[Federal Register Volume 67, Number 26 (Thursday, February 7, 2002)]
[Notices]
[Pages 5842-5844]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-2905]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service


National Institute of Environmental Health Sciences (NIEHS); 
National Toxicology Program (NTP); Report on the Revised Up-and-Down 
Procedure: A Test Method for Determining the Acute Oral Toxicity of 
Chemicals; Notice of Availability and Request for Public Comments

SUMMARY: Notice is hereby given of the availability of the report 
entitled, ``The Revised Up-and-Down Procedure: A

[[Page 5843]]

Test Method for Determining the Acute Oral Toxicity of Chemicals,'' NIH 
Publication 02-4501. The report contains the final test recommendations 
on the `` Revised Up-and-Down Procedure'' (Revised UDP) by the 
Interagency Coordinating Committee on the Validation of Alternative 
Methods (ICCVAM), the results of an independent scientific peer review 
evaluation of the Revised UDP, and the final test guideline for the 
Revised UDP. The NTP Interagency Center for the Evaluation of 
Alternative Toxicological Methods (NICEATM) is seeking public comment 
on this report on behalf of the ICCVAM prior to transmittal to US 
Federal agencies in accordance with Pub. L. 106-545. The report and 
public comments will be transmitted to appropriate Federal agencies 
following this public comment period.

Availability of the Report

    The report is available electronically (PDF and HTML) on the 
ICCVAM/NICEATM Web site, http://iccvam.niehs.nih.gov. A limited number 
of printed reports are available. To receive a printed copy, please 
contact NICEATM at PO Box 12233, MD EC-17, Research Triangle Park, NC 
27709 (mail), 919-541-2384 (phone), 919-541-0947 (fax), or 
[email protected] (e-mail).

Request for Public Comments

    NICEATM invites written public comments on the report. Comments 
should be sent to NICEATM no later than March 25, 2002. 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, at PO Box 12233, MD EC-17, 
Research Triangle Park, NC 27709 (mail), 919-541-0947 (fax), or 
[email protected] (e-mail). 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 by the above deadline 
will be posted on the ICCVAM/NICEATM Web site, http://iccvam.niehs.nih.gov, and forwarded to the appropriate Federal agencies 
with the report.

Background

    The Organisation for Economic Cooperation and Development (OECD) 
Test Guidelines Program (TG 425; OECD 1998) adopted the UDP in 1998. 
The U.S. Environmental Protection Agency (EPA) subsequently determined 
it was necessary to revise the UDP to: (1) Conform to a newly 
harmonized global hazard classification scheme for acute toxicity 
(OECD, 2001) and (2) ensure that regulatory and testing needs would be 
met with the Revised UDP prior to OECD's proposed deletion of the 
conventional acute oral toxicity test (OECD, 1987). In August 1999, the 
EPA asked ICCVAM to evaluate the validation status of the Revised UDP 
as a substitute for the existing conventional LD50 test (U.S. EPA 
870.1100, 1998; OECD Test Guideline (TG) 401, 1987).
    The Revised UDP test method submitted to ICCVAM for evaluation 
included three components:
     A Primary Test for estimating the median lethal dose using 
sequential testing.
     A Limit Test for evaluating substances anticipated to have 
minimal or no toxicity.
     A Supplemental Test to determine the slope and confidence 
interval (CI) for the dose-response curve.
    An initial Federal Register notice (Vol. 65, No. 34, pp. 8385-8386, 
February 18, 2000) requested data and the nomination of expert 
scientists to participate in the independent scientific peer review 
evaluation of the Revised UDP. A second Federal Register notice (Vol. 
65, No. 106, pp. 35109-35110, June 1, 2000) announced the peer review 
panel meeting, availability of a background review document on the 
Revised UDP, and requested public comments.
    The first meeting of the Panel to evaluate the Revised UDP was held 
on July 25, 2000. The public meeting was organized by the ICCVAM and 
NICEATM and was sponsored by the NIEHS, NTP, and EPA. The Panel 
evaluated the extent to which the Revised UDP addresses established 
validation and acceptance criteria (ICCVAM, 1997) and developes 
conclusions regarding the usefulness and limitations of the Revised 
UDP.
    The Panel agreed that the Primary and Limit tests would perform as 
good or better than the respective existing conventional LD50 and limit 
tests. They also agreed that the revised test methods would reduce 
animal use compared to the current test methods. The Panel provided 
other recommendations for revision of the Revised UDP test guideline 
and did not recommend the UDP Supplemental Test.
    Based on the Panel's July 25, 2000 conclusions and recommendations, 
the EPA UDP Technical Task Force modified the UDP Primary and Limit 
Tests and removed the UDP Supplemental Test. A computational procedure 
was added to calculate the confidence interval (CI) for the estimated 
LD50. The EPA also developed a software program that would calculate 
subsequent test doses, determine when to stop the test, estimate the 
LD50, and calculate a CI for the LD50. The publicly available software 
was developed to mitigate complexity for the user and to facilitate 
correct performance of the Revised UDP.
    A Federal Register notice (Vol. 66, No. 121, pp. 33550-33552, June 
22, 2001) requested public comment and announced availability of the 
revised draft test guideline for the Revised UDP, the procedure for 
calculating the confidence interval for the estimated LD50, and the 
software program. A subsequent Federal Register notice (Vol. 66, No. 
133, pp. 36294-36295, July 11, 2001) announced a second public meeting 
of the UDP Panel.
    The second meeting of the UDP Panel was held by teleconference on 
August 21, 2001. The Panel reviewed and endorsed modifications to the 
Revised UDP, the CI procedure, and the software program. The Panel 
recommended additional clarifications to the Revised UDP. Written 
reports of the Panel meetings are included in the final report.
    Following the August 21st meeting, the EPA UDP Technical Task Force 
revised the UDP Guideline in response to the Panel's recommendations. A 
discussion of software program limitations and information about using 
in vitro cytotoxicity data to estimate starting doses for in vivo 
studies were added. An ICCVAM Acute Toxicity Working Group and the 
ICCVAM reviewed and endorsed the final Revised UDP Test Guideline, and 
developed and adopted ICCVAM test method recommendations for the 
Revised UDP. In accordance with P.L. 106-545, the ICCVAM test 
recommendations will be forwarded to appropriate Federal agencies for 
acceptance consideration.
    The final report comprises two volumes. The first volume (143 
pages) includes the final ICCVAM test method recommendations on the 
Revised UDP procedure, the final Revised UDP Test Guideline, and the 
two peer review panel meeting reports. Volume 2 (291 pages) contains an 
updated background review document and other information considered by 
the Panel for the July 2000 meeting. Following receipt of public 
comments, the report will be forwarded to Federal agencies in 
accordance with Pub. L. 106-545.

[[Page 5844]]

Additional Information About ICCVAM and NICEATM

    The NICEATM and ICCVAM were established to facilitate development, 
validation, and regulatory acceptance of improved toxicological methods 
that predict human health risks while reducing, refining, and/or 
replacing animal tests and to promote communication with stakeholders. 
The NICEATM coordinates activities for the ICCVAM and is located at the 
NIEHS, Research Triangle Park, NC. ICCVAM, with 15 participating 
Federal agencies, originally established in 1997, was formally 
authorized and designated as a permanent interagency coordinating 
committee by the ICCVAM Authorization Act of 2000 (Pub. L. 106-545). 
ICCVAM's duties include the technical evaluation of new and alternative 
testing methods, the development of test recommendations based on those 
technical evaluations, and the forwarding of its test recommendations 
to Federal agencies for their consideration. The ICCVAM also 
coordinates interagency issues on toxicological test method 
development, validation, regulatory acceptance, and national and 
international harmonization. Additional information about ICCVAM and 
NICEATM can be found on the ICCVAM/NICEATM Web site at http://iccvam.niehs.nih.gov.

References

    Interagency Coordinating Committee on the Validation of Alternative 
Methods (ICCVAM). 1997. Validation and regulatory acceptance of 
toxicological test methods: A report of the ad hoc Interagency 
Coordinating Committee on the Validation of Alternative Methods. NIH 
publication no: 97-3981. National Institute of Environmental Health 
Sciences, Research Triangle Park, North Carolina. Available: http://iccvam.niehs.nih.gov/docs/guidelines/validate.pdf (cited October 1, 
2001).
    National Institute of Environmental Health Sciences (NIEHS). 2000a. 
National Toxicology Program: Request for Data and Nomination of Expert 
Scientists to Participate in the Independent Peer Review Evaluation of 
the Revised Up-and-Down Procedure for Assessing Acute Oral Toxicity. 
Evaluation of the Up-and-Down Procedure. 65 FR 8385. February 18, 2000.
    NIEHS. 2000b. National Toxicology Program: Notice of Peer Review 
Meeting on the Revised Up-and-Down Procedure (UDP) as an Alternative 
Test Method for Assessing Acute Oral Toxicity. Request for Comments. 65 
FR 35109. June 1, 2000.
    NIEHS. 2001a. National Toxicology Program: The Revised Draft Up-
and-Down Procedure for Assessing Acute Oral Toxicity. Notice of 
Availability and Request for Public Comments. 66 FR 33550. June 22, 
2001.
    NIEHS. 2001b. National Toxicology Program: Notice of Peer Review 
Meeting on the Revised Up-and-Down Procedure (UDP) as an Alternative 
Test Method for Assessing Acute Oral Toxicity. 66 FR 36294. July 11, 
2001.
    OECD. 1998. OECD Guideline for the Testing of Chemicals, Revised 
Test Guideline 425, Acute Oral Toxicity, Up-and-Down Procedure. OECD, 
Paris. Available: http://www.oecd.org//ehs/test/health.htm (cited 
October 1, 2001).
    OECD. 2001. Harmonized Integrated Classification System for Human 
Health and Environmental Hazards of Chemical Substances and Mixtures. 
ENV/JM/MONO(2001)6. OECD, Paris. Available: http://www.oecd.org/ehs/class/HCL6.htm (cited December 13, 2001).
    OECD. 1987. OECD Guideline for the Testing of Chemicals, Test 
Guideline 401, Acute Oral Toxicity. OECD, Paris. Available: http://www.oecd.org//ehs/test/health.htm (cited October 1, 2001).
    U.S. EPA. 1998. Health Effects Test Guidelines, OPPTS 870.1100, 
Acute Oral Toxicity. Washington, DC, U.S. Environmental Protection 
Agency. Available: http://www.epa.gov/docs/OPPTS Harmonized/870 Health 
Effects Test Guidelines/Series/(cited October 1, 2001).

    Dated: January 11, 2002.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences.
[FR Doc. 02-2905 Filed 2-6-02; 8:45 am]
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