SOW_FINAL.pdf

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STATEMENT OF WORK

FOR THE SUPPORT OF THE RESEARCH EFFORT

TO EVALUATE TOXICITY

FOLLOWING EARLY LIFE EXPOSURE TO TEST ARTICLES

FOR THE NATIONAL TOXICOLOGY PROGRAM (NTP)

May 3, 2012

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TABLE OF CONTENTS

Page

1. BACKGROUND, RATIONALE AND AIMS

2. REQUIREMENTS

General Requirements

General Activities

Data Management

Test Article and Test Article Analysis

Disease Screening

3. PROJECT MANAGEMENT

4. GENERAL STUDY INFORMATION

5. GOVERNMENT FURNISHED MATERIALS

6. REPORTING AND SUBMISSIONS

Periodic Reports

Study Reports

Submission of Archival Materials

Other Submissions

7. MILESTONES/PERFORMANCE/DELIVERY SCHEDULE

8. REFERENCES

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STATEMENT OF WORK

FOR THE SUPPORT OF THE RESEARCH EFFORT TO EVALUATE TOXICITY

FOLLOWING EARLY LIFE EXPOSURE TO TEST ARTICLES

FOR THE NATIONAL TOXICOLOGY PROGRAM (NTP)

1. BACKGROUND, RATIONALE AND AIMS

The National Toxicology Program (NTP, http://ntp.niehs.nih.gov/) is responsible for evaluating the toxic potential of a diverse range of environmental chemicals that may pose health hazards to citizens of the United States. The NTP was established in 1978 and is a federal interagency program headquartered at the National Institute of Environmental Health Sciences (NIEHS).

There is continuing concern among the public and in the scientific community that exposure to various chemicals during early life stages, such as during prenatal and postnatal development, produces adverse health outcomes in children and adults. This concern arises from the knowledge that the developing organism passes through a continuum of stages or “windows of vulnerability” as it matures. These windows are unique for the development of each organ system. During development, critical activities such as cell recognition, migration, and differentiation are events that must occur in a precisely ordered fashion in order to result in a fully functioning mature organism. In addition, the normal hormonal milieu must be present in order to program the responses at the cellular level for the remainder of the lifetime. The “windows of vulnerability” concept also implies that some chemicals will have little effect in adults, or require high doses to produce effects in adults, but cause permanent changes after developmental exposure, and will do so at lower doses than those required in adults. Many examples of this concept exist, including di-n-butyl phthalate, which causes an anti-androgenic response in fetuses producing structural and functional malformations that are persistent through life (Mylchreest, et al., 2000). It is well known that early life exposure to lead (Pb) in young children leads to decreases in cognitive function at low doses not causing the same effect in adults (Lidsky and Schneider, 2003). Prenatal exposure to diethylstilboestrol produced clear cell carcinoma in girls of mothers who took this drug during pregnancy (Swan, 2000).

These examples demonstrate that early life is a vulnerable period when chemical exposure may cause effects in ways not experienced by adults, and these changes can be permanent. Thus, the aim of this effort is to support the NTP in conducting a series of studies in which animals are exposed to selected test articles during early life stages and perform ongoing evaluations for adverse effects during different phases of life.

2. REQUIREMENTS

General Requirements

The Contractor shall have the ability to support and assist the NTP research effort to evaluate the effects of early life exposure to test articles in laboratory animals. The Contractor shall have the ability to conduct toxicity testing on a diverse range of test articles that may include but not be limited to: environmental chemicals, chemicals used in industrial or manufacturing settings;

food additives, colorants or flavorings; pharmaceuticals; herbal remedies and naturally occurring http://ntp.niehs.nih.gov/

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chemicals; nanomaterials; pesticides; ingredients found in a wide variety of consumer products including soaps, lotions, perfumes and cosmetics; detergents and cleaners, etc.

Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, procedures (SOPs), materials, equipment and facilities not otherwise provided by the Government as needed to perform the work described herein.

The work shall be conducted in accordance with the “Specifications for the Conduct of Studies to Evaluate Reproductive and Developmental Toxicity of Chemical, Biological and Physical Agents in Laboratory Animals for the National Toxicology Program” and any updates (http://ntp.niehs.nih.gov/ntp/Test_Info/FinalNTP_ReproSpecsMay2011.pdf). These specifications provide explicit details regarding the work to be performed. (From time to time some special studies may be required for which specifications are found at http://ntp.niehs.nih.gov/ntp/Test_Info/FinalNTP_ToxCarSpecsJan2011.pdf)

Studies shall be conducted in compliance with Good Laboratory Practice Regulations established by the FDA for non-clinical laboratory studies as most recently updated (http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr58_01.html). The Contractor shall have in place a quality management plan. Information on quality management plans can be found at http://www.epa.gov/quality/qmps.html.

The Contractor shall have an approved animal welfare assurance on file with OLAW prior to contract award, and shall be AAALAC accredited. The contractor shall comply with PHS Policy, the Animal Welfare Act and regulations, the Guide for the Care and Use of Laboratory Animals, and all local state or federal regulations.

The Contractor shall have on staff experienced key personnel to conduct the work described herein. The Principal Investigator, Discipline Leaders for General Toxicology, Reproductive and Developmental Toxicology, Chemistry, Pathology, Laboratory Animal Management, Health and Safety, Quality Assurance, as well as study directors shall be employees (eg., not consultants or subcontractors). The daily interaction and constant coordination of efforts needed among these discipline areas throughout the studies makes it preferable that they be physically and organizationally together. At the request of the COR, a yearly trip by the Principal Investigator and one other person to the NIEHS for project discussions may be required.

The Contractor shall have the ability to conduct multiple studies per year under the contract.

The types of research efforts anticipated each year will vary in terms of study designs and study duration depending on the needs of the NTP and available funds. (Refer to “Special Business Proposal Instructions” for estimating effort and costs.)

General Activities

Ongoing and recurring evaluations shall be conducted to assess reproductive, prenatal, and postnatal effects following dosing of test articles. Specific endpoints to be evaluated during the course of each study may vary depending on the nature of the test material and the needs of the Government.

Study activities shall typically use rats (Harlan Sprague Dawley), although in some cases mice (such as CD-1) or another species such as the New Zealand White rabbit may be required. In all cases, the Contractor shall obtain animals from a supplier designated by the NTP Contracting Officer’s Representative (COR). Animals shall be ordered according to protocol needs.

http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr58_01.html http://www.epa.gov/quality/qmps.html

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As a general approach, exposures shall be initiated during early life stages. In studies to assess prenatal development, fetuses shall be evaluated after dosing pregnant dams. In studies to assess reproductive effects, exposures of parental animals may start prior to mating and continue as the parental animals produce litters for evaluation. Subsets of offspring from these litters may be specified for short-term evaluations, production of additional generations or for longer-term evaluations, up to lifetime.

Activities (core work) may include, but are not limited to the following:

a. dosing of animals by various routes of exposure including but not limited to dietary, drinking water and gavage (including gavage dosing of pre-weaned animals)

b. in-life activities including but not limited to: clinical observations; measurement of body weights, food consumption and water consumption; specific evaluations such as functional observation battery; biological sample collection

c. mating of animals and measurement of reproductive endpoints over multiple generations including but not limited to mating performance, fertility, birth index, live birth index, viability index and lactation index

d. identification of sex-specific adverse reproductive findings using methods such as cross-over matings or dominant lethal studies

e. anogenital distance measurement; age for attainment of developmental landmarks including vaginal opening and preputial separation

f. sperm evaluations (in some cases, samples provided by outside labs may be evaluated)

g. vaginal cytology evaluations (in some cases, samples provided by outside labs may be evaluated)

h. evaluation for nipple retention and mammary gland development

i. postnatal evaluations for manifestations of toxicity such as, but not limited to developmental neurotoxicity, developmental immunotoxicity (immunotoxicity portion usually involves only dosing, sample collection and/or shipment of animals/samples to an NTP designated contractor for evaluation), reproductive capacity of the progeny, or development of tumors, or alteration of biochemical markers

j. teratology assessments including external, internal and skeletal observations of fetuses

k. measurement of organ weights or other parameters

l. histology and histopathologic evaluation including tissues from animals at different ages

m. collection and preservation of blood or tissue samples by freezing or other means as directed by the COR

n. analytical chemistry activities to support toxicology studies. This includes but is not limited to purity and identity confirmation of the bulk test material upon receipt; purity confirmation every 24 + 2 weeks while the bulk test article is at the testing laboratory;

dose formulation preparation and routine analysis, homogeneity verification, and analysis for test article concentration. Analytical methods are provided to the testing laboratory. Calculation of total amount of bulk test article needed for each phase of a study; preparation of buffers to support research activities

o. submission of timely interim and final reports with appropriate data analysis for all studies; provision of electronic data in electronic format in cases where it is not collected in an NTP computer system

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Other activities (may be considered non-core work) include but are not limited to:

a. measurement of clinical pathology parameters (hematology, clinical chemistry, urinalysis); P450 or other enzymes; analyses for various hormones such as testosterone, estrogen, progesterone, FSH, LH, corticosterone, or thyroid hormones (T3, T4, TSH); glutathione, or other special analyses

b. new tests for toxicity evaluation or mode of action evaluation as needed

c. shipment of study animals, study diet or other materials such as buffers to an NTP specified laboratory for specialized evaluations such as immunology or sperm evaluation

Data Management

The Contractor shall use the hosted NTP version of the Provantis system, or any other system specified by the COR, for collection of study data. Study data shall be entered directly into the system. The Contractor shall not record data on paper (or other means) for which an NTP electronic data capture system is available, unless the server is unavailable. NTP will provide licensed access to the system. The Contractor shall provide the computer hardware and high speed internet connection (Citrix client solution) to access the hosted server. NTP’s version of a leased system is currently under development and the NTP will provide additional information, system support and training for the system. Note: The Provantis system is not government-owned and the Contractor is not expected to need access to government computer systems.

Test Article and Test Article Analysis

Typically the test article will be provided to the Contractor and will have been evaluated for identity and purity prior to shipment to the contractor. Methods for Bulk chemical analysis (identity and purity) and dose formulation and analysis shall generally be provided to the contractor. Formulation stability information shall also be provided. “Pre-start chemistry” activities shall be performed by the contractor to confirm identity and purity as well as validate the chemistry methods. A report on the results of these “pre-start” chemistry activities shall be provided to and accepted by the COR prior to dosing of animals. The Contractor shall also conduct purity confirmation every 24 + 2 weeks while the bulk test article is at the testing laboratory, dose formulation preparation and routine analysis for formulations (refer to the Chemistry section of the NTP Specifications for Reproductive Studies).

Disease Screening

The Contractor shall have an animal disease screening program (refer to the Laboratory Animal Management section of the NTP Specifications for Reproductive Studies). The NTP will provide the address for shipment of samples for disease screening.

3. PROJECT MANAGEMENT

Although the contract, as a whole, shall be for the ongoing support of the NTP research and testing activities, the COR shall manage the daily administration of the contract on a “Study Assignment” basis, with Assignments initiated and administered by the COR. Study Assignments will be prepared and issued for each study, test article or group of test articles to be studied under the contract. The Study Assignment may contain analytical chemistry activities, range-finding study activities, and/or definitive study activities. The Study Assignment may be revised as the project progresses.

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Each Study Assignment prepared by the COR will include a description of work to be performed. The Contractor will be asked to submit a technical and business proposal to include a description of how the work shall be conducted, a study-specific protocol, schedule of events, list of key personnel, estimate of cost and effort, and an estimate of the amount of test article needed to complete the Study Assignment. This proposal should only include those details specific for the proposed Study Assignment and not generic procedures previously provided in the original proposal submitted at the time of contract award.

An Administrative Assignment will be issued for the Contractor to use for preparation and submission of Technical and Cost proposals for each study, monthly reports, water analysis reports, and Health and Safety reports.

Within 60 days of finishing all work required for each test article under a Study Assignment, the Contractor shall submit a confirmation of final cost and level of effort to the COR for that Study Assignment indicating that all activities have been performed and/or deliverables have been submitted and provide a final accounting of all costs and effort expended on that Study Assignment.

4. GENERAL STUDY INFORMATION

The following general types of study designs that are anticipated include but are not limited to:

Developmental and Reproductive Toxicology Study using the NTP Modified One Generation Design (described below)

Prenatal Developmental Toxicity Reproductive Assessment by Continuous Breeding (RACB) Postnatal Developmental Toxicity Short term studies such as range-finders for the above study designs or targeted male or female toxicity studies (such as sperm evaluation, dominant lethal or estrous cyclicity).

Prior to starting a study, the COR will provide a test-article-specific study outline containing specific information on the individual test article, route of exposure, endpoints to be evaluated, and goals of the study. Treatment regimens, species used, day of weaning, endpoints to be measured, etc. may vary between studies depending on the specific test article used.

Sentinel animals are required for studies over 6 weeks duration, and when possible culls shall be used for this purpose. Range-finding studies shall typically be conducted prior to definitive studies. Details regarding these studies can be found in the NTP Specifications for Reproductive and Developmental Toxicity Studies.

It is anticipated that multiple test articles will be evaluated using the NTP Modified One Generation Design. The study design for the NTP Modified One Generation (MOG) Study will be structured such that the NTP may incorporate varied endpoints in each design, depending on the test article. Some studies will begin with a pre-breed dosing period (1-10 weeks), but most are anticipated to begin with time-mated dams. After weaning, offspring shall be evaluated for growth and attainment of developmental landmarks including preputial separation and vaginal opening. Pups shall also be assigned to various cohorts for evaluation of specific parameters based on the needs of the specific test article. Examples of the various cohorts include but are not limited to (number of animals/group shall vary):

Prenatal Developmental Toxicology (teratology) (minimum 20/sex/group)

Fertility Evaluation (minimum 20/sex/group)

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Subchronic 90-day Toxicity (10/sex/group core study, 10/sex/group special study animals if required)

Toxicity Cohort for greater than 90-days (up to 50/sex/group, depending on duration of study)

Immunotoxicity (minimum 20/sex/group) (anticipated to require shipping of animals to a laboratory designated by the NTP COR)

Neurotoxicity (10-20/sex/group)

Mammary Gland/biological sampling (up to 10/sex/group at 2-3 time points)

Maternal Transfer of test article (10-16/group)

For MOG studies, NTP will choose the endpoints and cohorts for ongoing evaluations based on effects seen or anticipated for specific chemicals (not all of these cohorts will be included in an individual MOG study, but this list is intended to give an idea of the breadth of types of ongoing evaluations that will be required). Histopathology with emphasis on reproductive organs shall be conducted on parental animals and offspring. Details for the endpoints to be measured in the various cohorts will be specified in the test article specific study outline provided to the testing laboratory at the time of study assignment. From time to time, a 13-week mouse study (B6C3F1/N or other) may be conducted concurrently with a 13-week rat cohort in an MOG study. This mouse study shall be conducted in accordance with the NTP specifications for general toxicity studies (most recent update) (http://ntp.niehs.nih.gov/ntp/Test_Info/FinalNTP_ToxCarSpecsJan2011.pdf).

In some cases, Prenatal Developmental Toxicity Studies (teratology) will be conducted as part of the MOG study, while in other cases a stand-alone study will be required. For a stand-alone study, generally, a range-finding and a definitive study may be conducted. The range-finding study will usually consist of 5 dose groups and a control. Time-mated females shall be dosed by gavage (usually GD6-20 for the rat). Clinical signs and body weights shall be recorded daily.

Food consumption shall also be measured. On GD21, animals shall be given a cesarean section and data collected for parameters including but not limited to: gravid uterine weight, individual fetal weights, number of live and dead fetuses by sex, number of early and late resorptions, corpora lutea counts and external fetal evaluations including cleft palate. Definitive studies will typically be designed with 3 dose groups and a vehicle control with approximately 25 time-mated animals per group. Evaluations shall be similar to those for the range-finder except that in addition to external fetal exams, internal (Staples technique) and skeletal examinations shall also be included. Half of the fetuses shall be decapitated prior to dissection and heads fixed and examined for soft tissue abnormalities. Skeletons of all fetuses shall be evaluated using Alcian blue/Alizarin Red S double-staining.

The NTP Specifications for Reproductive and Developmental Toxicology Studies provides full details for required evaluations and assessments.

Note: Preparation of Technical and Business Proposals Sample Study Assignments have been included in Attachment 6 of the RFP in order to provide offerors with examples of study designs that might be conducted under this contract. Offerors are to provide technical and cost information in their proposal for each of the Sample Study Assignments.

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5. GOVERNMENT FURNISHED MATERIALS

The following items will be furnished to the contractor as required:

a. test articles and information on manufacturer and purity

b. analytical methods for test article characterization – identity and purity

c. methods for dose formulation and dose analysis

d. information on storage and stability for test article and dose formulations

e. Access to Provantis (or other specified) data management system used by NTP.

(Currently NTP is moving toward the use of a customized hosted Provantis system for which NTP would supply licensed access and Contractor would supply hardware and internet connection. Note: The Provantis system is not government-owned so the contractor will not need access to government computer systems.)

f. Information on NTP-designated suppliers such as those for test animals, feed, and disease screening will be provided after award.

6. REPORTING AND SUBMISSIONS

Electronic deliverables must be compliant with Section 508 regarding accessibility. In some cases, there may be accommodations for which the COR will provide information annually.

Periodic Reports

Monthly Progress Update A Monthly Progress Update shall be mailed by the fifteenth (15th) day of each month. Each Monthly Progress Update shall be submitted in the format indicated in the NTP Specifications for Reproductive Studies. No QAU audit of this progress report is required.

Water Analysis Water samples shall be collected for analysis and the results sent to the COR at least once per year during a study. Results of each analysis shall be submitted at the time of their receipt.

Study Reports

Prestart Chemistry Report For each test article evaluated, this report shall be submitted in accordance with the Prestart Chemistry Report format instructions in the NTP Specifications for Reproductive Studies.

Draft Final Report (audited) An audited draft final report shall be provided to the COR prior to finalization of a final report.

The audited draft final report shall be considered, in the estimation of the contractor, a final report subject only to review and approval by the COR. If the review results in changes to the report, a new version of the draft final report reflecting the changes is required.

Final Report A final report shall be submitted for each study. Final reports shall be submitted in accordance with instructions in Study Assignments as well as instructions in this Statement of Work. Final study reports shall be concise and include sections for materials and methods, results, data tables, discussion, summary and references. The abstract shall contain a concise carefully reasoned integrated summary of the data. Reports shall include tables, charts, graphs, 10 ATTACHMENT 3 tabulations and pictures as necessary for explanation or support of the narrative. Final reports shall be provided in formats specified by the COR such as pdf and Word.

All final reports shall be dated and signed by the individual(s) responsible, including key personnel / discipline leaders, and the QAU.

Submission of Archival Materials

Archival Materials (Study Data) - See NTP Specifications for Reproductive Studies for details.

Histopathology Materials - See NTP Specifications for Reproductive Studies for details.

Other Submissions

Specific reporting requirements are listed in the Milestone/Performance/Delivery Schedule below. Also listed below are the submission time frames and number of copies of reports required. All submissions shall be sent directly to the appropriate recipient as indicated in the table and shall be delivered f.o.b. destination in accordance with the NTP Specifications for Reproductive Studies and in the time frames specified. In cases where data for a portion of a study is not collected in NTP’s Provantis (or other NTP designated data management system), the Contractor shall provide data in an electronic format such as Excel or other COR-designated format.

Any incident or unforeseeable occurrences not listed in this document, or any physical modifications to the laboratory facilities, as well as any changes in personnel that might have an impact on the conduct or results of study activities, shall be reported immediately to the COR. In the case where there is a question regarding the interpretation of the Statement of Work, the COR will provide the final interpretation.

7. MILESTONES/PERFORMANCE/DELIVERY SCHEDULE

For study types not listed, refer to the study specific protocol.

Abbreviation and General Delivery Addresses follow the list of performance requirements.

Exact Names and Addresses to be supplied by the COR. In the case of extremely long reports, the COR may instruct the Contractor to reduce the number of copies requested.

PERIODIC SUBMISSIONS

PER FACILITY WHILE

ASSIGNMENTS IN

PROGRESS

FREQUENCY TIME FRAME

DISTRIBUTION

(Number of copies)

Monthly Progress Update 1/Month Mail by 15th each month CC - (1) (paper)

Sanitation Methods Once 90 Days after contract award CC - (2) (paper)

Water Analysis

At a minimum 1/yr;

for new labs an analysis is required 30 days

Submit results of analyses to COR upon their receipt

CC - (2) (paper)

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after receipt of award

Health and Safety Chemical Hygiene Plan

At Award Within 30 days of receipt of award CC - (1) (paper)

PRE-START CHEMISTRY

(Validation of Chemistry Methods)

FREQUENCY TIME FRAME

DISTRIBUTION (Number of copies)

Start of Pre-Start Chemistry Upon receipt of approved Study

Assignment and test article

NA

Submission of Pre-Start Chemistry Audited Draft

Report

Within 10 weeks of receipt of Study Assignment and test article

CC (2 paper)

Submission of Final Pre- Start Chemistry Report

1 Within 1 week of approval of Draft Report CC (2 paper and CD /DVD)

NTP Review and Approval to Proceed to Next Phase

NA

Within 2 weeks of receipt of final Pre-Start Chemistry report

NA

RANGE-FINDING

STUDIES

FREQUENCY TIME FRAME

DISTRIBUTION

(Number of copies)

Start of Range-finding Study

NA Upon receipt of approval to Proceed NA

Study Protocol (Contractors IACUC approved)

1 Prior to dosing animals CC (2 paper) COR email signed version

Start of Range-Finding Study In-life

Within 4 weeks of approval to proceed NA

Littering update (if littering is part of study design)

At time of collection of littering data COR (telephone and email)

Submission of Range- Finding Audited Draft Study

Report Within 6 weeks after last necropsy CC (2 paper)

Submission of Range- Finding Final Study Report

1 Within 1 week after approval of draft CC (2 paper and CD /DVD)

Submission of Range- Finding Study Raw Data

To be submitted at the same time as definitive study if conducted, or if no definitive is to be run, within 4 weeks of approval of Final Report

CC - Copy of transmittal letter & inventory REP-Archival back-up CD/DVD of all original documentation

Electronic Submission of data not in NTP data mgmt system (typically Excel files on a CD/DVD)

Upon approval of Final Reports CC (1) (CD/DVD)

NTP Review & Approval to Proceed to Definitive Study

NA According to Program needs NA

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NON-RANGE-FINDING

FREQUENCY TIME FRAME

DISTRIBUTION

(Number of copies)

Start of Study NA Upon receipt of approval to Proceed NA

Study Protocol (Contractor’s IACUC approved)

Prior to dosing animals CC (2 paper) COR email signed version

Study In-Life Start Within 4 weeks of approval to proceed NA

Serum Samples for Disease Screening

For studies over 6 wks: at 4 wks after study start, 6 mos intervals & terminal euthanasia

As collected SA Send Samples for Evaluation

Littering Update (if littering is part of study design)

At time of collection of littering data COR (telephone and email)

Clinical Lab. Study Data Per protocol within 7 days of analysis CC (2), PC (1)

Blood for micronuclei determination

Per protocol within 24 hours of collection REP - decoding information MI - Copy of transmittal letter decoding

Tissues for Sperm Count, Slides for Vaginal Cytology, Accompanying data Per protocol As collected

SCVCE - Send or receive materials for evaluation if required CC - Copy of transmittal letter

Copies of IANR Forms (for life time studies only)

Twice a month On the 1st and the 15th of each month if required CC (1 paper)

Audited Draft Final Report for Prenatal Dev Tox Study

Within 12 weeks post necropsy CC (2 paper copy)

Audited Draft Final Report for RACB Study

Within 24 weeks post necropsy CC (2 paper copy)

Audited Draft Final Report for MOG or Postnatal Dev Tox Study (including study with lifetime exposure)

Within 26 weeks post necropsy (or per protocol depending on study length)

CC (2 paper copy)

Other draft report

As per protocol CC (2 paper copy)

Study Final Report Within 2 weeks of approval of draft CC (2 paper copy and 1

CD/DVD)

CO (Cover page only)

Slides, Blocks and Inventory, Histology

Processing Records, and Notification of Storage on NTP data mgmt system.

IANR Forms (if used).

Within 30 days of approval of Final Report

REP

CC, PC - Copy of Transmittal Letter to include notification of pathology storage on data mgmt system

Electronic submission of data not in NTP data mgmt system (typically excel files on a CD/DVD)

Within 30 days of approval of Final Report CC (1) (CD/DVD)

Wet Tissues and Inventory Within 30 days of Approval of Final Report

REP

CC, PC Copy of Transmittal Letter

Archival Records/Study Raw Data Records and

CD/DVD

Same as wet tissues

REP

CC-Copy of Transmittal Letter and Inventory

Notification of intention to 1/test article 30 days prior to shipment COR (email)

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NON-RANGE-FINDING

FREQUENCY TIME FRAME

DISTRIBUTION

(Number of copies) ship residual test article

Shipment of 100 g aliquot & residual test article to Chemistry Contractor

1/article At time of final bulk analysis

CH

CC-Copy of Transmittal Letter

IANR = Individual Animal Necropsy Record

Note for draft reports: In some cases the COR may require CD/DVD and paper copy

Abbreviations and General Addresses for Submissions (Complete names and addresses will be supplied by the COR upon award.)

CC Contracts Coordinator

NIEHS, NTP

Research Triangle Park, NC 27709

CH Chemistry Contractor

TBD

CO

Contracting Officer

NIEHS, OA

Research Triangle Park, NC 27709

COR Contracting Officer’s Representative

NIEHS, NTP

Research Triangle Park, NC 27709

HS NTP Health and Safety

NIEHS, NTP

Research Triangle Park, NC 27709

MI Micronuclei Evaluation

NIEHS

Research Triangle Park, NC 27709

PC

Pathology Coordinator Research Triangle Park, NC 27709

REP

Repositories:

Archival Material - Raw Data or Wet Tissues and Blocks or Frozen Samples

TBD

SA Sentinel Animal Samples TBD

SCVCE Sperm Count/Vaginal Cytology Evaluation TBD

8. REFERENCES

Lidsky, T and Schneider, J (2003). Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 126, 5-19.

Mylchreest, E, Wallace, DG, Cattley, RC and Foster, PMD (2000). Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to di(n-butyl)phthalate during late gestation. Toxicol. Sci. 55, 143-151.

Swan, SH (2000). Intrauterine exposure to diethylstilbestrol: long-term effects in humans. APMIS 108, 793-804.

NTP Specifications (2011). http://ntp.niehs.nih.gov/ntp/Test_Info/FinalNTP_ReproSpecsMay2011.pdf