[Federal Register Volume 66, Number 121 (Friday, June 22, 2001)]
[Notices]
[Pages 33550-33552]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-15770]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service


National Institute of Environmental Health Sciences (NIEHS); 
National Toxicology Program (NTP); The Revised Draft Up-and-Down 
Procedure for Assessing Acute Oral Toxicity: Notice of Availability and 
Request for Public Comments

Summary

    Notice is hereby given of the availability of a revised draft Up-
and-Down Procedure for assessing acute oral toxicity and solicitation 
of public comment. Documents available include: (1) A revised draft Up-
and-Down Procedure (UDP) test guideline (hereafter, revised draft UDP); 
(2) A procedure incorporated into the revised draft UDP for calculating 
the confidence interval for the estimated median lethal dose (LD50); 
and (3) A software program for use in establishing test doses, 
determining when to stop the test, and estimating the LD50 and the 
confidence interval for the estimated LD50.

Availability of Revised Draft UDP Documents

    The revised draft UDP was proposed by the U.S. Environmental 
Protection Agency (U.S. EPA) to the Interagency Coordinating Committee 
on the Validation of Alternative Methods (ICCVAM) as an alternate for 
the existing conventional LD50 test (EPA 870.1100) used to evaluate the 
acute oral toxicity of chemicals. A previous version of the draft UDP 
was reviewed by the UDP Peer Review Panel (hereafter, Panel) at a 
meeting on July 25, 2000 organized by the NTP Interagency Center for 
the Evaluation of Alternative Toxicological Methods (NICEATM) and 
ICCVAM. This revised draft UDP incorporates modifications made in 
response to the conclusions and recommendations of the Panel and may be 
obtained electronically from the NICEATM/ICCVAM web site at
http:/iccvam.niehs.nih.gov/methods/updocs/udprpt/udp_ciprop.htm. For a 
paper copy (a limited number are available), contact NICEATM at (919) 
541-3398, or via e-mail at [email protected].
    The proposed procedure for calculating the confidence interval for 
the estimated LD50 is a statistical calculation and does not require 
the use of test animals beyond what is needed to estimate the LD50. 
This procedure helps to place the estimated LD50 in a statistical 
context for hazard and risk assessment purposes. The confidence

[[Page 33551]]

interval procedure may be obtained electronically from the NICEATM/
ICCVAM web site at http://iccvam.niehs.nih.gov/methods/updocs/udprpt/udp_ciprop.htm. For a paper copy (a limited number are available), 
contact NICEATM at (919) 541-3398, or via e-mail at 
[email protected]. For technical clarification or questions 
regarding the confidence interval procedure, contact Dr. Amy Rispin, 
U.S. EPA, by telephone at (703) 305-5989 or via e-mail at 
[email protected].
    Because the generation of parameters for this revised draft UDP is 
computationally intensive, the U.S. EPA developed a simple-to-use 
software program to aid in dose selection, test-stopping decisions, 
calculation of an estimate of the LD50, and calculation of a confidence 
interval around the LD50. The confidence interval procedure may be 
obtained electronically from the NICEATM/ICCVAM web site at http://iccvam.niehs.nih.gov/methods/udpdoc/udprpt/udp_ciprop.htm. To obtain a 
diskette of this software program, (a limited number are available), 
contact NICEATM at (919) 541-3398 or via e-mail at 
[email protected]. For technical clarification or questions 
regarding the software package contact Dr. Elizabeth Margosches, U.S. 
EPA, by telephone at (202) 260-1511 or via e-mail at 
[email protected], or Ms. Deborah McCall, U.S. EPA, by 
telephone at (703) 305-7109, or via e-mail at [email protected].

Request for Public Comment

    NICEATM invites written public comments on the revised draft UDP, 
the confidence interval proposal, and the software program. Comments 
should be sent to NICEATM through August 6, 2001. Comments submitted 
via e-mail are preferred; the acceptable file formats are MS Word 
(Office 98 or older), plain text, or PDF. Comments should be sent to 
Dr. William S. Stokes, Director, NICEATM, NIEHS, MD EC-17, P.O. Box 
12233, Research Triangle Park, NC, 27709; telephone 919-541-2384; fax 
919-541-0947; e-mail [email protected]. Persons submitting written 
comments should include their contact information (name, affiliation, 
address, telephone and fax numbers, and e-mail) and sponsoring 
organization, if any. Public comments received in response to this 
Federal Register notice will be posted on the NICEATM/ICCVAM web site 
(http://iccvam.niehs.nih.gov). In addition, they will be available for 
viewing Monday through Friday, from noon to 4 p.m., excluding legal 
holidays, at the U.S. EPA under docket control number: AR-228, Up-and-
Down Procedure. [U.S. EPA, Office of Prevention, Pesticides, and Toxic 
Substances, Non-Confidential Information Center, Room 607B, Northeast 
Mall, 401 M Street, SW., Washington, DC 20460, telephone: (202) 260-
7099]. This docket also contains background and supporting materials 
for the revised draft UDP.
    The comments will also be provided to the Panel for consideration 
in preparation for a final meeting tentatively planned for August 2001. 
This meeting is anticipated to be held as a teleconference with 
opportunity for public participation. An announcement of the Panel 
meeting with additional details will be published in a future Federal 
Register notice. The focus of this meeting will be to discuss the 
revised draft UDP, the proposed procedure for calculating the 
confidence interval for the estimated LD50, and the software program. 
Following the Panel meeting, a final report of the Panel's findings and 
recommendations will be published and made available to the public 
through NICEATM. In accordance with Public Law 106-545, ICCVAM will 
develop and forward test recommendations on the UDP to Federal agencies 
for their consideration. The ICCVAM recommendations will also be made 
available to the public.

Background

    In 1999, the Organization for Economic Cooperation and Development 
(OECD) proposed deletion of its standard test guideline (TG) for 
assessing the acute oral toxicity of chemicals (TG 401; OECD, 1987). 
The rationale for deletion was that three alternative acute toxicity 
test methods had previously been adopted and could be used instead. 
Each method uses fewer animals than the procedure described in TG 401. 
One of these test methods is the UDP (OECD TG 425). Prior to formal 
deletion of TG 401, OECD determined that it was necessary to revise the 
three alternative methods to conform to the newly harmonized OECD 
hazard classification scheme (OECD, 1998). The U.S. EPA agreed to 
organize a Technical Task Force to revise the UDP (OECD TG 425). The 
revised UDP test method included two procedures different from the 
original UDP: a Limit Test for substances anticipated having minimal 
toxicity, and a Supplemental Test to determine the slope and confidence 
interval for the dose-response curve.
    ICCVAM and NICEATM convened an international independent scientific 
peer review panel July 25, 2000, to evaluate the validation status of 
the revised UDP. The Panel concluded that the revised UDP Primary Test 
provided an improved estimate of acute oral toxicity with a reduction 
in the number of animals used compared to the existing conventional 
LD50 test (e.g., EPA 870.1100, TG 401). The Panel concluded that the 
proposed Limit Test procedure would be expected to perform as well as 
or better than the currently used EPA 870.1100 or TG 401 limit test for 
hazard classification, while using fewer animals. The Panel did not 
recommend the proposed UDP Supplemental Test procedure for use. 
Information on previous deliberations of the Panel can be found on the 
Internet at http://iccvam.niehs.nih.gov/udp.htm.
    In recognition of the need for a procedure to calculate the 
confidence interval for the estimated median lethal dose determined 
using the UDP, the UDP Technical Task Force developed a procedure for 
use with UDP data from the primary procedure. As recommended by the 
Panel, the Supplemental Procedure has been deleted in the revised draft 
UDP and no further work on a procedure to generate dose-response slope 
information has been proposed. A specialized software program was 
subsequently developed by the U.S. EPA to facilitate implementation and 
use of the revised UDP.
    Background for the UDP, including the availability of review 
materials, can be found in previous Federal Register notices (see FR 
Volume 65, Number 34, pages 8385-8386, February 18, 2000, and FR Volume 
65, Number 106, pages 35109-35110, June 1, 2000). Minutes from the UDP 
Peer Review Panel meeting held July 25, 2000, may be found at http://iccvam.niehs.nih.gov/udp.htm.

Additional Information About ICCVAM and NICEATM

    ICCVAM, with 15 participating Federal agencies, was established in 
1997 to coordinate interagency issues on toxicological test method 
development, validation, regulatory acceptance, and national and 
international harmonization. The ICCVAM Authorization Act of 2000 (Pub. 
L. 106-545) formally authorized and designated ICCVAM as a permanent 
committee. The NICEATM was established in 1998 to collaborate with the 
ICCVAM to facilitate the development, scientific review, and validation 
of novel toxicological methods that predict human health risks while 
reducing, refining, and/or replacing animal tests and to promote 
communication with stakeholders. The NICEATM is located at the NIEHS in 
Research Triangle Park, NC. Additional information concerning ICCVAM 
and NICEATM can be found

[[Page 33552]]

on the ICCVAM/NICEATM web site at http://iccvam.niehs.nih.gov.

References

    U.S. EPA (1998). Health Effects Test Guidelines, OPPTS 870.1100, 
Acute Oral Toxicity. Washington, DC: U.S. Environmental Protection 
Agency, 1998. Available on the Internet at http://www.epa.gov/docs/ 
OPPTS_Harmonized/870_Health_ Effects_ Test_Guidelines/Series/.
    OECD (1987). TG 401. OECD Guideline for the Testing of Chemicals, 
Acute Oral Toxicity, Adopted February 24, 1987, OECD, Paris, France.
    OECD (1998). Harmonized Integrated Hazard Classification System for 
Human Health and Environmental Effects of Chemical Substances as 
endorsed by the 28th Joint Meeting of the Chemicals Committee and 
Working Party on Chemicals in November 1998. Available on the Internet 
at http://www.oecd.org/ehs/Class/HCL6.htm.

    Dated: June 6, 2001.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences.
[FR Doc. 01-15770 Filed 6-21-01; 8:45 am]
BILLING CODE 4140-01-U