

Table 5. EDSP Tier 1 Screening Assays

Protocol Version Provided to

Laboratories

Group A: In vitro tests

Rat uterine cytosol estrogen receptor binding (Rat ER binding) 6/17/08

Rat prostate cytosol a ndrogen receptor binding (Rat AR binding) 8/29/08

Human placental & recombinant aromatase (Human aromatase) 8/28/08

Human cell line (H295R) steroidogenesis (Human steroidogenesis) 7/31/08

Human estrogen receptor- α transcriptional activation (Human ER transcriptional) 6/5/08

Group B: In vivo rat tests

Uterotrophic 10/16/07

Hershberger 9/2/08

Pubertal female 2008, v.3

Pubertal male 2008, v.3

Group C: In vivo tests of aquatic species

Amphibian metamorphosis 6/25/2008

Fish short-term reproduction Undated, v. 1
July 6, 2006 for histopathology guidelines

18Since a comprehensive list of laboratories capable of conducting endocrine disruptor testing is not readily available from the industry, EPA identified a 32 labora tories (both U.S. and foreign) believed to have the capabilities to perform testing in one or more of the groups of Tier 1 endocrine disruptor assays shown in Table 5. The identification process for these la boratories is described in Section 2.

From the list of laboratories (provided in Appendix A), EPA randomly selected six to eight laboratories with capabilities in each testing area (Groups A, B, and C in Table 5). This process initially resulted in a total of 17 laboratories to be interviewed, with a handful of the larger laboratories asked to provide estimates for two different test groups. Of the original 17, four replacement laboratories were required to

substitute for ones that either dec lined an interview, could not provide the information in the required timeframe, or provided cost estimates that did not meet EPA’s data quality objectives. 43 Ultimately, 15

laboratories contributed cost data.

Laboratories that agreed to provide cost informa tion were sent the most current version of each assay protocol for their group(s), a list of example questions (Appendix B), and the list of potential chemicals to initially be screened (Appendix C). EPA provided th e laboratories sufficient time to familiarize themselves with this material prio r to the interview. A majority of the interviews were conducted by phone though responses for some of the more common protocols, such as the in vivo rat assays, were collected via email. In order to ensure the integrit y of the data, EPA investigated any potential outliers (i.e., cost was significantly higher or lower than other laboratory estimates). A follow-up discussion was

held to determine the reasons for th e potential discrepancy and to ensure that the cost estimates were not inadvertently including support work (e.g., pre-tes ting validation of dosing concentration, analytical chemistry) with the cost of the actual testing. Sec tion 5.2 focuses on the actual cost of testing, followed Section 5.3’s discussion of ancillary costs such as method validation and analytical chemistry work.

5.2 A SSAY C OSTS

5.2.1 Assumptions

EPA instructed the laboratories to provide estim ates for performing the tests under GLP. During the interviews, three laboratories indicated that perform ing the tests under GLP would increase the price for conducting the test by 10 to 25 percent. 44 The increased price is due to the higher level of effort required in the report writing and additional quality control m easures that need to be undertaken. The estimates provided in this report are what laboratories expect to charge per assay if such requests were made by industry. Laboratories were asked to estimate the cost of the assay without including the price of methods development and any analytical work including me thod validation, preliminary analytical work, verification of dosing concentrati ons, and confirmation of the chem ical’s identity and purity. These

additional costs are discussed in Section 5.3.

43 EPA’s primary determinant in deci ding whether the cost information wa s deemed acceptable was the laboratory contact’s understanding of the protocol. For example, one laboratory admitted that they had conducted similar assays for FDA requirements, but their price was based on that work and they had not reviewed EPA’s protocols to determine how the price would differ.

44 Personal communication with David Geter, Toxicology Specialist, Dow Chemical Company. June 19, 2009; personal communication with Nikou Hessami, Toxicology Specialist, Molecular Diagnostics. June 6, 2009, and personal communication with Irv Schultz, Seni or Scientist, Battelle. June 8, 2009.

195.2.2 Cost Data

Table 6 summarizes the cost data for the Tier 1 assays provided by the laboratories participating in this study. Some laboratories provided a range of costs while others provided a point estimate. For laboratories that provided a range (i.e., low and high co st), the mean of the high and low cost was taken to obtain a single averaged cost estimate for each assay. The in vitro rat and human ER transcriptional assays cost approximately $22,000 each. The human steroi dogenesis is estimated to cost approximately $16,000 and the human aromatase test was priced at $28,000. As seen in the table, the range in the estimates provided is large.

Table 6. Cost Estimates for EDSP Tier 1 Screening Assays

Costs Assay Median Minimum Maximum # of Responses

In vitro Rat ER binding $17,250 $7,000 $55,000 7 Rat AR binding $17,250 $7,000 $55,000 7

Human aromatase $25,000 $4,000 $60,000 6 Human steroidogenesis $13,750 $4,500 $31,400 4 Human ER transcriptional $15,000 $3,000 $55,000 6

In vivo rat tests Uterotrophic $43,050 $9,500 $65,500 6 Hershberger $47,400 $9,200 $72,000 6

Pubertal female $87,100 $47,200 $152,500 6

Pubertal male $93,500 $47,200 $160,000 6 In vivo tests of aquatic species Amphibian metamorphosis $80,597 $20,000 $97,700. 6 Fish reproduction $92,500 $85,000 $137,650 7

Total All 11 assays $532,397

For the in vivo tests, the median of laboratories reported costs for conducting the rat uterotrophic and Hershberger assays were $43,050 and $47,400, respec tively. The low and high cost estimates for these assays were approximately $9,000 to $72,000. The median cost for the rat pubertal in vivo assays were $87,100 (female) and $93,500 (male). The price varia tion between the low and high estimates for these assays was more than $100,000, with the low e nd at $47,000 and the high end at $160,000. The amphibian metamorphosis and fish short-term reproductive assay had median costs of approximately $80,597 and $92,500, respectively; however, this does not include the cost for setting up the delivery system, which is a one time cost applicable to bo th the amphibian and fish assay and is discussed in

Section 5.3.

Given the wide variation in the cost estimates, EPA plotted the individual laboratory estimates along with

the median cost to better illustrate the data. These are shown in Figure 1 ( in vitro assays) and Figure 2 ( in

vivo assays). The figures also plot the estimates provided by EPA in support of the EDSP ICR. With the exception the fish short-term reproduction assay, the ICR estimates are all within the range given by laboratories in this study. For most tests, there is a large disparity between the minimum and maximum estimates. A single laboratory prov ided the highest estimates for all in vitro tests and another provided all the lower bound estimates. The highest estimates for the in vivo testing are shared by two companies as

are the lowest estimates. All of the laboratories with high and low estimates are familiar with ED testing

20either with EPA protocols or similar protocols. For this reason, EPA found no reason to exclude any

estimates.

Figure 1. Price Estimates for Five In Vitro EDSP Tier 1 Screening Assays

In Vitro EDSP Assay Costs

$0 $10,000 $20,000 $30,000 $40,000 $50,000 $60,000 $70,000(AR) binding-ratprostate(ER) binding-ratuterusERTranscriptional(human)Steroidogenesis(human)Aromatase(human) O = median of estimates
 = ICR estimate ($2008)

+ = individual lab estimate

21Figure 2. Price Estimates for Six In Vivo EDSP Tier 1 Screening Assays

In Vivo EDSP Assay Costs

$0 $20,000 $40,000 $60,000 $80,000 $100,000 $120,000 $140,000 $160,000 $180,000Uterotrophic(rat)Hershberger(rat)Pubertal female(rat)Pubertal male(rat)AmphibianMetamorphosisFish Short-TermReproduction O = median of estimates
 = ICR estimate ($2008)

+ = individual lab estimate

5.2.3 Limitations

One of the limitations faced by EPA in collecting cost data using this approach was the varying knowledge of the laboratory contact about the assay protoc ols. Several laboratories had participated in the validation of the protocols and these laboratories tended to provide estimates at the higher end of the cost range. EPA believes these interviewees may be able to make more informed estimates based on what they had learned from their validation work. Many of the low-end estimates came from laboratories that demonstrated the capacity to perform the testing, but may have based their cost estimates on a quick read of the protocols or on their experience performing the assays with similar, but not identical, protocols. 45

5.3 A DDITIONAL C OSTS

As noted in Section 5.2, EPA requested that laborat ories not include in their estimates any costs not directly related to the assays themselves. Costs for ancillary activities including method development and validation, verification of dosing c oncentrations, and confirmation of th e chemical’s identity and purity,

are not included in the cost estimates shown in Ta ble 6. EPA found these additional costs to be highly dependent on the nature of the chemical being tested and more easily discussed in the context of the cost per chemical, separate from the cost of the assays them selves. The laboratories also had a more difficult time providing itemized estimates for these activities and the Agency collected fewer specific data points.

45 The in vitro rat ER binding, steroidogenesis, and fish protocols are over 50 pages long with the other eight protocols ranging from 17 to 32 pages.

225.3.4 Analytical Methods and Validation

In conducting the cost interviews, EPA provided each la boratory with the most current version of protocol and informed them they would have to follow the prot ocol instead of developing their own method. Thus, method/protocol 46 development was excluded as a relevant co st but EPA asked laboratories to discuss the ancillary costs they incur before conducting the t est under GLP requirements, which have not been included in the cost estimates reported in the previous section.

Laboratories conduct method validation to optimize method performance of a given assay with their personnel and equipment, and establish quality control limits. For many of the in vitro assays and in vivo rat assays, this is accomplished by running the assay using a known chemical at a known dosage and comparing the laboratory’s results against results publis hed in the assay protocols. For example, for the uterotrophic assay, a specified concentration of 17 α -ethinyl estradiol can be used as a control substance to verify the proficiency of the laboratory with the assay. Laboratories excluded these costs in their estimated price of each assay because this “validation” is conducted every six months (as required in the uterotrophic protocol) or prior to routin ely conducting the assay (as required in the in vitro ER binding rat protocol). Laboratories indicated that the cost of conducting validation would be spread over the volume of chemicals being tested and among similar tests, ma king it difficult for them to provide an exact cost per chemical. Although all the laboratories intervie wed were asked about these costs, very few felt comfortable providing specific costs.

In Vitro Assays

One laboratory provided an average cost for valid ation as $8,000 for the complete set of the five in vitro assays. They provided a range of $7,000 to $9,000, with the lower price representative of chemicals that had similar properties to one that was already vali dated, while the higher end of the range would be charged for chemicals that the laboratory is less familiar with.

In Vivo Rat Assays

One laboratory provided an average validation cost of $11,500 for the complete set of in vivo rat assays. This average is calculated from their low and high es timates of $8,000 to $15,000; the cost determination related to the chemical proprieties and the labor atory’s experience with the test substance.

In Vivo Aquatic Assays

Three laboratories provided validation costs for th e aquatic assays. The protocol validation includes performing analysis of the test substance in water to verify that the delivery system is working and dispensing the chemical in water as prescribed in the protocol. The average cost was $7,333, with a low and high range of $5,000 to $10,000. This validation is a one-time cost per chemical as the same delivery system method can be used for both the amphibian and fish assays. One laboratory explained that the cost of validation is based on the equipment needed for validation. 47 When a high-performance liquid chromatography (HPLC) is sufficient, the costs ar e at the lower end of the range; however, some

validations are unsuccessful on HPLC and are re done on an HPLC with mass spectrometry which increases the laboratory’s costs.

46 Laboratories used the terms protocol and method interchangeablely.

47 Personal communication with John Aufderheide, Senior Toxicologist, ABC Laboratories. June 2, 2009.

235.3.5 Preliminary Analytical Work

In addition to validation costs, laboratories also indicated there is also preliminary analytical work that is not included in the assay costs presented in Table 6. This section describes this wo rk and associated costs.

Preliminary Solubility and Delivery Trials

Prior to the protocol validation, laboratories conducting the fish and amphibian tests need to perform preliminary solubility and delivery trials. This work is necessary to understand how the chemical delivery system will function in water, and for these two aquatic species tests, this is part of verifying that the delivery system delivers the correct dosing concentrati on to the test subjects. Three laboratories provided estimates for this preliminary work. Each estimated th at for a water soluble chemical it would cost $5,000 per chemical. Chemicals with limited water solubility would be more expensive at an average of $15,000. Their estimates ranged from $5,000 to $20,000. This wo rk is completed per chemical since the same delivery system is used in the amphibian and fish assays. Laboratories also noted that if they were creating delivery systems for chemicals with similar properties that the cost for additional chemicals would reduce to less than $5,000 each.

Verification of Dosing Concentration

Laboratories must, on a regular basis, verify that the dosage of chemical s used in these assays is consistent. Many laboratories make stock solutions of the chemical at a known concentration which can be used for delivery on multiple animals over a period of weeks, while other laboratories make smaller batches of stock solution, sometimes daily. Regardless of the method, laboratories must verify that they are administrating the correct dosage of chemical . Creation of the solutions and quality control verification of the dosing concentration could potent ially be done for multiple assays at a time. Three laboratories estimated the average cost at $2,000 per chemical for the four in vivo rat assays with a low to high range of $1,000 to $2,500. A la boratory explained that much of this range arises from how many batches of varying concentrations are required by the protocol. For the in vivo amphibian and fish assay, the verification of the dosing concentration is comple ted as part of the delivery system step and is not presented as a separate cost. For in vitro assays, this cost was already included in the estimates of conducting the assays.

Verification of the Chemical’s Identity and Purity

Most of the laboratories interviewed expected that th e manufacturer of the chemical would be responsible for verification of the chemical’s identity and purity. As part of GLP protocol the manufacturer typically submits a form verifying the identity and purity of the compound to the laboratory performing the testing. Several laboratories said that if a chemical provider did not verify the identity and purity of a compound, they would charge between $2,000 and $5,000 per chemical. This was based on estimates from three laboratories with an average one time cost of $3,500 . This additional cost was not included in Table 7 because contract laboratories stated they rarely are required to perform such testing.

5.3.6 Additional Cost Summary

The additional costs presented above in Section 5.3 ar e summarized in Table 7. This work is conducted on a per chemical basis.

24Table 7. Summary Table of Additional Costs

Additional Costs

Method Validation Preliminary Analytical Work Assay Range Average Range Average Average Total

Additional Costs

In vitro Rat ER binding Rat AR binding

Human aromatase Human steroidogenesis Human ER transcriptional $7,000 to $9,000 $8,000 Included in the cost of the assay (Table 6). $8,000

In vivo rat tests Uterotrophic Hershberger

Pubertal female

Pubertal male $8,000 to $15,000 $11,500 $1,000 to $2,500 a $2,000 a $13,500

In vivo tests of aquatic species Amphibian

Fish $5,000 to $10,000 $7,333 $5,000 to $20,000 b $10,000 c $17,333

a For verification of dosing concentration

b For preliminary solubility and delivery trial setup

c The average for soluble compounds was $5,000 while le ss soluble compounds was $15,000. The mean of these two averages is $10,000.

5.3.7 Chemicals

Laboratories were asked to review the list of chemic als in Appendix C and discuss whether their test cost estimates would need to be adjust ed for specific substances. The laboratories performing the fish and amphibian assays noted that the protocols require the development of special delivery systems for those chemicals that are not very water soluble (e.g., py rethroids, phthalates, trifluran). Testing these less soluble chemicals would be at the high end costing about $15,000 to $20,000 (approximately $10,000 to $15,000 more than water soluble ones costing approxim ately $5,000). This is reflected in the range provided in Table 7. Laboratories also stated that chemicals with higher vapor pressures could also add complexity (i.e., cost) to the fish and amphibian assays. Several of the laboratories said that if the fish and amphibian protocols allowed for the use of other solvents (as is the case in the other nine protocols), the costs of conducting the test would be similar to th at for water soluble chemicals; however, the cost savings could be partially or completely offset by th e need to run a control test measuring the endocrine disrupting potential of the solvent.

Laboratories indicated that the properties of the chemical s to be tested have less of an impact on cost for

the in vitro assays and in vivo rat assays than the fish and amphibian assays. A couple of laboratories noted that the list contained chemicals that require the use of respirators during handling, which could increase the time to conduct the tests. The impact on the testing cost, however, would be minimal.

5.4 D ISCOUNTS

EPA asked laboratories if they would offer discounts to customers requesting the full suite of Tier 1 assays or for customers requesting multiple chemical s be tested. Most laboratories indicated that discounts are offered to existing customers that request a large volume of work (e.g., $2.5 million). When

25asked for more specifics, however, most of the laborat ories stated that these discounts are determined on a case-by-case basis and hesitated to quantify them.

EPA found that laboratories performing in vivo assays, particularly the fish and amphibian tests, felt that discounts to attract customers are unnecessary given thei r expertise niche. They speculated that with the limited time frame likely required by the EDSP test or ders, they will be working at capacity and have been in discussion already with existing clients. 48 However, a couple of laboratories said that they would consider discounts for customers with multiple chem icals with similar prope rties for the fish and amphibian assays since they could potentially use the same delivery system for each chemical for the assays (as described in Section 5.3), but again th ey hesitated to quantify these discounts. Other laboratories conducting in vivo tests reported that the labor intensiv e nature of the work with animals does not benefit from much economies of scale when multiple chemicals are tested. In general, EPA found that there would be little to no discounts passed on to customers for in vivo testing.

EPA found that with the in vitro rat assays, in particular, laboratories could perform the tests at significant discounts when dealing with multiple chemical request s. One interviewee explained that both the ER and AR rat binding assays require a large amount of setup work (e.g., chemical acquisition, cytosol preparation, characterization by a saturation assay) mu ch of which can be done once for multiple assays. This laboratory estimated that while the cost of performing these assays for one chemical might be $55,000 each, they would reduce their price to $13,200 pe r chemical if 20 or more chemicals were being tested. EPA spoke with another laboratory that provided cost estimates for all five in vitro tests (Group A in Table 5). They indicated that for an individual assay the per chemical cost when analyzing 10 chemicals together was approximately 40 percent less th an the per chemical cost of performing that assay with a single chemical. The laboratory explained that after performing the initial in vitro assays for one chemical, the level of effort required to perform subsequent chemicals is significantly less. 49 A third laboratory explained how in contrast to the in vivo assays, the in vitro assays can be set up in a high throughput manner. Sets of three or more chemicals can easily be loaded into machines thus lowering the per chemical cost of the assay as more chemical s with similar properties are analyzed at once. 50 A fourth laboratory did not provide a cost estimate for running the steroidogenesis test wi th one chemical as they typically only run the test using several chemicals at a time to minimize level of effort and cost. Their estimate was $15,000 to $21,500 on the basis of running 10 to 20 compounds.

5.5 C OST S UMMARY

This section summarizes the estimated cost for the su ite of the 11 Tier 1 EDSP assays. For laboratories that provided a range (i.e., low and high cost), the mean of the high and low cost was taken to obtain a single averaged cost estimate. Altogether, the in vitro assays cost approximately $118,000 per chemical.

The in vivo rat toxicology assays cost approximately $284,000 per chemical, while the two in vivo aquatic assays are estimated to be $193,000. The estimated total of performing all 11 assays including ancillary testing prep work is $595,698 as shown in Table 8. A ma jority of this estimate, $556,865 is the cost for conducting the assays, with an additional cost of $38,8 33 for the analytical work (e.g., method validation, dosing concentration).

48 As discussion in Section 2, EPA identified the least number of laboratories capable of performing fish and amphibian tests.

49 Personal communication with Alexander Lyubimov, Director, University of Illinois at Chicago, Toxicology Research Labs. June 15, 2009

50 Personal communication with David Geter, Toxicology Specialist, Dow Chemical Company. June 19, 2009.

2627 Table 8. Summary Table of the Full Suite of Testing for One Chemical

Costs

Assay Assay Cost Method
Validation Preliminary Analytical Work Subgroup Totals

In vitro Rat ER binding $21,729 Rat AR binding $22,214

Human aromatase $28,200 Human steroidogenesis $15,850 Human ER transcriptional $22,267 $8,000 Already included $118,260

In vivo rat tests Uterotrophic $37,867 Hershberger $42, 208

Pubertal female $93,592

Pubertal male $96,975 $11,500 $2,0 00 $284,142

In vivo tests of aquatic species Amphibian $73,399

Fish $102,564 $7,333 $10, 000 $193,296

Total All 11 assays $556,865 $26,833 $12,000 $595,698

Table 8 was calculated with the assumption that labo ratories would only be testing one chemical at a time; however, several laboratories stated that conducting multiple in vitro tests achieves economies of scale and they would charge significantly less (on the order of 40 to 50 percent less) when performing

them in batches of 10 or more chemicals. This could potentially drop the subtotal of all five in vitro tests from approximately $118,000 to $65,000.

Laboratories did not report any significant economies of scale with in vivo tests. Some laboratories indicated that some of the analytical work in pr eparing for these assays could be reduced if chemicals with similar properties are tested together; however, th is is not likely to reduce the cost from the estimate

in Table 8 by more than a few thousand dollars.APPENDIX ALABORATORIES CAPABLE OF TIER 1 SCREENINGThe information provided in this Appendixis primarily based on information collected from online research and from exhibitorsfrom theToxExpo in March 2009. The tables are neither an industry directory nor a statistical sample of the entire chemical testing industry. Rather, TableA-1 suggests laboratories that would be ableto conduct endocrine disruptor tests.Table A-1. Laboratories Claiming to HaveCapabilities to Perform EDSP Tier 1 Assays51NameCorporateHeadquarterLocationWeb site Rat uterine cytosol estrogen receptor binding Human recombinant estrogen receptor b i n d i n g Rat prostate cytosol androgen rece p tor bindin g Human cell line steroidogenesis Human placental & recombinant aromatase Rat uterotrophic and hershberger Rat pubertal female and male Amphibian metamorphosis Fish short-term reproductionABCLaboratoriesUSAwww.abclabs.comXXAdvinusTherapeuticsPvt. Ltd.Indiawww.advinus.comXXXXBattelleUSAwww.battelle.org/pharmaceuticalXXXXXXXBayerCropScience52Francewww.bayercropscience.comXXXXXXXXXBioAgri PharmaBrazilwww.bioagri.com.brXXBrixham LabUKwww.brixham-lab.comXCalvert LabsUSAwww.calvertlabs.comXXXXXXXCantestCanadawww.cantest.comXX51Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, doesnot constitute or imply itsendorsement, recommendation, or favoring by the United States Government.52They are an in-house laboratory, but they expressed willingness todo testing for third parties.A-1NameCorporateHeadquarterLocationWeb site Rat uterine cytosol estrogen receptor binding Human recombinant estrogen receptor binding Rat prostate cytosol androgen rece p tor bindin g Human cell line steroidogenesis Human placental & recombinant aromatase Rat uterotrophic and hershberger Rat pubertal female and male Amphibian Fish short-term

metamorphosis reproductionCeetoxUSAwww.ceetox.comXXXXXCharles RiverLabsUSAwww.criver.comXXCITFrancewww.citox.comXDow ChemicalCompany53USAwww.dow.comXXXXXXXXXFortEnvironmentalLaboratoriesUSAwww.fortlabs.comXXThe HamnerUSAwww.thehamner.orgXXXXXXXHarlan LabsUSAwww.harlan.comXXIITRI ResearchInstituteUSAwww.iitri.orgXXXXXXXINA ResearchJapanwww.ina-research.co.jpXXIntegratedLaboratorySystems, Inc.USAwww.ILS-INC.comXXXXXXXJRFInternationalUnitedKingdomwww.jrfonline.comXMB ResearchLabsUSAwww.mbresearch.comXXXX53They conduct in-house testing only.A-2A-3NameCorporateHeadquarterLocationWeb site Rat uterine cytosol estrogen receptor binding Human recombinant estrogen receptor binding Rat prostate cytosol androgen rece p tor bindin g Human cell line steroidogenesis Human placental & recombinant aromatase Rat uterotrophic and hershberger Rat pubertal female and male Amphibian metamorphosis Fish short-term reproductionMidwestResearchInstitute (MRI)USAwww.mriresearch.orgXXMolecularDiagnosticServices, Inc.USAwww.mds-usa.comXXXXXXXXXMPI ResearchUSAwww.mpiresearch.comXXNOTOXTheNetherlandswww.notox.nlXXXXXXXXXRTIInternationalUSAwww.rti.orgXXXXXXXSingulex, Inc.USAww.singulex.comXXXSNBL USAUSAwww.snblusa.comXXXXXXSpringbornSmithersLaboratoriesUSAwww.springbornsmithers.comXXStillmeadowUSAwww.stillmeadow.comXXUniversity of ILat ChicagoUSAwww.uic.edu/labs/toxXXXXXXXWIL ResearchLabs. Inc.USAwww.wilresearch.comXXXXWildlifeInternationalUSAwww.wildlifeinternational.comXX

## APPENDIX B EXAMPLE COST AND CAPACITY QUESTIONS

Prior to conducting the interviews, EPA provided th e laboratories with the following list of example questions for the interviews:

1. EPA will require that the Endocrine Disruptor Screening Program (EDSP) studies be conducted in compliance with Good Laboratory Practices (GLPs). Are you familiar with EPA’s GLP requirements in 40 CFR part 160? Do you routinely follow th ese GLPs when conducting tests? If not, do you

follow other GLPs?

2. What would you estimate the average cost of conducting [insert test assay] will be? What assumptions have you made in making this estimate?

3. Looking at the attached chemical list, are there cer tain chemicals that would cause you to adjust the cost estimate you provided in Question 2 hi gher or lower? Which ones, and why?

4. For the attached chemical list, we are interested in understanding the analytical cost and range finding requirements, such as:

a. Verification of the chemical’s identity and purity

b. Verification of dosing concentrations

Can you provide a cost estimate for methods development, sample preparation, and analysis for this type of testing (assuming these costs were not given as part of the answer to Question #1)? Please

assume that the results for in vitro binding assays would be made available for in vivo tests.

5. How would these cost estimates you provided in Question #4 change if the methods did not need to be developed (i.e., for an existing chemical)?

6. How many of these tests would you be able to conduct in one year?

7. Would there be any discounts to a customer reques ting the full suite of Tier 1 assays? Or any other reason? If yes, please elaborate.

8. Would there be any discounts to a customer reques ting multiple chemicals to be tested? Or any other reason? If yes, please elaborate.

B-1

## APPENDIX C POTENTIAL CHEMICALS TO BE TESTED AS PART

OF EDSP

EPA published in the Federal Register on April 15, 2009 a list of initial pesticide active ingredients and pesticide inert ingredients the Agency will require to be screened as part of EDSP. Laboratories were asked to base their testing cost est imates on this list of chemicals.

Table C-1: List of Chemicals Provided to Laboratories to Base Cost Estimates On

Chemical Type or Description
Acephate Organophosphate
Chlorpyrifos Organophosphate

Diazinon Organophosphate

Dimethoate Organophosphate

Disulfoton Organophosphate
Ethoprop Organophosphate

Glyphosate Organophosphate, but not representative

Malathion organophosphate
Methamidophos Organophosphate

Methidathion Organophosphate
Methyl parathion Organophosphate

Phosmet Organophosphate
Carbaryl Carbamate

Carbofuran Carbomate
Methomyl Carbamate
Oxamyl Carbamate

Bifenthrin Pyrethoids
Cyfluthrin Pyrethorid
Cypermethrin Pyrethroid

Esfenvalerate Pyrethroid

Permethrin Pyrethroid

Resmethrin Pyrethroid
Butyl benzyl Phthalate

Captan Phthalate
DCPA (or chlorthal–dimethyl) Phthalate
Dibutyl phthalate Phthalate
Diethyl phthalate Phthalate
Dimethyl phthalate Phthalate
Di–sec–octyl phthalate Phthalate

Atrazine Triazine

Metribuzin Triazine

Simazine Triazine

C-1Chemical Type or Description
Propiconazole Triazole

Tebuconazole Triazole
Myclobutanil Azole

Triadimefon Azole
Folpet Carboximide
Gardona (cis–isomer) ( aka tetrachlorvinphos) Carboximide

Benfluralin Dinitroaniline

Trifluralin Dinitroaniline

Dicofol Organochlorine

Quintozene Organochlorine

Abamectin Fermentation product of streptomyces avermitilis

Acetone
Carbamothioic acid, dipropyl–, S–ethyl ester

Chlorothalonil Chloronitrile

Dichlobenil Nitrile

Endosulfan Chlorinated hydrocarbon

Fenbutatin oxide

Flutolanil Benzanilide
Imidacloprid Chloro-nicotinyl
Iprodione Dicarboximide
Isophorone Unsaturated cyclic ketone

Linuron Substituted urea
Metalaxyl Benzxenoid
Methyl ethyl ketone

Metolachlor

Norflurazon Pyridazinone
o–Phenylphenol
Piperonyl butoxide
Propachlor Chloroacetanilide
Propargite Organosulfite
Propyzamide Benzamide Pyridine, 2-(1-methyl-2-(4- phenoxyphenoxy)ethoxy)

Toluene

C-2