United Stales
          Environrrtntal Protection
          Agency
  of Pesticides Programs
Washington. DC 20*60
PB90-213885
EPA 540/09-90-092
May 1990
vvEPA     Studies/Chronic

          Data Formats for
          Chronic/Oncogenicity Rodent
          Bioassays

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                                        June  1989
STUDIES Format for Toxicological Data

    from Chronic Rodent Bioassays
            prepared under
     EPA Contract No. 68-08-0056
       to Dynamac Corporation
          EPA Task Manager
           Richard A. Levy

       Dynamac Project Manager
            Brion T. Cook

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                         TABLE OF CONTENTS


i.    Disclaimer                                                   iii

ii.    Interagency Electronic Data Transfer Workgroup                      iv

iii.   Acknowledgements                                               v

I.    Introduction                                                    1

n.   Background                                                     2

m.   Philosophy                                                     4

IV.   Data File Naming Conventions                                     6

V.   STUDIES Format Data File Descriptions                             7

     A.    Outline of File Descriptions
            1.   INDEX.CHR                                        8
            2.   ANIMAL.CHR                                      12
            3.   PATH.CHR                                        14
            4.   BODYWT.CHR                                     16
            5.   FOODCS.CHR                                      17
            6.   ORGANWT.CHR                                   18
            7.   CLINOBS.CHR                                     19
            8.   HEMATO.CHR                                     20
            9.   CLINCHEM.CHR                                   22
           10.   URINAL.CHR                                      24
           11.   PATHGLOS.CHR                                .   27
           12.   TISSUE.CHR                                       28
           13.   TEXT.CHR                                        29

     B.    Detailed File Descriptions                                   30
            1.   INDEX.CHR                                       31
            2.   ANIMAL.CHR                                      35
            3.   PATH.CHR                                        38
            4.   BODYWT.CHR                                     40
            5.   FOODCS.CHR                                      41
            6.   ORGANWT.CHR                                   42
            7.   CLINOBS.CHR                                     43
            8.   HEMATO.CHR                                     45
            9.   CLINCHEM.CHR                                   47
           10.   URINAL.CHR                                      49
           11.   PATHGLOS.CHR                                   51
           12.   TISSUE.CHR                                       52

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VI.   Data Submission Specifications                                         53
Vn.   Appendix A List of Tissues and Tissues Codes                          54
    .  Appendix B List of SNOP Codes for Pathology                         56
                                      u

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                                  DISCLAIMER
This report was prepared under contract to an agency of the United States government.
Neither  the  United  States  government  nor  any  of  its  employees,   contractors,
subcontractors, or their employees makes any warranty, expressed or implied, or assumes
any legal liability or responsibility for any third party's use or the results of such use of
any information, product, or process disclosed in this report, or represents that its use
by such third party would not infringe on privately owned rights.

Publication of this data in this document does not reflect the joint or separate views and
policies of each sponsoring agency.   Mention of trade names  or commercial products
does not constitute endorsement  or recommendation for use.
                                        1U

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                        Interacencv Electronic Data Transfer Workerouo
Richard A, Levy, M.P.H. Chairman
Senior Scientist, Biostatistics
Science Analysis and Coordination Branch
Health Effects Division
Office of Pesticide Programs
U.S. Environmental Protection Agency

Reto  Engler, Ph.D.
lexicologist
Chief, Science Analysis and Coordination
       Branch
Health Effects Branch
Office of Pesticide Programs
U.S. Environmental Protection Agency

Herbert 'Pepi' Lacayo, Ph.D.
Statistician
Statistical Policy Branch
Office of Policy, Planning,  and Evaluation
U.S. Environmental Protection Agency

Marion Copley, D.V.M.
Pathologist
Section Head, Toxicology Branch I -
       Insecticides /Rodenticides
Health Effects Division
Office of Pesticide Programs
U.S. Environmental Protection Agency

Roger Gardner, M.S.
Toxicologist
Toxicology Branch I -  Insecticides/
       Rodenticides
Health Effects  Division
Office of Pesticide Programs
U.S. Environmental Protection Agency

William R. Fairweather, Ph.D.
Statistician
Chief, Statistical Application Branch
Center for Drugs and  Biologies
Food and Drug Administration
Janet Springer, M.S.
Statistician
Director, Division of Mathematics
Center for Food  Safety and Applied Nutrition
Food and Drug Administration

James J.  Colaianne, Ph.D.
Statistician
Chief, Biometrics Branch
Center for Veterinary Medicine
Food and Drug Administration

Robert J. Condon, Ph.D
Mathematical Statistician
Biometrics Branch
Center for Veterinary Medicine
Food and Drug Administration

Michael  W. O'Donnell, Ph.D.
Statistician
ChiefV Environmental Design and Evaluation Branch
Division of Mathematics
Center for Food Safety and Applied Nutrition
   Food and Drug Administration

Judy S. Chen, Ph.D.
Statistician
Center for Medical Devices and Radiologic Health
Food and Drug Administration

Fred A.  Hines, D.V.M
Pathologist
Diagnostic Pathology Branch
Division of Pathology
Center for Food  Safety and Applied Nutrition
Food and Drug Administration

Prem Dua, D.V.M.
Pathologist
Diagnostic Pathology Branch
Division of Pathology
Center for Food  Safety and Applied Nutrition
Food and Drug Administration
                                              IV

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Murray S. Conn, Ph.D.                      Ralph L. Kodell, Ph.D.
Toxicologist                                Mathematical Statistician
Chief, Division of Health Effects             Biometry Staff
Consumer Product Safety Commission        National Center for lexicological Research
                                           Food and Drug Administration
James J. Chen, Ph.D.
Mathematical Statistician
Biometry Staff
National Center for Toxicological Research
Food and Drug Administration

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                      ACKNOWLEDGMENTS

The authors, Richard A. Levy of the Environmental Protection Agency's Office of
Pesticide Programs and Brion T. Cook of Dynamac Corporation, wish to thank the
members  of  the interagency  Electronic  Data  Transfer  Workgroup for their
dedication  and  effort  in the development  of  the formats described  in this
document  The authors also wish to acknowledge  the support, encouragement, and
counsel provided by Reto Engler of the Environmental Protection Agency and the
willingness of Dave Gaylor of the National Center of Toricological Research in
providing support and comments to these documents. In addition, the authors wish
to acknowledge the efforts of Roy Sjoblad and Mike loannou of the Environmental
Protection  Agency and Todd Holderman,  Karen Maher, Kevin Junghans, Tom
England  and Lori Brunsman of Dynamac Corporation for their technical support.

This document  was reviewed by:

            Reto Engler, Ph.D.
            Toxicologist
            Chief, Science Analysis and Coordination Branch
            Health Effects Division
            Office of Pesticide Programs
            U.S. Environmental Protection Agency

            Philip Ross, Ph.D.
            Statistician
            Chief, Statistical Policy Branch
            Office of Policy, Planning, and Evaluation
            U.S. Environmental Protection Agency

            James Skaptason,
            Computer Scientist
            FIFRA '88 Implementation Task Force
            Office of Pesticide Programs
            U.S. Environmental Protection Agency

            Murray S. Conn, Ph.D.
            Toxicologist
            Chief, Division of Health Effects
            Consumer Product Safety Commission

            Ralph L.  Kodell, Ph.D.
            Mathematical Statistician
            Biometry  Staff
            National Center for Toxicological Research
            Food and Drug Administration
                                 VI

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Fred A. Hines, D.V.M.
Pathologist
Diagnostic Pathology Branch
Division of Pathology
Center for Food Safety and Applied Nutrition
Food and Drug Administration
                    vu

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I.     Introduction

The purpose of this document is to present file formats for the electronic transfer of
individual animal toxicological data generated from long-term rodent chronic/oncogenicity
studies.  Through cooperation and discussions between the US Environmental Protection
Agency  (EPA),   the Department of Health  and Human Services' Food  and  Drug
Administration (FDA), the National Center for Toxicological Research (NCTR), and the
Consumer Product Safety Commission (CPSC) these formats  have been developed to
meet the electronic data submission requirements of these agencies.  It is intended that
these formats be available for all electronic transfer of toxicological data between the
chemical industry and the government, within the chemical industry itself and between
government  agencies.

This document presents  the  electronic data submission formats for parameters in  a
chronic/oncogenicity bioassay. The categories of parameters which are described include:
                   pathology data - gross and microscopic
                   body weight
                    	1     o	
                   food  consumption
                   organ weight
                   clinical chemistry
                   hematology
                   urinalysis

Users of this document should read the data submission specifications found in Section
VII on page 53 before using these formats.

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n.    Background

Both the EPA and the FDA are responsible for the evaluation of data generated from
long-term rodent oncogenicity studies  to  fulfill regulatory mandates.  These studies,
conducted by the chemical industry,  are routinely submitted to the  responsible  agency
only in  a hard copy format  Since a great amount of data are generated during these
studies  the evaluation process can be very complex and  time  consuming.  Discussions
between these  two  agencies  and other  agencies including  CPSC  and  NCTR have
considered developing a format by which the chemical industry could submit data to the
agency  on some electronic media.  It is acknowledged by everyone concerned that  this
would greatly enhance the review process by permitting the amount of time to evaluate
the study to decrease and the effort given  to the analysis to increase.  Data provided in
electronic form would allow for customized tabulation and summarization,  and more
efficient use of computers for statistical analysis since hand counts and data transcription
would  no longer be necessary,  thus reducing  human  error.  These ideas  were first
realized by the FDA in  1986 with the first description of such a format prepared by the
Statistical Application and Research Branch of the  Center for Drug  Evaluation  and
Biologies.  The EPA envisioned  a more global  approach  and an expanded format that
could be constructed for all categories measured in a chronic  bioassay and coined the
acronym,  STUDIES,  Submitters  Toxicological  Uniform  Data Information  Exchange
Standard, as the  name  of this standard format.   Categories evaluated in  a chronic
bioassay and hence could be included in the STUDIES format are:

                         o  tumor  incidence data
                         o  body weight
                         o  food consumption
                         o  organ weights
                         o  clinical chemistry
                         o  hematology
                         o  urinalysis


In addition, the STUDIES format could be applied to other types of studies submitted
to these agencies for lexicological review.   These studies  include:

                         o  acute toxicity studies
                         o  subchronic studies
                         o  teratology
                         o  reproduction

While all lexicological studies described above could  be encompassed by the  STUDIES
format,   one study  type  must   be  chosen to use  as  a  pilot  effort.    Because
chronic/oncogenicity studies serve as  a large portion of the overall weight-of-evidence in
judging  the lexicological potential of a  chemical it was chosen  as the study type to use
in developing the first STUDIES format.

The STUDIES chronic rodent bioassay  format was designed, recognizing that the needs

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of the various agencies involved may differ in content but that the goals of the format
are the same. This document contains: 1)  descriptions of computer file structures, and
2) the parameters necessary for data evaluation, and 3) a description of how these
various files relate to each other.

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ffl.   Philosophy

The STUDIES format provides a modular approach to the evaluation of lexicological
data submitted to regulatory agencies.  While the different types of lexicological studies
may require data that are unique to that type of study, there are parameters that are the
same from study type to  study type.  The STUDIES format allows for similar data from
different lexicological studies to be submitted in similar file formats, while also providing
for those parameters that are  unique to a specific study type.  This  modular approach
gives a system that is easily adapted or modified as the data requirements change.  These
formats  as designed offer  portability  for  use in  a  mainframe environment or
minicomputer  as well as  a personal computer  since they follow the ASCII standard for
data representation.

The data from a lexicological study is submitted as a set of computer files.  There is one
file which  contains background information concerning the study which has the same
format for  each different study type. This provides consistency from study type to sludy
type. Other files contain daia  regarding specific lexicological parameters. For example,
all daia concerning animal body weights resides on one daia file. The structure  of this
file is ihe same for every sludy type for which  animal body weights are to be submitted,
whether  ii  be  a chronic rodenl bioassay, leralology, or reproduction sludy.  Daia which
is  unique  lo  a specific  sludy type, such as  tumor incidence  from a  chronic  rodenl
bioassay, would have a formal  unique lo that type of study.  A subset of the background
information has been identified as information lo be  included as a 'header* record for
every other data file to be submitted with thai  study. This provides a logical connection
between files and insures easy identification of files that correspond  to a specific study.

The format of the data files  have  been  designed to be as flexible as possible.  As
described in this document, Ihe formal allows for daia lo be submitted in either fixed
length fields or variable  length fields.  For the fixed length field approach a definitive
number of  characters are allowed for each parameter. The variable length field approach
allows for  a specific character lo be used  as ihe delimiter between fields.

It  is envisioned that a library of glossaries will be established lo provide descriptions of
lexicological events that are more easily provided in coded form on the daia files. For
example, pathological observation codes presented in a daia file would be linked lo a file
containing  the set of all possible codes and its  associated description  of the pathological
observation.   A defaull glossary  (codes  and descriptions) has been  established for
pathological observations for Ihe chronic rodenl bioassay formal based on ihe National
Toxicology Program's Standard Nomenclature of Palhology (SNOP).  Additional glossaries
for pathological observations and other lexicological evenls could be provided by ihe daia
submitters  to describe their data.  These would be kept on file and used on future data
submissions.  These glossaries  would also be used by more than  one  agency or by more
than one data submitter.

The STUDIES format approach allows for ihe consistent and accurate tracking of data
submitted lo various agencies.  These formats  also could be used as  a standard for ihe

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organization  of toxicological  data for exchange  of  data and  information within the
regulated industries.

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IV.   Data File Naming Conventions

All data for a given lexicological study have  the same  data file extensions as shown
below:

                  .CHR - chronic/oncogenicity rodent bioassay
                  .ACU - acute studies
                  .SCR - subchronic rodent studies
                  .TER - teratology rodent studies
                  .REP - reproduction rodent studies

STUDIES formats for non-rodent species (i.e.,dog, primate, guinea pig) will be addressed
at some time  in  the future.  This document will focus  only on  the  STUDIES  for
chronic/oncogenicity rodent bioassays.

All data files for a specific category of parameters have the same name as shown below:

                  INDEX - study background information
                  ANIMAL - individual animal background
                          information concerning tissues,
                          hematology, clinical chemistry,
                          and urinalysis parameters examined.
                  PATH - pathology observations
                  BODYWT -  body weight data
                  FOODCS - food consumption data
                  ORGANWT - organ weight data
                  CLINOBS - clinical observations
                  HEMATO -  hematology data
                  CLINCHEM - clinical chemistry data
                  URINAL - urinalysis data
                  PATHGLOS - pathology observations code glossary  file
                  TISSUE - tissue code glossary  file
                  TEXT - additional information as necessary

For example, the clinical chemistry data submitted for a chronic/oncogenicity study would
be named, CLJNCHEM.CHR and the organ weight  data submitted for a teratology study
would be named,  ORGANWT.TER.  The specific  contents and structure of these data
files are described in detail in Section V.

Thirteen  different types  of  files  could  be  submitted under the chronic/oncogenicity
STUDIES format. A separate set of files would be submitted for each  sex.

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             V.    STUDIES Format Data File Descriptions

                   A.    Outline of File Descriptions

The STUDIES format for chronic/oncogenicity rodent bioassay data consists of up to
twelve files which contain data describing the toxicological effects for individual animals
generated from a chronic/oncogenicity bioassay.

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1.    FORMAT FOR INDEX.CHR

This file contains background information about the chronic/oncogenicity study.  This file
exists as one single record.
Item Field Length
1 1
2 200
3 100
4 100
5 100
6 8
7 8
8 100
9 50
10 50
11 100
12 15
13 15
14 15
15 50
16 1
Description
Record Type
F = fixed
V = variable
Chemical Name 1
Chemical Name 2
Study Type Description
Study Sponsor
Study beginning date (in the
form MMDDYYYY)
Study ending date (MMDDYYYY)
Conducting Laboratory
Animal Species
Animal Strain
Source, of Animal
Study Identification Code 1 -
conducting laboratory study identification
Study Identification Code 2 -
sponsor study identification
Study Identification Code 3 -
internal Agency identification
Pathologist
External Peer Review
                                             1 = no external peer review
                                             2 = external peer review
                                        8

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FORMAT FOR INDEX.CHR (continued')

	Item	Field Length	Description	

      17                 50               Route of Administration (dermal,
                                          oral, dietary, etc.)

      18                  2               Days of Dosing

      19                  2               Dose Unit Code
                                           1  = ppm
                                           2  = mg/kg
                                          Additional codes are to be
                                          explained  in TEXT.CHR.

      20                240               Dosing Regimen (i.e., two times per
                                          week by dermal injection, etc.)

      21                  2               Number of Dose Groups

      22                  3               Number of Animals per Dose
                                          Group by Study Design - there are as
                                          many values as indicated in Item 21.
                                          Each value is treated as a separate
                                          field.

      23                  2               Number of Satellite Groups

      24                  3               Number of Animals in  each Satellite
                                          Group - there are  as many values as
                                          indicated  in Item 23.  Each value is
                                          treated as a separate field.

      25                  2               Number of Animals per Cage

      26                  1               Sex
                                           M = male
                                           F = female

      27                  6               PATHGLOS.CHR File Code-will include
                                          an  agency designation  code,  version
                                          designation code and a company glossary
                                          code. Default is the NTP SNOP codes.

      28                  8               File Version Date  (MMDDYYYY)

      29                  2               Number of Tissues Examined

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FORMAT FOR INDEX.CHR (continued^

     Item _ Field Length
      30                 6               TISSUE.CHR File Code - structure same
                                         as the glossary file code. Default is the
                                         NTP tissue codes.

      31                 1               Body Weight Measurement Unit
                                          M  = milligrams  (mg)
                                          G  = grams  (g)
                                          K  = kilograms (kg)

      32                1                Food Consumption Measurement Unit
                                          M  «• milligrams  (mg)
                                          G  = grams  (g)
                                          K  - kilograms (kg)

      33                1                Organ Weight Measurement Unit
                                          M  = milligrams  (mg)
                                          G  = grams  (g)
                                          K  = kilograms (kg)
                                     10

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FORMAT FOR INDEX.CHR (continued^

The following Items from the INDEX.CHR file would also be included as the first record
in every additional file submitted for the study.  This will be referred to as the 'header
record' and will be referenced in each additional file.  The 'header record'  is not a
separate record in  INDEX.CHR as it  is a subfile of INDEX.CHR. The 'HEADER
RECORD' is used to link files common to a single study.

    Item	 Field Length	Description	

      1              200                 Chemical Name 1

      2                15                 Study Identification Code 1 -
                                         conducting laboratory study identification

      3                15                 Study Identification Code 2 -
                                         sponsor study identification

      4               "15                 Study Identification Code 3 -
                                         internal Agency identification

      5                 8                File Version Date (MMDDYYYY)

      6                 1                Sex
                                          M  = Males
                                          F  = Females
                                      11

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FORMAT FOR ANIMAL.CHR

This file contains information about the individual animal tissues examined for gross and
microscopic  pathology,  the dosing regime,  and the  animals scheduled for hematology,
clinical  chemistry, and/or urinalysis evaluation.

	Item	Field Length	    Description	

      1-6                                  Header record (see page 11)

        7                 8                Animal Number

        8                12                Animal Necropsy Accession Number

        9                10                Dose value for treated or control animals

        10                 1                Dose Code
                                            1 = untreated controls
                                            2 = vehicle controls
                                            3 = positive controls
                                            4-8 =  optional groups
                                            9 = animal was treated

        11                 1                Hematology Evaluation Code - Animal
                                           included in hematology evaluation
                                            1 = yes
                                            2 = no

        12                 1                Clinical  Chemistry Evaluation Code -
                                           Animal  included  in  clinical  chemistry
                                           evaluation
                                            1 = yes
                                            2 = no

        13                 1                Urinalysis  Evaluation  Code  -Animal
                                           included in urinalysis evaluation
                                            1 = yes
                                            2 = no

        14                 8                Date dosing started (MMDDYYYY)

        15        -         8                Date dosing ended (MMDDYYYY)

        16                 8                Date of death (MMDDYYYY)

        17                 4                Interval between  date dosing
                                           started and date dosing ended in days

                                       12

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FORMAT FOR ANIMAL.CHR (continued^

	Item	Field Length	Description	

       18                 4                Interval between date dosing
                                           started and date of death in days

       19                 2                Animal Disposition
                                            1  = Death on Study
                                            2  = Interim Sacrifice # 1
                                            3  - Interim Sacrifice # 2
                                            4  = Interim Sacrifice # 3
                                            5  = Terminal Sacrifice
                                            6  — Missing animal
                                            7  = Accidental kill animal
                                            8  = Moribund sacrifice
                                            9   or  greater   =   optional,   use
                                           TEXT.CHR file to explain

       20                10                Cage Identification

       21                 1                Ever Examined Code
                                            1  s at least one  tissue was examined
                                            2  = no tissues were examined

       22                 1                Tissue Examination Code
                                            1  = tissue examined, suitable
                                                 specimen
                                            2  = tissue examined, unsuitable
                                                 specimen
                                            3  = tissue not examined

       23                 2                Number of Tissue  Sections

       24                 2                Number of Slides Prepared

       25                 1                Autolysis Code
                                            1  = tissue was at least partially
                                                 autolyzed
                                            2  = tissue was not autolyzed
                                            3  = not applicable (tissue not examined)
Thus, there are as many sets of Tissue Examination Codes,  Number of Tissue Sections,
Number of Slides Prepared, and Autolysis Codes as there are number of tissues examined
in Item 29 of INDEX.CHR.

                                       13

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FORMAT FOR PATH.CHR

This file contains the individual animal pathology incidence data.

_ Item           Field Length _ Description _ _

      1-6                                   Header record (see page 11)

       7                   8                Animal Number

       8                   3                Field  Count  - the  number  of distinct
                                           pathology descriptions given for this
       9                  16               Pathology Code
                                           Up to 16 characters for lesions code from
                                           the PATHGLOS.CHR  file.  Dependent
                                           upon  specific glossary.   Only codes for
                                           observed lesions  are  to be recorded.
                                           Default  is the NTP SNOP codes.

       10                   2               Tissue code
                                          The tissue code from the TISSUE.CHR
                                           file for the observed pathology.

       11                   1               Lesion Distribution Code
                                            1 =  focal
                                            2 =  multifocal
                                            3 =  diffuse
                                            4 =  segmental
                                            5 =  diffuse, multifocal
                                            6 =  other
                                            7 =  not applicable, neoplastic lesion

       12                   2               Multiplicity code
                                           The number  of lesions described in Item
                                           9 above  for this tissue

       13                   1               Severity  Code
                                           As defined by the company and explained
                                           in TEXT.CHR

       14                   1               Lesion Disposition Code
                                            1 =  Lesion present, primary cause of
                                                 death
                                           . 2 =  lesion  present,  contributory cause
                                                 of death

                                       14

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FORMAT FOR PATH.CHR (continued')

	Item	Field Length	Description	

                                             3 =  Lesion present, could not be
                                                  determined if cause of death
                                             4 =  Lesion present, not cause of death
                                             5 =  Lesion present, cause of death
                                                  determination  not attempted
                                             6 =  Not a lesion
Items 9-14 would be repeated for as many distinct pathology observations in Item 10
Field Count.  For  example, if the  value if Item 8 was  5,  indicating  5 pathology
observations were to be described, there would be 5 sets of Items 9-14 to describe these
5 observations.
                                        15

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FORMAT FOR BODYWT.CHR   Body Weight Data

This file contains individual animal body weight information.

     Item          Fieli Length	Description
1-6
7
8
9
10
11
Header record (see page 11)
8
10
3
3
10
Animal number
Dose value
Number of Distinct
Observations
Time of observation
Body weight - body


Time Periods
in Days
weight for time


of

in
                                         Item 10.
Items 10 and 11 would be repeated  for every time period in Item 9. Example, body
weight data for one year collected once a month would result in 12 pairs of time and
body weight data.  The value of Item 9 would be 12.
                                      16

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FORMAT FOR FQQDCS.CHR  Food Consumption Data

This file contains individual animal food consumption information.

	Item	Field Length	Pescription	

      1-6                                 Header record (see page 11)

       7                 8                Animal number

       8                10                Dose value

       9                 1                Multiple Caged Animals code for food
                                          consumption based on individual animal
                                          values or cage averages.
                                           1 =  values are individual animal food
                                                consumptions.
                                           2 =  values are cage averages.

      10                 3                Number of  Distinct  Time  Periods  of
                                          Observation

      11                 3                Time of observation in Days

      12                10                Food Consumption - food consumption for
                                          time in Item 11.
Items 11 and 12 would be repeated for every time of food consumption data. Example,
food consumption data for one year collected once a month would result in 12 pairs of
time and food consumption data.  The value of Item would be  12.
                                      17

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FORMAT FOR ORGANWT.CHR  Organ Weight Data

This file contains individual animal organ weight information.

     Item	Field Length	Description
1-6
7 8
8 10
9 10
10 3
11 2
Header record (see page 11)
Animal number
Dose value for treatment groups
Final Body Weight - for calculation
organ-to-body weight ratios.
Time of observation in Days
Organ Code - use the same codes
of
as
                                           defined in the TISSUE.CHR file

      12                 10                 Organ Weight - organ weight for organ
                                           coded in Item 11 and determined at time
                                           in Item 10.

      13                  1                 Bilateral Organ  Code
                                            1  = organ is not bilateral or weight is
                                                for  only one  of the two bilateral
                                                organs
                                            2  = organ is  bilateral  and weight is
                                                expressed as  combined weight of
                                                each organ

Items 11-13 would be repeated for each organ with one record per animal. If 10 organ
weight values are to reported, there  would 10 combinations of  time, organ code and
organ weight values.
                                       18

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FORMAT F QT? CJJNOBS.CHR Clinical Observations

This file contains individual animal clinical observations with one animal per  record.
This file contains information such  as animal appearance, animal activity, and palpable
masses.

	Item	Field  Length	Description

       1-6                                   Header Record (see page 11)

        7                  8                 Animal Number

        8                10                 Dose value

        9                  3                 Clinical  Observation  Field Count - the
                                            number   of   different  distinct  clinical
                                            observations for this animal by study end.

       10                80                 Clinical Observation Description

       11                  1                 Palpable/Not Palpable Mass Designation
                                             1 =  if description described in Item 10
                                                  above is a palpable mass
                                             2 =  if description in Item 10 above is
                                                  not a palpable mass

       12                  2                 Description Field Count - the  number of
                                            times the description in Item 10 above is
                                            recorded  for this animal.

       13                  8                 First Date Observed - date observation in
                                            Item  10  above   was  first   observed
                                            (MMDDYYYY)

       14                  8                 Last Date Observed - date observation in
                                            Item  10  above   was  last   observed
                                            (MMDDYYYY)

The dates in Items 13 and 14  above are used to describe  a continuous time period
during which a specific clinical observation was observed. If the observation was observed
for only one week then only the  date the observation was first observed (Item 13 above)
would be completed with the date last observed (Item 16) remaining blank.  There are
as many pairs of Items 13 and 14 as there are field counts in  Item 12. Items 10-14 would
be repeated for as many  distinct  pathology observations in Item 11, Clinical Observation.
Field  Count. For  example, if  the value  if  Item 11  was  5, indicating  5 pathology
observations were to be described, there would be 5 combinations  of Items 12-16 to
describe these 5 distinct  types of clinical observations.

                                        19

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FORMAT FOR HEMATO.CHR Hematology Data

This file contains individual animal hematology data with one record per animal.

	Item	Field Length	Description	

      1-6                                 Header Record (see page 11)

       7                 8                Animal number

       8                10                Dose value

       9                 2                Number of Measurements - maximum
                                          number   of  hematology   parameters
                                          measured  in  each animal.  This value
                                          describes the  number of measurements
                                          beginning  with  Item   12.    Certain
                                          parameters listed below are required while
                                          others are  optional.  Other parameters
                                          not listed below  may also be included.
                                          Additional parameters are to be described
                                          in  TEXT.CHR.  A default  value of  6
                                          should be used when the six required
                                          measurements below are reported.

      10                 3                Number of  Distinct Time  Periods  of
                                          Observations

      11                 3                Time of observation in Days
                          •
      12                10                Hematocrit (%)

      13                10                Hemoglobin (g/d)

      14                10                Leukocyte  count (xlO3)

      15                10                Erythrocyte count (xlO6)

      16                10                Platelet count (xlO3)

      17                10                Leukocyte  differential count  (%)

      18                10                *Plateletcrit (%)

      19                10                *Mean corpuscular Hb (pg)

      20                10               . "Mean corpuscular Hb concentration (g/d)

                                      20

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FORMAT FOR HEMATO.CHR  ^continued')
	Item	Field Length	Description	
      21                 10                "Mean corpuscular volume  (MM3)
      22                 10                'Reticulocyte  count (%RBC)
      23                 10                •Thromboplastin time (seconds)
      24                 10                'Clotting time (seconds)
      25                 10                *Prothrombin time (seconds)

Items 11 through  25 would be repeated for  every  time period of hematology data
collection Example, hematology values measured at 3,6, and 9 months would result in 3
sets of items 11 through 25 as one record.  The value of Item 10 would be 3.
* not generally required for chronic studies
                                      21

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FORMAT FOR CLINCHEM.CHR   Clinical Chemistry

This file contains individual animal clinical chemistry data with one record per animal.

	Item   	Field Length	Description	

      1-6                                 Header record (see page 11)

       7                 8                Animal number

       8                10                Dose value

       9                 2                Number of Measurements  - maximum
                                          number of clinical chemistry parameters
                                          measured  in  each animal. This value
                                          describes the  number  of measurements
                                          beginning  with  Item 12.    Certain
                                          parameters listed below  are required
                                          while   others  are   optional.   Other
                                          parameters not listed below may  also be
                                          included.  Additional parameters  are to
                                          be described in TEXT.CHR. A default
                                          value  of 14 should be used when only
                                          the 14 required measurements below are
                                          reported.

      10                 3                Number of  Distinct  Time Periods  of
                                          Observations

      11                 3                Time of observation in Days

      12                10                Calcium (mg/d)

      13                10                Chloride (mg/d)

      14                10                Phosphorous (mg/d)

      15                10                Potassium  (mg/d)

      16                10                Sodium (mg/d)

      17                10                Albumin (g/d)

      18                10                Blood urea nitrogen (mg/d)

      19                10                Glucose (mg/d)
                                      22

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FORMAT FOR CLINCHEM.CHR (continued)
Item
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Field Length
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Description
Blood creatinine (mg/d)
Cholesterol (mg/d)
Total serum protein (g/d)
Creatine phosphokinase
(u/d)
Serum alanine aminotransferase (SGPT)
(u/d)
Serum aspartate
aminotransferase SCOT) (u/d)
•Magnesium (mg/d)
•Triglyceride (mg/d)
•Total bilirubin (mg/d)
•Alkaline phosphatase (u/d)
•Cholinesterase (u/d)
•Lactic acid dehydrogenase (u/d)
•gamma glutamyl transferase (u/d)
•Glutamate dehydrogenase (u/d)
*alpha-l-globulin (g/d)
•alpha-2-globuUn (g/d)
•beta-globulin (g/d)
•gamma-globulin (g/d)
Items 11-37 would be repeated for every  time  of  clinical chemistry data collection.
Example, clinical chemistry values measured at 3,6, and 9 months would result in 3 sets
of items 12-37 as one record.  The value of Item 10 would be 3.
• not generally required for chronic studies.

                                      23

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FORMAT FOR URINAL.CHR Urinalysis Data

This file contains individual animal urinalysis data with one animal per record.

	Item	Field Length	Description      	

      1-6               10                Header record (see page 11)

       7                 8                Animal number

       8                10                Dose value

       9                 2                Number of Measurements  - maximum
                                          number   of    urinalysis   parameters
                                          measured  in each animal.  This value
                                          describes the  number of measurements
                                          beginning  with  Item  12.      Certain
                                          parameters listed  below are  required
                                          while   others   are   optional.   Other
                                          parameters not listed below  may also be
                                          included.  Additional parameters are to
                                          be described in TEXT.CHR. A default
                                          value of nine should be used when only
                                          the nine  required measurements below
                                          are reported.

      10                 3                Number of  Distinct Time  Periods  of
                                          Observations

      11                 3                Time of observation in Days

      12                10                Volume (ml)

      13                10                Specific gravity

      14                 1                Protein
                                           0  = measurement   performed,   not
                                                present
                                         1-8  = values for possible grading scale.
                                                Scale to be described in
                                                TEXT.CHR
                                           9  = measurement not performed

      15                 1                Glucose
                                           0  = measurement   performed,   not
                                                present
                                         1-8  = values for possible grading scale.

                                      24

-------
FORMAT FOR URINAL.CHR (continued*!

	Jtem	Field Length            Description	

                                                Scale to be described in
                                                TEXT.CHR
                                           9  = measurement not performed
      16
       17
       18
       19


       20

       21

       22
25


25

10

10
 Ketones
 0  = measurement   performed,   not
      present
1-8  = values for possible grading scale.
      Scale to be described in
      TEXT.CHR
 9  = measurement not performed

 Bilirubin
 0  = measurement   performed,   not
      present
1-8  = values for possible grading scale.
      Scale to be described in
      TEXT.CHR
 9  = measurement not performed

 Blood
 0  = measurement   performed,   not
      present
1-8  = values for possible grading scale.
      Scale to be described in
      TEXT.CHR
 9  = measurement not performed

 Sediment (microscopic) -  description of
 finding

 Appearance - description of finding

 *PH

 •Nitrate
 0  = measurement   performed,   not
      present
1-8  = values for possible grading scale.
      Scale to be described in
      TEXT.CHR
 9  = measurement not performed
                                      25

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FORMAT FOR URINAL.CHR (continued^

	Item	Field Length	Description	

      23                 10                'Urobilogen
                                            0  = measurement   performed,    not
                                                 present
                                          1-8  = values for possible grading scale.
                                                 Scale to be described in
                                                 TEXT.CHR
                                            9  = measurement not  performed
Items 11-23 would be repeated for every time of urinalysis data collection.  Example,
urinalysis values measured at 3, 6 , and 9 months would result in 3 sets of item 11-23
as one record.  The value of Item 10 would be 3.

* not generally required for chronic studies
                                       26

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FORMAT FOR PATHGLOS.CHR

Optionally, this file can be provided  by the company if they do not wish  to use the
default NTP SNOP codes, which exist as a file with this format.  Each Pathology Code,
Pathology Description and Tissue Code  occur as one record.

	Item	Field Length	Description  	

      1-6                                  Header record (see page 11)

       7                 16               Pathology Code

       8                 100               Pathology description corresponding to
                                          the pathology code

       9                  2               Tissue Code -  from the list provided by
                                          the submitter in TISSUE.CHR as default
                                          NTP  codes.
                                      27

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FORMAT FOR TISSUE.CHR

Optionally,  this file can be submitted by the company if they do not wish to use the
default NTP tissue codes, which exist as a file with this format. Each Tissue Code and
Tissue Description occur as one record.
Item
1-6
7
8
Field Length
2
100
Description
Header record (see page
Tissue Code
Tissue Description

10)
If a company submits its own list of Tissue Codes, a PATHGLOS.CHR file must also
be submitted with the correct tissue codes.  This is true even if the company uses the
NTP SHOP Codes for pathology .
                                      28

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FORMAT FOR TEXT.CHR
This file would contain any optional individual animal data that the company wished to
provide on an individual animal basis. The format for this file  would be structured but
can vary in format and would have to be submitted by the company.  This file could
contain a variety of different information.  It would contain any additional data that the
company wished to submit to support their  position that is not  provided for in these
formats, including  any codes used to qualify  the data.  This file would also  be used to
explain any optional codes for data in these formats, i.e., additional codes  for  animal
dispositions as described in ANIMAL.CHR Items 21.  This file would also  be used to
describe in narrative form any peculiarities in the study as well as descriptions of gross
pathology observations. It is to be used by each respective Agency as needed. It is also
possible to  have  multiple  TEXT.CHR files  with  names  such   as  TEXT1.CHR,
TEXT2.CHR, etc.

This file must also contain a list of the files  being submitted with this package, i.e, the
ten files containing  data from the chronic/oncogenicity  study, the  two optional files
containing the NTP Tissue codes and the NTP SNOP codes, and any TEXT.CHR files.
This file must begin with the 'header record'.  In addition, this file must also contain a
description of the  experimental design of the study including any satellite groups.
                                       29

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                        DETAILED FIELD DESCRIPTIONS
This section provides  the detailed descriptions of the data files described above.  A
definition of each field is provided.  When using these descriptions it should be kept in
mind that each file  is made of a number of data records with one record per animal,
with the exception  of the 'header record', one record  at the beginning of  each file
(except INDEX.CHR) that contains background information from the study and is used
as the logical link between all data files for a  study.
                                      30

-------
INDEX.CHR

1.     Record Type  - This is a one character field used to denote if the data in this
      file is in fixed  or variable format. A fixed record format is designated  with an
      'F.   A variable record format  is designated  with  a 'V.  For variable length
      records a '#' is used to  indicate the end of a  field.   For files  submitted  in
      variable length formats, the field length in characters described below would not
      be used.   Instead the field would  contain as many characters  as needed  to
      display  the value of the field, with the '#' symbol denoting the end of the field.
      The next field would then  begin with the next  position.  Under the  variable
      length format, a field that is not used is represented by '##' to indicate  that the
      field  is empty.   A '$' would  be used to indicate  the end of a record.   An '$$'
      would be used to indicate the  end of a file.   Under the fixed format, the
      required number  of columns must  remain vacant to describe a field that  is
      empty.

2.    Chemical Name 1 - A 200 character field for the chemical name.

3.    Chemical Name 2 - A 100 character field for the chemical name.  This field is
      used  for synonyms or alternative names to the chemical in Item 2  above.

4.    Study Type Description -  A 100 character field for a  description of the study
      type (i.e., chronic/oncogenicity bioassay).

5.    Study Sponsor  -  A 100 character field for the name of the company sponsoring
      the study.

6.    Study Beginning Date - The  date on which the study began (i.e., dosing began)
      in the form MMDDYYYY  in which MM is a two-digit  number for .the month,
      DD is a two-digit  number for the day, and YYYY is a four-digit number for the
      year. The date January 15, 1989, would be represented as 01151989.

7.    Study Ending Date -  The date  on  which the study ended (i.e., the last animal
      was sacrificed) in  the form MMDDYYYY. The date December 20, 1991, would
      be represented as 12201991.

8.    Conducting Laboratory -  A 100 character field for the  name of the laboratory
      at which the study was conducted.

9.    Animal Species -  A 50 character  field for  the  species of animal used in the
      study.

 10.   Animal Strain  -  A 50 character field for the strain of animal used in the study.

 11.    Source of Animal -  A 100 character field for the source of
       the animals for the study including address and location.
                                        31

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INDEX.CHR (continued')

12.   Study Identification Code 1 -   A fifteen character code used for a study code
      provided by the laboratory conducting the study.

13.   Study Identification Code 2 -   A fifteen character code used for a study code
      provided by the study sponsor.  This may be a different number than Study
      Identification Code  1 if the study was not performed at the sponsor's laboratory.

14.   Study Identification Code 3 •   A fifteen character code used as a code by the
      Agency reviewing the data. This code will be added to the file by the reviewing
      Agency and should  be  submitted blank.

15.   Pathologist - A 50 character field for the study pathologist.

16.   External Peer Review -   A one character field indicating  if an  outside peer
      review has been performed on the study.  A T indicates no external peer review
      has been conducted. A '2' indicates  that a peer review has been conducted.

17.   Route of  Administration -   A  50  character  field  to describe  the  how the
      chemical was administered to the animals in the study, i.e., dermal, oral,  dietary.

18.   Days  of Dosing -  A two character field for  the number of days per week the
      animals were dosed. A feeding in which animals were administered the chemical
      in their diet would be indicated by a value of '7', indicating the animals were
      dosed each day of the week.  A dermal injection in which animals were dosed
      twice  a week by injection would be indicated  by a value of '2'.

19.   Dose  Unit Code -  A  two digit field used to describe the dosing units.  For A
      value  of T is used to  indicate dosing in ppm, a value of '2' is used to indicate
      dosing in mg/kg.  Other  dosing unit codes can be used and should be described
      in TEXT.CHR.

20.   Dosing  Regimen  -   A 240 character field  for the  description of the dosing
      regimen and provides the doses used for the study.  This field is also used to
      describe changes in the dosing pattern or peculiarities in the dosing regimen. For
      example, a study with a vehicle control,  a  positive control, and two  treated
      groups may be described  as 'VEHICLE CONTROL, POSITIVE CONTROL, 100
      PPM, and  1000 PPM DOSE GROUPS OF 50 ANIMALS'.

21.   Number of Dose Groups  - a two digit field used to indicate the  number  of dose
      groups in the study.

22.   Number of Animals per Dose Group by Study Design - a three digit, field used
      to indicate the  number animals in each  dose group. Each value is treated as a
      separate field with as many fields as  the value of Item 21  above.
                                       32

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INDEX.CHR (continued*)

23.   Number of Satellite Groups - a two  digit field used to indicate the number of
      satellite groups used in the study.

24.   Number of Animals in each Satellite Group - a three digit field used to indicate
      the number gui'm^k in each satellite group.  Each value is treated as a separate
      field with as many fields as the value of Item 23 above.

25.   Number of Animals per Cage - a  two digit field used to indicate the number of
      animals to each cage by study design.

26.   Sex - A one character field indicating  the sex of the animals  under  study.  A
      value of 'M' is used  to designate males;  an 'F is used  to designate females.
      Each  sex will have a separate set  of STUDIES files.

27.   PATHGLOS.CHR File Code - A six character field to indicate which pathology
      glossary file is being used for  pathology descriptions.  This field is assigned by
      the Agency after approval of  the pathology glossary, and includes a two-digit
      code identifying the Agency, a  two-digit code identifying the company submitting
      the glossary, and  a  two-digit  code identifying  the version of the code.  For
      example,  a pathology glossary file  code  of 010203  may  indicate  a glossary
      approved  by the US  EPA (01) by Company X  (02) as the third  glossary (03)
      approved for that company.  Specific glossary file codes are the responsibility of
      the Agency to which the data are  submitted.   The  default PATHGLOS.CHR
      Code File is the NTP SHOP codes.

28.   File Version Date -  An eight character field in the  form MMDDYYYY (see
      description in  6 above) used to indicate the date the current file of data is being
      submitted.

29.   Number  of Tissues Examined -   A  three character  field  used to indicate the
      number of tissues  examined for pathology  observations. The value of this field
      is the same as the number of  pairs of  Tissue Examination Codes and Autolysis
      Codes in ANIMAL.CHR.

30.   TISSUE.CHR File Co4g - A six character field used to designate the tissue code
      file which provides  the codes for  each tissue  examined in the  study.   The
      structure of this field is the same as  the PATHGLOS.CHR File Code.  The
      default file is the  NTP  Tissue Codes in Appendix  A. If a company  submits its
      own list of Tissue  Codes, a PATHGLOS.CHR file  must also be submitted with
      the associated tissue  codes.  This is true even  if  the company uses the NTP
      SNOP Codes for pathology .

31.   Body Weight  Unit Measurement - the  unit of measurement of the body  weight
      data where, M = milligrams (mg), G = grams (g),  and K  = kilograms (kg).
                                       33

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INDEX.CHR (continued)

32.    Food  Consumption Unit Measurement - the unit of measurement of the food
      consumption data where, M =  milligrams (mg),  G  = grams  (g),  and K =
      kilograms (kg).

33.    Organ Weight Measurement Unit - the unit of measurement of the food organ
      weight data where, M = milligrams (mg),  G = grams (g), and  K = kilograms
      (kg).
                                     34

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ANIMAL.CHR

1-6.  "        Header Record - The first record of the file is the  header record which
             contains 6  fields from the  INDEX.CHR file.   This record is the first
             record of all subsequent files associated with this study.  It serves as the
             method of identification of all files associated with this study. Since every
             study  contains an ANIMAL.CHR file and the information is  unique to
             that study, the information in the  header record is used to identify a study
             and all files submitted with it.

The  remaining records contain specific lexicological data with one record per animal.
Thus a file for an animal study with 240 animals would have 241  records including the
header record.

 7.    Animal Number - An  eight  character  field for the  unique identifier of  each
       animal T

 8.    Animal Necropsy Number - A twelve  character field for the unique identifier of
       each animal  used in the necropsy process.  This field  would  be  used  in  a
       situation  when the  necropsy  number  is different from  the  animal number;
       otherwise it would remain blank.

 9.    Dose  Value  - A  ten  character field for the dose value  administered  to the
       animal. Control groups should also be coded.

10.    Dose  Treatment - A one character field containing a code for dose  treatment.
       The codes are as  follows:
                    1 =  untreated controls
                    2 =  vehicle controls
                    3 -  positive controls
                    4-8 = optional groups
                    9 =  animal was treated

       Codes 1-3 are used to identify the type of control used in  the  study.  Values of
       4-8 are used  to identify other types of controls.   A value of 9  is used when the
       animal is a treated animal.

11.    Hematology Evaluation Code - A one  character  field to indicate if  the animal
       was part of the hematology evaluation. A value  of 1  is used  to indicate 'Yes',
       and a value of 2 is used to indicate 'No'.

12.    Clinical Chemistry Evaluation Code - A one character field to  indicate if the
       animal was part of the clinical  chemistry evaluation.  A value of 1  is used to
       indicate 'Yes', and a value of 2 is used  to indicate 'No'.

13.    Urinalysis Evaluation Code - A one character  field to  indicate  whether the
       animal was part of the urinalysis evaluation.  A value of 1  is used to indicate

                                        35

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ANIMAL.CHR (continued^

      'Yes', and a value of 2 is used to indicate 'No'.

14.    Date  Dosing Started  - The date dosing began in each animal  in the format
      MMDDYYYY  (see Item  6 in  the  INDEX.CHR  detailed  field description for
      format).

15.    Date  Dosing Ended - The date  dosing ended  for each animal  in the format
      MMDDYYYY (see  Item 6 in the INDEX.CHR detailed descriptions for format).

16.    Date  of Death  - The  date  each animal  died in the format  MMDDYYYY (see
      Item 6 in the INDEX.CHR detailed instructions).

17.    Interval between date  dosing started and date dosing ended -The time interval in
      days that has elapsed  between the date  dosing started for each animal and the
      date that dosing ended.

18.    Interval between date  dosing started and date animal died - The time interval in
      days that has elapsed  between the date  dosing started for each animal and the
      date each animal died.

19.    Animal Disposition  -  A one character value for a code describing the  type of
      death or final condition of each animal.  The codes to be used are as follows:
                  1  = Death on Study
                  2  = Interim Sacrifice # 1
                  3  = Interim Sacrifice # 2
                  4  = Interim Sacrifice # 3
                  5  - Terminal Sacrifice
                  6  = Missing Animal
                  7  = Accidental kill animal
                  8  = Moribund sacrifice
                  9 or greater = optional disposition

      A value of 1 is used to describe animals that are  found dead during the course
      of the study apparently of natural causes and no intervention.  A  value of 2-4 is
      used to indicate animals that were  sacrificed  as part of a scheduled kill other
      than a terminal sacrifice.  These codes  allow up to 3 such sacrifices.  If greater
      than three interim sacrifices are scheduled a value of 9 or  greater is used.  A
      value of 5  is used to  indicate animals that are  sacrificed as  part of a scheduled
      sacrifice  at the  termination of the study.  A value of 6  is used to indicate
      animals that become  missing during the course of the  study.  A value of 7 is
      used for animals that  are accidentally killed during the study.  A value of 8
      is used for animals  that are sacrificed in a moribund condition or in extremis.
      Values of 9 and greater are use for animals that die from conditions other than
      those described by codes 1 through 8. (If these values of 9  or greater are used,
      the descriptions associated with  each code is to be submitted in TEXT.CHR.

                                       36

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ANIMAL.CHR (continued')

20.    Cage Identification - A ten character field for an animal cage identification.

21.    Ever Examined Code - A one character field used to indicate if any tissues from
       an animal were ever examined for pathological events.  A value of 1 is used to
       indicate that at least one tissue was examined. A value of 2 is used to indicate
       that no tissues were examined.

22.    Tissue Examination Code - A one character field used to  indicate if a particular
       tissue was examined for pathological events.  A value of 1 is used to indicate the
       tissue was examined and was suitable for evaluation, a  value of 2 is used to
       indicate the tissue was examined but was unsuitable for evaluation, or a value of
       3  is used to indicate that the tissue was not analyzed.

23.    Number of Tissue  Sections  - A two  digit field for the  number  of sections
       examined for that tissue.

24.    Number of Slides  Prepared - A two digit  field  for the  number of slides that
       were prepared for examination.  It is assumed that all prepared slides will be
       examined.

25.    Autolvsis Code - A one  character fields used to indicate  the autolysis condition
       of the tissue being examined.  A value of 1 is used to indicate  that the tissue
       was at least partially autolyzed.  A  value of 2 is used to indicate that the tissue
       was not autolyzed.  A value of 3  is used to  indicate that the tissue is designated
       not applicable  because  it was not  examined.   In this situation  the Tissue
       Examination Code in 22  above must have a value of 3.

       There are as  many combinations of Items 22 through 25  as  there are number of
       tissues to be examined as reflected  in Item 29 of INDEX.CHR.
                                        37

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PATH.CHR

1-6.         Header Record - The first record of the file is the header record which
            contains 6 fields from the INDEX.CHR  file.  This  record is the first
            record of all subsequent files associated with this  study.  It serves as the
            method of identification of all files associated with this study. Since every
            study contains an ANIMALCHR file and the information is unique to the
            study, the information in the header record is used to identify the study
            and all  files submitted with it

The  remaining records contain specific lexicological data with  one  record per animal.
Thus a file for an animal study with 240 animals  would have 241 records including the
header record.

 7.    Animal Number - An  eight  character field for the unique identifier  of  each
      animal.

 8.    Field Count  -  A  3 character field  for indicating the distinct number  of
      pathological observations for the  animal. For example, if 15 different lesions are
      coded and described, this value  would be  15.  It will vary between animals as
      the number of pathological observations varies.

 9.    Pathology Code - A 16 character code for  the pathological condition observed in
      the  animal   These are  described in the  PATHGLOS.CHR  file which is
      identified  by Item 27, PATHGLOS.CHR File Code, in the INDEX.CHR file.

10.    Tissue  Code - A  two  character field for the tissue in which  the  pathology
      observation coded in Item 9 above  is found.   These are described in the
      TISSUE.CHR  file which is identified by Item 30, TISSUE.CHR File Code in the
      INDEX.CHR file.

11.    Lesion Distribution Code - A one digit field to describe the distribution of the
      pathology  observation coded in Item 9 above. The codes are  as follows:
                         1 =   focal
                        2 =   multifocal
                        3 =   diffuse
                        4 =   segmental
                        5 =   diffuse, multifocal
                        6 =   other
                        7 =   not applicable, observation is a neoplastic lesion

      If a code  of '6'  is used to indicate  the lesion distribution is different from the
      available codes, the additional codes should be described in TEXT.CHR.

12.    Multiplicity Code - A  two digit field to  describe  the  occurrence of multiple
      lesions.  It is the number of the  same type of lesion found in the tissue.
                                       38

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PATH.CHR fcnntimied'l

13.    Severity Code - A one character field to describe the severity of the pathological
      observation.   If used, the codes  for  this field are  to be described  in the
      TEXT.CHR file.

14.    Lesion Disposition Code - A one character field  to describe the condition of
      the observed lesion.  The codes are as follows:
                   1 =  Lesion present  and the lesion is the primary  cause of death
                         of the animal
                   2 =  Lesion present  and the lesion  is  a contributory cause of
                         death of the animal
                   3 =  Lesion present, but the relationship of the  lesion to the
                         cause of death  while attempted
                         could not be determined
                   4 =  Lesion present, but it did not cause the death of the animal
                   5 =  Lesion present, but the cause of death of the animal is not
                         attempted
                   6 =  The pathological observation is not a lesion.

      There are as many combinations of Items  9-14  as there are values of Item  8,
      Field Count.
                                        39

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BODYWT.CHR

This file contains the individual body weights of the animals in the study.

1-6.          Header Record - The first  record of the file is the header record which
             contains 6 fields from the INDEX.CHR  file.   This  record  is the first
             record of all subsequent files associated with this study.  It serves as the
             method of identification of all files associated with this study.  Since every
             study contains an ANIMAL.CHR file and the information is unique to the
             study, the  information in the header record  is used to identify the study
             and all files submitted with it.

The remaining records contain specific lexicological  data  with  one  record  per animal.
Thus a file for an animal study with 240 animals would have 241 records including the
header record.

 7.    Animal  Number  - An eight  character field for the unique  identifier  of each
       animal.

 8.    Dose Value for Treatment Groups -  A ten character  field  for the dose value
       administered to the
 9.   Number of Distinct Time Periods of Observations - A three digit field for the
      number  of different time  periods  for  which body weight values are  to  be
      reported.

10.   Time of Observation - A three character field for the time  for which the body
      weight value in Item 11 below is associated.  This value  must be in days.

11.   Body Weight Value - A ten character field for the body weight of the animal for
      the time in Item 10 above.

      Items  10 and  11 are repeated for every time for which body weight  data are
      presented.  If  the value of Item 9 is  12 indicating that  12 sets of body weight
      values are to be reported, there would be 12 sets of Items 10 and 11.
                                        40

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FOODCS.CHR

This file contains the individual food consumption of the animals in the study.

1-6.          Header Record - The first record of the file is the header record which
             contains 6 fields from the  INDEX.CHR file.   This record is  the  first
             record of all subsequent files associated with this study.  It serves as the
             method of identification of all files associated with this study.  Since every
             study contains an ANIMAL.CHR file and the information is unique to the
             study, the  information in the header record is used to identify the study
             and all files submitted with it.

The remaining records contain specific lexicological data with  one record per animal.
Thus a  file for an animal study with 240 animals would have 241 records including the
header  record.

 7.    Animal Number  - An eight character  field for the unique  identifier of each
      animal.

 8.    Dose Value  for' Treatment  Groups - A ten character field for the dose value
      administered to the animal.

 9.    Multiple Caged Animal - A one digit code  to indicate if the food consumption
      values are based on  individual animal measurements or on cage averages.  A
      value of T indicates food consumption values are for individual animals, a value
      of '2' indicates that values are based an cage averages.

10.    Number of Distinct Time Periods  of Observations - A three digit field for the
      number of different time  periods for which food consumption values are to be
      reported.

11.    Time of Observation  - A three character field for the  time for which  the food
      consumption value in Item 12 below is associated.  This value  must be  in days.

12.    Food Consumption Value - A ten character field for the  food consumption value
      for the animal for the time in 11 above.

      Items  11  and 12 are  repeated for every time for which food consumption  data
      are presented.  If the value of Item  10 is 12 indicating that 12 sets  of food
      consumption values are to be reported, there would be 12 sets of Items 11 and
      12.
                                       41

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ORGANWT.CHR

This file contains the individual organ weight values of the animus in the study.

1-6.   Deader Record - The first record of the file is the header record which contains
      6  fields  from  the INDEX.CHR  file.   This record is the first record of all
      subsequent  files  associated with  this  study.   It serves as  the  method  of
      identification of all files associated with this study.  Since every study contains an
      ANIMAL.CHR file and  the information is  unique to the study, the information
      in the header record is used to identify the study  and all files submitted with it.

The  remaining  records contain specific lexicological data with one record per animal.
Thus a file for  an animal study with 240 animals would have 241 records including the
header record.

 7.    Animal Number - An eight character field  for  the unique  identifier of  each
      animal.

 8.    Dose Value for Treatment Groups - A ten  character field for the dose  value
      Administered to the animal.

 9.    Final Body Weight - A  ten digit field used for  the final body weight of the
      animal to be used in calculating organ-to-body weight ratios.

10.    Time of  Observation in Days - A three  character field for the  time for which the
      organ weight value in Item 12 below is associated. This value must be in Days.

11.    Organ Code - A  two character  code for  the organ.   This code must coincide
      with the  tissue codes  presented in the TISSUE.GHR file.

12.    Organ Weight - A ten character value for the organ weight  for the animal for
      the time in Item 10 and the organ in Item 11 above.

13.    Bilateral Organ Code  - A one character code indicating if the condition of the
      organ weight  for  bilateral  organs. Thie code is used to distinguish between
      weights for bilateral organs where the weight reported for one of the bilateral
      organs from where the weight reported is  the sum of both bilateral  organs. A
      code of  T is  used if the organ is not a bilateral organ or if one of a pair of
      bilateral organ weights is being reported.  A code  of '2' is used if  the  organ
      weight being  reported is bilateral and the combined weight of both organs is
      being reported.

      Items 10-13 are  repeated for every time for which  organ weight data are
      presented.
                                        42

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dJNOBS.CHR

This file contains information on the clinical observations made for each animal during
the course of the study.


1-6.   Header Record - The first record of the file is the header record which contains
      6 fields  from  the  INDEX.CHR file.   This record is the first record of all
      subsequent  files  associated  with this  study.   It serves as  the method  of
      identification of all files associated with this study.  Since every study contains an
      ANIMAL.CHR file and the information is unique to the study,  the information
      in the header record is used to identify the study and all files submitted with it.

The remaining records contain specific lexicological data with one record per animal.
Thus a  file for an animal study with 240 animals would have  241 records including the
header  record.

 7.   Animal  Number  -  An eight  character field for the  unique identifier of  each
      animal.

 8.   Dose Value ...for....Treatment  Groups  - A  ten character field for the dose value
      administered to the animal.

 9.   Clinical  Observation Field Count - A 3 character field  for indicating the distinct
      number  of  clinical observations for the  animal.  For example, if IS different
      clinical observations are coded and described,  this value would be 15.  It will
      vary between animals as the number of clinical observations varies.

10.   C]jnigaJiObservation Description - An 80 character field use for the description
      of the clinical  observation.

11.   Palpable Mass/Not Palpable Mass Designation - A one character field used to
      indicate  if the  description described in 12 is or  is not  a palpable mass.  This is
      used to  indicate  palpable masses.   A value of T is  used to indicate that the
      observation is  a palpable  mass.  A value  of '2' is  used to indicate that the
      observation is  not a palpable mass.

12.   Observation Field Count  -  A  two digit  number to  indicate if how  many
      observation periods described in Item 10 are to be recorded for this animal.

13.   First Date  Observed - the  date the clinical observation in 15  above was first
      observed in the MMDDYYYY format

14.   Last Date  Observed - the  date the clinical observation in  15 above was last
      observed.  The dates in Items 13 and 14 are used to describe a continuous time
      period   during which a specific  clinical  observation  was  observed.  If the
      observation was observed for only one week then only the date  the observation

                                        43

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CLINOBS.CHR (continued^

      was first observed (Item  13 above)  would be  completed  with the date last
      observed (Item 14) remaining blank.   There are  as many pairs  of Items 13 and
      14  as there are field counts in Item 12.

      Items  11-14 would be repeated for as many distinct  pathology observations  in
      Item 9 Clinical Observation Field Count. For example, if the value if Item  13
      was 5, indicating  5 pathology observations were to be  described, there would  be
      5 combinations of Items 11-14 to describe these 5 observations.
                                       44

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HEMATO.CHR

This file contains information on hematology parameters.

1-6.          Header Record - The first record of the file is the header record which
             contains 6 fields from the INDEX.CHR file.   This record is  the  first
             record of all subsequent files associated with this study.  It serves as the
             method of identification of all files associated with this study.  Since every
             study contains an ANIMAL.CHR file and the information is unique to the
             study, the  information in the header record is  used to identify the study
             and all files submitted with it.

The remaining records  contain specific lexicological data with one record per animal.
Thus a file for an animal study with 240 animals would have 241 records  including the
header record.

 7.    Animal  Number  -  An eight character  field for the  unique identifier  of  each
       animal.

 8.    Dose Value for  Treatment Groups - A ten character field for the dose value
       administered to the animal.

 9.    Number of Measurements - A two digit field used for the maximum number  of
       hematology parameters  per animal  being reported  in  this  file.   Fourteen
       parameters are listed below in Items 13-26.  If all  of these parameters were
       measured in each animal the value of his field would  be 14.  A default value  of
       8 should be used for the 8  required measurements.  Certain of the parameters
       below may be optional for chronic studies (indicated by an asterisk).

10.    Number of Distinct Time Periods of Observations - A three digit field for the
       number of different  time  periods  for which  hematology values  are to be
       reported.

11.    Time  of Observation - A three  character field  for the  time for which the
       hematology parameters items below is associated.  This value must be in days.

12.    Hematocrit - the value is expressed as a percentage (%).

13.    Hemoglobin - the value is  expressed in g/dl.

14.    Leukocyte Count - the value is expressed in xlO3.

15.    Ervthrocvte Count -the value is  expressed in xlO6.

16.    Platelet - the value is expressed in xlO3.

17.    Leukocyte Count - the value is expressed in percentage (%).

                                       45

-------
18.    Plateletcrit - the value is expressed in percentage (%).

19.    Mean Corpuscular Hb - this value is expressed in picograms
      (Pg).

20.    *Mean corpuscular Hb concentration - this value is expressed in g/d.

21.    *Mean Corpuscular Volume - this value is expressed in MM3.

22.    *Reticulocyte Count - this  value is expressed as percent red blood cells.

23.    *Thromboplastin Time - this value is expressed in seconds.

24.    *Clotting Time - this value is expressed in seconds.

25.    *Prothrombin Time this value is expressed in seconds.

Items 11  through 25 would be  repeated  for  every time  period of hematology data
collection with  one record per animal.

* not generally required for chronic studies
                                        46

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CLINCHEM.CHR

This file contains information on clinical chemistry parameters.

1-6.   Header Record - The first record of the file is the header record which contains
      6 fields from  the  INDEX.CHR file.  This record  is the  first record  of  all
      subsequent  files  associated  with this study.    It  serves  as the  method  of
      identification of all files associated with this study. Since every study contains an
      ANIMAL.CHR file and  the information is unique to the  study, the information
      in the header record is used to identify the study and all files submitted with it.

The remaining records the file contain  specific lexicological data with one record per
Animal.   Thus a file for an animal study with 240 animals would have 241 records
including the header record.

 7.   Animal  Number  - An eight  character field for the unique  identifier of each
      animal.

 8.   Dose Value for Treatment Groups  - A ten character field  for  the dose value
      administered to the animal.

 9.   Number of Measurements - A two digit field used for the maximum number of
      clinical chemistry parameters per animal being reported in this file. Twenty-six
      parameters are listed  below in Items  12-37.  If all of these parameters were
      measured in each animal the value of his field would be 26.   A default value of
      14 should be used for  the 14 required measurements. Certain of the parameters
      below may be  optional for chronic studies (indicated by an asterisk).

10.   Number of Distinct Time Periods of Observations - A three digit field for the
      number of different time periods for which  clinical chemistry values  are to be
      reported.

11.   Time of Observation in Days - A three character field for the time for  which the
      clinical chemistry parameters  items below is associated.   This value must be in
      days.

12.   Calcium - this value is expressed in mg/d.

13.   Chloride - this value is expressed in mg/d.

14.   Phosphorous - this value is  expressed in mg/d.

15.   Potassium - this value is expressed in mg/d.

16.   Sodium - this value is expressed in mg/d.

17.   Albumin - this value is expressed in g/d.

                                        47

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CLINCHEM rHR  fcontinued^

18.    Blood Urea  Nitrogen - this value is expressed in mg/d.

19.    Glucose - this value  is expressed in mg/d.

20.    Blood Creatinine - this value is  expressed in mg/d.

21.    Cholesterol - this value is expressed in mg/d.

22.    Total Serum Protein - this value is expressed in g/d.

23.    Creatinine phosphokinase - this value is expressed in u/d.

24.    Serum Alanine Aminotransferase (SGPT) - this value is  expressed in u/d.

25.    Serum Aspartate Aminptransferase (SGOT) - this value  is  expressed in u/d.

26.    "Magnesium - this value  is expressed  in mg/d.

27.    *Triglyceride - this value is expressed in mg/d.

28.    'Total Bilirubin - this value is expressed in mg/d.

29.    'Alkaline phosphatase - this value is expressed in u/d.

30.    * Cholinesterase - this value is expressed in u/d.

31.    ^Lactic Acid Dehydrogenase - this value is expressed in  u/d.

32.    'gamma - Glutamyl  Transferase - this value  is expressed in u/d.

33.    "Glutamate  dehydrogenase - this value is expressed  in u/d.

34.    *alpha-l-globulin - this value is  expressed in g/d.

35.    * alpha-2-globulin - this value is  expressed in g/d.

36.    *beta-globulin - this  value is expressed in g/d.

37.    * gamma-globulin - this value is expressed in  g/d.

Items  11  through  37 would be repeated  for every time of  clinical chemistry data
collection with one record per animal.

* not generally required for chronic studies


                                        48

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URINAL.CHR

This file contains information on urinalysis parameters.

1-6.          Header Record - The first record of the file is the  header record which
             contains 6 fields from the INDEX.CHR file.   This record is the first
             record of all subsequent files associated with this study.  It serves as the
             method of identification of all files associated with this study. Since every
             study contains an ANIMAL.CHR file and the information is unique to the
             study, the  information in the header record is  used  to identify the study
             and all files submitted with it.

The remaining records contain specific lexicological  data with one record per animal.
Thus a  file for an animal study with 240 animals would have 241  records including the
header record.

 7.    Animal Number  - An  eight character field  for the  unique identifier of  each
      animal.

 8.    Dose Value  for Treatment  Groups - A ten  character field for the dose value
      administered to the animal,

 9.    Number of Measurements - A two digit field  used for the  maximum number of
      urinalysis parameters  per animal being reported in this file. Twelve parameters
      are listed below  in Items 12-23. If all of these parameters were  measured in
      each  animal  the value of his field would be 12.  This value should be used as
      the default value since these 12 measurements are required. A default value of
      9 should be used for the 9 required measurements.   Certain of the parameters
      below may be optional for chronic studies (indicated by an asterisk).

10.    Number of Distinct Time Periods of Observations - A three digit  field for the
      number of different time  periods  for which hematology values are  to  be
      reported.

11.    Time  of Observation - A three character  field  for the  time  for  which the
      urinalysis parameters  below is associated.  This value  must  be in  days.

12.    Volume - the volume of the urine is expressed in milliliters (ml).

13.    Specific Gravity - the value is expressed in g/g.

14.    Protein - A scaled coding system is used for this parameter depending  on the
      magnitude or the severity of the response. A value of '0* is used to indicate that
      while the measurement was performed, the parameter was not observed.  Values
      of T through '8' are  used to indicate the  magnitude  or the severity of the
      response.  A value  of '9'  is used to  indicate that  the measurement was not
      performed for that animal.  A description of the scale used is to  be provided in

                                       49

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URINAL.CHR (continued")
      TEXT.CHR.
15.   Glucose - A scaled coding system is used for this measurement  See 14 above
      for codes.
16.   Ketones - A scaled coding system is used for this measurement  See 14 above
      for codes.
17.   Bilirubin - A scaled coding system is used for this measurement  See 14 above
      for codes.
18.   Blood - A scaled coding system is used for this measurement  See 14 above for
      codes.
19.   Sediment - a 25 character  field used to  describe the microscopic sediment
      findings in urine.
20.   Appearance - a 25 character fields used to describe the appearance of the urine.
21.   *pH - a ten character field for the pH of the urine.
22.   'Nitrate - A scaled coding system is used for this measurement  See 14 above
      for codes.
23.   *Urobilogen  - A scaled coding  system is used  for this  measurement  See  14
      above for codes.
Items 12-23 would be  repeated for  every time of urinalysis  data collection with one
record per animal.
* not generally required for chronic studies
                                       50

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PATHGLOS.CHR

This file contains  codes and descriptions for each code for pathological observations.  A
default PATHGLOS.CHR has been established for submitters that do not provide their
own pathology file.  The default code is the National Toxicology  Program's Standard
Nomenclature of Pathology (SNOP).  Copies of these programs are included.

Alternatively, this file can be provided by the company if they do  not wish to use the
default NTP SNOP codes.  However, the submitted PATHGLOS.CHR file must be in
the format described below and must be approved by the agency to which the data are
being submitted.   It is  envisioned that a  file  approved by one agency would be
acceptable to all  other agencies using these formats.  This would provide consistency
between agencies and eliminate the need for submitters to supply each agency with  a
different  pathology coding scheme.   Once a file is approved, it will  be assigned  a
PATHGLOS.CHR File Code which is to  submitted with  the data  in Item 24  of
INDEX.CHR.

1-6.          Header Record - The first record of the file is the header record which
             contains 6 fields from the INDEX.CHR file.   This record is  the  first
             record of all subsequent files associated with  this study.  It serves as the
             method of identification of all files associated  with this study. Since every
             study contains an ANIMAL.CHR file and the  information is unique to the
             study, the information in the header record is used to identify the study
             and  all files submitted with it.

The remaining records contain specific lexicological data with  one record per animal.
Thus a file for an animal study with 240 animals  would have  241 records including the
header record.

 7.   Pathology Code - A 16  character field used for the pathology observation code.

 8.   Pathology Description - A 100 character field used for the pathology description
      associated with the Pathology Code  in 7 above.

 9.   Tissue Code - A  two character field for the tissue  code  associated  with the
      Pathology Code and Pathology Description in 7 and  8  above. These codes  must
      correspond with the code submitted in TISSUE.CHR or the default NTP Tissue
      Codes.
                                       51

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TISSUE.CHR

This file contains codes and  descriptions for each  tissue  examined in the study.   A
default TISSUE.CHR has been established for submitters that do have or do not wish
to provide their own tissue file.  The default code is the National Toxicology Program's
tissue list.  Copies of the file can be obtained from  each responsible agency.

 1-6.  Header Record - The first record of the file is the header record which contains
      6  fields from  the INDEX.CHR file.   This  record is  the first record of all
      subsequent files   associated  with  this  study.   It  serves as  the method  of
      identification of all files associated with this study. Since every study contains an
      ANIMAL.CHR file  and the  information is unique to the study, the information
      in the header record is used to  identify the study and all files submitted with it.

The remaining records  contain specific lexicological data with one record per animal.
Thus a file for an animal study with 240 animals would have 241 records including the
header record.

 7.   Tissue Code - A two character field for the tissue code.

 8.   Tissue Description - A 100  character field for the  tissue description associated
      with the tissue code in 7 above.
                                        52

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VII.  Data Submission Specifications

For the U.S. EPA, data is to be submitted only on 5.25 inch high density diskettes in
ASCII file format.  EPA would also prefer the use of the FIXED  format  data files.
Other  Agencies involved in this effort may allow a variety of  electronic  media for
electronic data submission.  Each agency should be contacted concerning its own media
specifications.
                                        53

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        APPENDIX A



List of Tissues and Tissue Codes
             54

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Code                       Tissue

  26                      Regional Lymph Node
  27                      Blood Smear
  28                      Skin
  29                      Mandibular Lymph Node
  30                      Mammary Gland
  31                      Salivary Gland
  32                      Thigh Muscle
  33                      Sciatic Nerve
  34                      Bone Marrow
  35                      Costochondral Junction Rib
  36                      Thymus
  37                      Larynx
  38                      Trachea
  39                      Lungs and Bronchi
  40                      Heart
  41                      Thyroid
  42                      Parathyroids
  43                      Esophagus
  44                      Stomach
  45                      Duodenum
  46                      Jejunum
  47                      Heum
  48                      Colon
  49                      Rectum
   50                     Mesenteric Lymph Nodes
   51                      Liver
   52                     Gall Bladder
   53                     Pancreas
   54                     Spleen
   55                     Kidneys
   56                     Adrenals
   57                     Bladder
   58           .           Seminal  Vesicles
   59                      Prostate
   60                      Testes
   61                      Ovaries
   62                      Uterus
   63                      Nasal Cavity
   64                      Brain
   65                      Pituitary
   66                      Eyes
   67                      External and Middle Ear
   68                      Spinal Cord
   69                      Other

                 55

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        APPENDIX B



List for SNOP Codes for Pathology
             56

-------