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SDF Download Page
FDAMDD: FDA Maximum (Recommended) Daily Dose
Database File
ogenic Potency Datab FDA Maximum(Recommended) Daily Dose Database
** Version 4b, updated 15 February 2008:
Includes 2 new summary activity fields (ActivityOutcome, ActivityScore) to coordinate with PubChem FDAMDD Assay deposits.
Includes new InChIKey Standard Chemical Field.
Description
New Users: For general information, see DSSTox Project Goals and About DSSTox. For additional information on DSSTox SDF (Structure Data Format) files and their use in Chemical Relational Databases, see More on SDF and More on CRDs.
Description: The Food and Drug Administration (FDA) Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Informatics and Computational Safety Analysis Staff's Maximum Recommended Daily Dose (FDAMDD) database contains values for over 1200 pharmaceuticals listed in Martindale: The Extra Pharmacopoeia (1973, 1983, and 1993) and The Physicians' Desk Reference (1995 and 1999). Most of the maximum recommended daily dose (MRDD) values in the database were determined from pharmaceutical clinical trials that employed an oral route of exposure and daily treatments, usually for 3-12 months. The pharmaceuticals were given as single or divided dose treatment regimens to achieve desired pharmacological effects. In contrast, roughly 5% of the pharmaceuticals in the FDAMDD database were antineoplastics and anesthetics and were administered intravenously and/or intramuscularly. When separate MRDDs were reported for different routes of exposure, only the oral MRDD was included in the database. In addition, some pharmaceuticals have different MRDD values for male and female adults, children, or elderly patients. In this situation, only MRDD values for the average adult patient were used. Pharmaceuticals that are administered orally are usually tested over a limited range of doses and have MRDDs reported as mg/day. The mg/day unit was converted to mg/kg-body weight (bw)/day based upon an average adult weighing 60 kg. In contrast, the dose unit for most antineoplastic drug MRDDs is reported as mg/m2, which was converted to mg/kg-bw/day using the formula mg/kg-bw/day = mg/m2/37 for an average adult. Additionally, a few drugs had MRDDs reported in parts per million (ppm), which were converted to mg/kg-bw/day on the basis that 1000 ppm equals 25 mg/kg-bw/day for an average 60 kg adult. MRDD values for the over 1200 chemicals in this dataset range from 0.00001 to 1000 mg/kg-bw/day. Some classes of chemicals were excluded from the FDAMDD database due to their unsuitability for most QSAR modeling programs. These were inorganic chemicals, high molecular weight polymers (>5000 Daltons), fibers, salts, mixtures of organic chemicals, and small molecules (<100 Daltons). FDAMDD is the non-proprietary portion of the database that was used in the QSAR analysis reported in the Main Citation listed below.
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Source Website: http://www.fda.gov/cder/Offices/OPS_IO/MRTD.htm
Source Contacts: FDA Center for Drug Evaluation Research, Rockville, MD;
email: Edwin Matthews matthewse@cder.fda.gov;
R. Daniel Benz, benzrd@cder.fda.gov.
Main Citation: Publications reporting use of DSSTox data files for the FDA Maximum Recommended Daily Dose database are asked to list the full DSSTox file name(s), including date stamp, and to cite as primary reference the following:
Matthews, E.J., N.L. Kruhlak, R.D. Benz, and J.F. Contrera (2004) Assessment of the health effects of chemicals in humans: I. QSAR estimation of the maximum recommended therapeutic dose (MRTD) and no effect level (NOEL) of organic chemicals based on clinical trial data, Current Drug Discovery Technologies, 1(1): 61-76.
Download PDF (PDF, 16 pp, 228 KB)
Posted with the permission of Bentham Science Publishers Ltd., The Netherlands . (http://www.bentham.org/
You will need Adobe Acrobat Reader, available as a free download, to view the Adobe PDF files on this page. See EPA's PDF page to learn more about PDF, and for a link to the free Acrobat Reader.
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DSSTox Additions & Modifications: The DSSTox FDAMDD database is an enhanced and modified version of the original FDA Source MRDD database posted on the FDA Source Website, the latter of which included 3 fields: Generic Chemical Name, MRTD (mg/kg-bw/day), and SMILES code. Although labeled as "maximum recommended therapeutic dose" (MRTD) in the original study, the term "maximum recommended daily dose (MRDD)" was indicated by the Source authors (private communication) to provide a more precise and accurate description. In addition to providing a STRUCTURE field for a specified pharmaceutical, DSSTox FDAMDD includes a STRUCTURE_CASRN registry number for all displayed structures. Additional CASRN are provided along with a brief description of the pharmaceutical derivative for over 900 entries in the Note_FDAMDD field. FDAMDD also includes Merck therapeutic categories (The Merck Index, 12th ed., Merck & Co., Inc.), TherapeuticCategory, for nearly all data records along with the original Source Dose_MRDD_mg activity values. DSSTox FDAMDD has 16 fewer records than the original MRDD Source database due to consolidation of partial structures (i.e., complexed entities) into a single record and elimination of duplicate entries. DSSTox FDAMDD also differs from the MRDD Source database in presenting complete structural information pertaining to the actual salt or complexed form corresponding to the listed TestSubstance_ChemicalName and TestSubstance_CASRN. According to the Source authors, there are a number of cases where multiple related forms or derivatives of a drug were listed as separate records but were assumed to fall under the same clinical toxicity assessment and, therefore, assigned the same Dose_MRDD_mg activity value. For the DSSTox FDAMDD, we have labeled these derivatives in the ChemClass_MRDD_grouping field and provide their counts in the ChemicalReplicateCount field to highlight their special nature.
For the purpose of facilitating future SAR analysis of the DSSTox FDAMDD, mg activity values were converted to millimolar equivalents, Dose_MRDD_mmol, inverted and converted to log scale, LOGINV_MRDD_mmol, and the latter mapped to a 0-100 integer scale, ActivityScore_FDAMDD (formerly N100_MRDD_mmol), with a value of 100 representing the most toxic chemicals (most potent, smallest MRDD dose) and 0 representing the least toxic chemicals (least potent, largest MRDD dose). To facilitate qualitative analysis, we mapped ActivityScore_FDAMDD values to 5 gross activity categories, ActivityCategory_MRDD_mmol, consisting of High, High-Moderate, Moderate, Low-Moderate, Low entries. These category cutoffs were chosen by purely subjective means to provide reasonable numerical representation within each categorical range of activity (see FDAMDD Data Distribution figure below). These categories correspond closely, however, to the results obtained by clustering methods (choosing 5 clusters) using KNN or agglomerative nesting based on Ward's minimum variance (Chihae Yang, personal communication). To provide approximate correspondence of the ActivityCategory_MRDD_mmol assignment to the original Source MCASE modeling study (Main Citation), we additionally include the MRDD activity categorization, ActivityCategory_MCASE_mg, based on cutoff values applied to the original Dose_MRDD_mg activity values (see additional discussion below and in the FDAMDD_FieldDefFile). The Main Citation of Matthews et al. reported two different sets of activity classification cutoffs used for separate MCASE analysis of “Inactives” and “Actives”. Upon closer examination, we found that these cutoffs corresponded reasonably closely between High and Marginal, and almost exactly between Marginal and Low categories. Solely to assist users in identifying both “Active” and “Inactive” classifications from that earlier study, we assigned ActivityCategory_MCASE_mg values in DSSTox FDAMDD to High, High-Moderate (the only set of compounds that are categorized differently in the two MCASE analyses), Moderate, and Low. In the figure below, the approximate mapping of these cutoffs to the ActivityScore_FDAMDD (formerly N100_MRDD_mmol) measure is presented. Users should consult the Main Citation for further details.
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Guidance for Use: Several features of DSSTox FDAMDD have the potential to impact on SAR analysis and should be taken into account in any future use of these data. Most prominent among these is the imprecise nature of the reported MRDD value, both in terms of the wide range of adverse or toxic effects that would be considered in assigning the MRDD, and in terms of the ambiguous chemical structure association with this dose measure. In DSSTox FDAMDD and the corresponding Source FDA MRDD database, there are several cases where a single Dose_MRDD_mg value is assigned to multiple related structural derivatives of a pharmaceutical, i.e., the same activity is assigned to multiple Structure/CASRN records in the database. In theory, an MRDD value will reflect the lowest dose of a drug producing adverse effects but for the FDA MRDD database this value has been derived from pooled clinical reports where more than one form of a drug may have been administered. When MRDD mg mass units are converted to mmol units for SAR analysis, a single Dose_MRDD_mg is converted to a range of mmol doses, taking into account the different molecular weights of the various drug derivatives. Assuming that these various drug derivatives have similar or equal molar potencies, the reported Dose_MRDD_mg could be presumed to reflect the dose of the smallest STRUCTURE_MolecularWeight derivative that would register as the highest molar content and, therefore, most potent for a given mass dose.
This variation in MRDD mmol doses for derivatives within a drug family (with the same reported MRDD mg) should be considered an additional source of imprecision and variability in the MRDD measure. The categorical activity, ActivityCategory_MCASE_mg, based on the mass measure, Dose_MRDD_mg, and used in the Main Citation study is also impacted by these considerations and, therefore, cannot be directly compared to the FDAMDD categorical activity (ActivityCategory_MRDD_mmol), which is based on the molar measure, Dose_MRDD_mmol.
The original MRDD database was designed and used by the Main Citation authors to construct MCASE toxicity prediction models (MCASE, Inc.). MCASE does not process complexed structures or salts, and its objective is to identify significant associations of activity with chemical structure fragments. Hence, the Main Citation authors in some cases assigned MRDD values to partial structures in separate records, and in other cases where multiple isomers or derivatives were known to exist, these were assigned identical MRDD values. In many other cases, only a single derivative of a known family of drugs is represented in the database. The implication for MCASE study, or any type of fragment-based SAR analysis, is that some drug frameworks (i.e., parent structures) will be more or less heavily weighted within the database depending on the number of structurally related derivatives represented. Our listing of additional CAS numbers (in TestSubstance_CASRN_Other and ChemicalNote) provides a user with an approximate sense for the number of derivatives that may exist. Converting the Source FDA MRDD database to the DSSTox FDAMDD, we consolidated records for complexes that had been split, but otherwise we mirrored the Source database, i.e., we did not collapse multiple derivative drug listings to a single record, nor did we expand a drug listing to multiple records when multiple derivative CAS numbers were known. The ChemClass_MRDD_grouping and ChemicalReplicateCount fields in FDAMDD have been added to aid in the identification of cases where multiple derivatives sharing the same Dose_MRDD_mg are listed as separate records within the database.
Finally, considering the activities represented in the FDAMDD Data Distribution graphic, which span nearly 9 orders of magnitude mmol dose variation (1.3E-8 to 1.1E+1), it is worth noting that this activity distribution is mostly flat across a narrow range of potencies. The majority of chemicals (> 770) within the FDAMDD database fall within the middle range of 25-50 on the N100 scale (LowMod, Mod, HighMod), corresponding to a less than 2 orders of magnitude mmol dose range of 6.3E-02 to 3.6E-04. This is an important consideration for future SAR studies. Attempts to distinguish structural features that can discriminate the highest potency chemicals from lowest potency chemicals, or predict a chemical’s activity class, must draw sufficient distinction between the classes used in the model development.
The FDAMDD Field Definition File provides essential documentation and should be downloaded with, and accompany any use of the DSSTox FDAMDD SDF file. The FDAMDD Log File provides database summary information (field, chemical counts, etc.) and a description of procedures and quality assurance checks used in SDF file creation. In addition, the Log File documents modifications incorporated into version/revision updates of the DSSTox FDAMDD SDF file. To report errors in any FDAMDD documentation or data file, click on File Error Report here or below. For additional information on DSSTox SDF files and their use in Chemical Relational Databases, see More on SDF and More on CRDs.
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Version 3 Update: FDAMDD_v3 has one fewer chemical records, diuron [330-54-1], and several minor QA corrections, field entry revisions, field changes, new CASRN, etc. Changes to DSSTox Standard Chemical Fields include new ID fields: DSSTox_RID, DSSTox_Generic_SID and DSSTox_FileID (replacing DSSTox_SID and DSSTox_ID_FileName - see More on Standard Chemical Fields), and entries in theTestSubstance_Description field have been simplified. All FDAMDD-specific information has been removed from standard ChemicalNote field and moved to new Note_FDAMDD field (replaces ToxicityNote). The fields TestSubstance_CASRN_Other and TestSubstance_ChemicalName_Other have been discontinued as Standard Chemical Fields and the contents moved to the Source-specific Note_FDAMDD field. In addition, the ChemicalReplicateCount field only occurs in FDAMDD and, therefore, has been reclassified as a Source-specific field. For more information and version history, consult the FDAMDD_LogFile in the Download Table below.
Version 3b Update: FDAMDD_v3b includes minor structure changes/modifications and one modified summary activity fields for use in PubChem and structure-activity relationship studies:ActivityScore_NCTRER (INTEGER[0-100]), formerly N100_MRDD_mmol. In addition, the new STRUCTURE_InChIKey field (25 character abbreviated InChI for use in structure-indexing applications) has been added as a DSSTox Standard Chemical Field to all DSSTox files.
For more information and version history, consult the NCTRER_LogFile in the Download Table below.
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DSSTox Standard Chemical Fields (19) * STRUCTURE_InChIKey field added in v4b
DSSTox Standard Toxicity Fields (3)
ChemicalReplicateCount
ChemClass_MRDD_grouping
TherapeuticCategory
Dose_MRDD_mg
Dose_MRDD_mmol
LOGINV_MRDD_mmol
ActivityScore_FDAMDD *modified in v3b (formerly N100_MRDD_mmol)
ActivityCategory_MRDD_mmol
ActivityCategory_MCASE_mg
Note_FDAMDD
* Note: For detailed information on SDF content, see FDAMDD_FieldDefinitionFile in Download Table below.
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FDAMDD SDF Content Summary - 15 February 2008
FDAMDD SDF Content |
Totals_v2b | Totals_v3a | Totals_v3b |
|---|---|---|---|
# Records
|
1217
|
1216
|
1216
|
DSSTox Standard Chemical Fields
|
20 |
18 |
19 |
DSSTox Standard Toxicity Fields
|
3 |
3 |
3 |
FDAMDD Source Fields
|
8 |
10 |
10 |
Total # Fields
|
31 |
31 |
32 |
Chemical Content |
Counts_v2b | Counts_v3a | Counts_v3b |
defined organic |
1217
|
1216
|
1216
|
inorganic |
0 |
0 |
0 |
organometallic |
0 |
0 |
0 |
no structure |
0 |
0 |
0 |
| STRUCTURE_TestedForm_ DefinedOrganic: |
|||
parent |
1136
|
1133
|
1131
|
complex |
24 |
26 |
27 |
salt |
57 |
57 |
58 |
salt complex |
0 |
0 |
0 |
| TestSubstance_Description: | |||
single chemical compound |
0
|
1215
|
1215
|
defined mixture or formulation |
1216 |
**(NA) |
**(NA) |
undefined mixture |
0 |
**(NA) |
**(NA) |
macromolecule |
1 |
1 |
1 |
mixture or formulation |
**(NA)
|
0
|
0
|
* (NA) = field entry not applicable for DSSTox file version indicated
Note: For SDF content summary information on previous versions of FDAMDD view FDAMDD_LogFile in Download Table below.
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File Download Notes: The following files are offered in the DownLoad table below:
Log File (PDF) provides SDF data file version history and summary information (field, chemical counts, etc.), and a description of procedures and quality assurance checks used in SDF file creation;
You will need Adobe Acrobat Reader, available as a free download, to view the Adobe PDF files on this page. See EPA's PDF page to learn more about PDF, and for a link to the free Acrobat Reader.
|
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These files constitute the main DSSTox products. DSSTox Documentation Files use standard templates, and DSSTox Structure Data Files and DSSTox File Names adhere to strict formatting standards and conventions. For additional information, see More on DSSTox Standard Chemical Fields, Known Problems & Fixes, Chemical Information Quality Review Procedures, and How to Use DSSTox Files.
Quick & Easy File Downloads: FTP Download
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Acknowledgements:
The original DSSTox SDF files for the FDA Maximum Recommended Daily Dose database
were created by Brian Rogers (EPA/NC Central Univ Student COOP; EPA) and
Ann Richard (EPA) with assistance from Maritja Wolf (EPA SEE Contract).
A special debt of gratitude is owed to Ed Matthews, Dan Benz, and Naomi
Kruhlak of the FDA CDER group for assistance with the DSSTox FDAMDD, for
careful review of documentation pertaining to the FDAMDD on this website,
and for clarifications and suggestions for improvements to the database
and documentation. Additionally, we thank Stephen Little (EPA) for contributing
Python program scripts, which significantly aided final SDF creation,
Chihae Yang (Leadscope, Inc) for careful review of the database and documentation
and for clustering analysis of the N100 frequency plot, Matthew Clark
(Locus Pharmaceuticals) for checking the accuracy of the FDAMDD SDF import
into multiple commercial applications, Marc Nicklaus (National Cancer
Institute) for providing the original IUPAC names (ACD/Name, version 8.05, ACD
Labs), Stephen Stein (NIST) for guidance in generating InChI codes for
FDAMDD, and David DeMarini (EPA) for careful review of the FDAMDD documentation
files. All QA review and structure modifications to FDAMDD_v2 and later versions were carried out by Maritja Wolf (Lockheed Martin, Contractor for EPA).
DSSTox Citation: Matthews, E.J., N.L. Kruhlak,
R.D. Benz, J.F. Contrera, B.A. Rogers, M.A. Wolf, and A.M. Richard (2008)
DSSTox FDA Maximum (Recommended) Daily Dose Database (FDAMDD): SDF Files
and Documentation, Updated version: FDAMDD_v3b_1216_15Feb2008, www.epa.gov/ncct/dsstox/sdf_fdamdd.html
Disclaimer: Every effort is made to ensure that DSSTox SDF files and associated documentation are error-free, but neither the DSSTox Source collaborators nor the EPA DSSTox project team make guarantees of accuracy, nor are any of these persons to be held liable for any subsequent use of these public data. The contents of this webpage and supporting documents have been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. See additional disclaimers.
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