[Federal Register Volume 66, Number 189 (Friday, September 28, 2001)]
[Notices]
[Pages 49685-49686]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-24371]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service


National Institute of Environmental Health Sciences (NIEHS) 
National Toxicology Program (NTP)

    EPISKINTM, EpiDermTM, and Rat Skin 
Transcutaneous Electrical Resistance Methods: In Vitro Test Methods 
Proposed for Assessing the Dermal Corrosivity Potential of Chemicals; 
Notice of Availability of a Background Review Document and Proposed 
ICCVAM Test Method Recommendations and Request for Public Comment.

Summary

    The NTP Interagency Center for the Evaluation of Alternative 
Toxicological Methods (NICEATM) announces availability of a background 
review document (BRD) entitled ``EPISKINTM, 
EpiDermTM, and Rat Skin Transcutaneous Electrical Resistance 
(TER) Methods: In Vitro Test Methods for Assessing the Dermal 
Corrosivity Potential of Chemicals,'' and proposed test method 
recommendations from the Interagency Coordinating Committee on the 
Validation of Alternative Methods (ICCVAM) on the use of these methods. 
The NICEATM invites public comment on the BRD and ICCVAM 
recommendations.

Availability of Background Review Document and Proposed ICCVAM 
Recommendations

    An electronic version of this BRD and proposed ICCVAM test method 
recommendations may be obtained from the NICEATM/ICCVAM web site at 
http://iccvam.niehs.nih.gov. For a paper copy (a limited number are 
available), please contact the NICEATM at (919) 541-3398 or via email 
at [email protected].

Request for Public Comment

    NICEATM invites written public comments on the BRD on in vitro 
corrosivity methods and the proposed ICCVAM recommendations for these 
methods. The deadline for submission of comments is November 13, 2001. 
Comments submitted via email are preferred; the acceptable file formats 
are MS Word (Office 98 or older), plain text, or PDF. Comments should 
be sent to Dr. William Stokes, Director, NICEATM, NIEHS, MD EC-17, P.O. 
Box 12233, Research Triangle Park, NC, 27709; telephone 919-541-3398; 
fax 919-541-0947; email [email protected]. Persons submitting 
written comments should include their contact information (name, 
affiliation, address, telephone/fax numbers, and email) 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 and provided to the ICCVAM. ICCVAM will consider 
all comments prior to finalizing its test recommendations on 
EpiDermTM, EPISKINTM, and Rat Skin TER. In 
accordance with Public Law 106-545, ICCVAM test recommendations will be 
forwarded to appropriate Federal agencies and will be made available to 
the public on the NICEATM/ICCVAM website.

Background

    ICCVAM and the ICCVAM Corrosivity Working Group (CWG) recently 
evaluated three in vitro test methods for assessing the dermal 
corrosivity potential of chemicals and chemical mixtures--
EpiDermTM, EPISKINTM, and Rat Skin TER. 
EpiDermTM and EPISKINTM utilize a three 
dimensional human skin model comprised of a reconstructed epidermis and 
a functional stratum corneum. The test chemical is applied to this 
reconstructed epidenmis for a specified time and subsequent cell 
viability is measured. Rat Skin TER assesses the skin corrosivity of a 
chemical by applying the test material to the epidermal surface of a 
rat skin disc for two and 24 hours; subsequently, the transcutaneous 
electrical resistance (TER) of the skin disc is measured. NICEATM 
prepared a background review document summarizing the available data 
and prior reviews for the three test methods, which was then considered 
by the CWG and ICCVAM. The CWG concluded, based on the information 
provided and outcomes of the previous reviews, that further evaluation 
by an independent scientific peer review panel did not appear 
necessary, and recommended that these methods undergo ICCVAM evaluation 
using an expedited review process (ICCVAM, 2001). ICCVAM agreed with 
the CWG recommendation for expedited review. This process involves the 
development of a draft ICCVAM position (proposed ICCVAM test 
recommendations) and publishing the position in the Federal Register 
for public comment. Public comments are considered by ICCVAM, and if no 
major problems are found, ICCVAM then finalizes its test 
recommendations and forwards to federal agencies for their 
determination of regulatory acceptability. If major problems are noted, 
then ICCVAM will determine an appropriate process for further 
evaluation, such as an independent peer review panel evaluation.

ECVAM Evaluation

    The European Center for the Validation of Alternative Methods 
(ECVAM) conducted validation studies on these three in vitro methods 
(Barratt et al., 1998; Fentem et al., 1998; Liebsch et al., 2000). The 
ECVAM Management Team concluded that EpiDermTM, Rat Skin 
TER, and EPISKINTM were scientifically valid for use as 
replacements for the animal test currently used to distinguish between 
corrosive and non-corrosive chemicals and for all chemical classes 
(Fentem et al., 1998; Liebsch et al., 2000).

Other Reviews

    The validation status of these three methods was then evaluated by 
the ECVAM Scientific Advisory Committee (ESAC). The ESAC also concluded 
that the Rat Skin TER, EpiDermTM, and the 
EPISKINTM tests were scientifically

[[Page 49686]]

valid for use as replacements for the animal test and were ready to be 
considered for regulatory acceptance (Balls and Corcelle, 1998; Balls 
and Hellsten, 2000). The European Scientific Committee for Cosmetic 
Products and Non-food Products (SCCNFP) evaluated the 
EPISKINTM and Rat Skin TER and concluded that they were 
applicable for the safety evaluation of cosmetic ingredients or 
mixtures of ingredients (Anon., 1999). The European Commission 
subsequently adopted EpiDermTM, EPISKINTM, and 
Rat Skin TER (Anon., 2000).

Proposed ICCVAM Recommendations

    ICCVAM proposes that these assays can be used to assess the dermal 
corrosion potential of chemicals in a weight-of-evidence approach in an 
integrated testing scheme [e.g., OECD Globally Harmonised 
Classification System (OECD, 1998); OECD Revised Proposals for Updated 
Test Guidelines 404 and 405: Dermal and Eye Corrosion/Irritation 
Studies (OECD, 2001a)]. These integrated testing schemes for dermal 
irritation/corrosion allow for the use of validated and accepted in 
vitro methods. In this approach, positive in vitro corrosivity 
responses do not generally require further testing and can be used for 
classification and labeling. Negative in vitro corrosivity responses 
shall be followed by in vivo dermal corrosion/irritation testing. 
(Note: The first animal used in the irritation/corrosivity assessment 
would be expected to identify any chemical corrosives that were false 
negatives in the in vitro test). Furthermore, as is appropriate for any 
in vitro assay, there is the opportunity for confirmatory testing if 
false positive results are indicated on a weight of evidence evaluation 
of supplemental information, such as pH, structure activity 
relationships (SAR), and other chemical and testing information.

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 
(Public Law 106-545) formally authorized and designated ICCVAM as a 
permanent committee administered by the NIEHS with specific duties that 
include the technical evaluation of new and alternative testing 
methods. ICCVAM is charged with developing test recommendations based 
on those technical evaluations, and forwarding these to Federal 
agencies for their consideration. The NICEATM was established in 1998 
to coordinate and facilitate ICCVAM activities, to provide peer review 
for validation activities and to promote communication with 
stakeholders. The NICEATM is located at the NIEHS, Research Triangle 
Park, NC. Additional information concerning ICCVAM and NICEATM can be 
found on the ICCVAM/NICEATM web site at http://iccvam.niehs.nih.gov.

References

    Anon. EU Commission Directive 2000/33/EC of 25 April 2000 
(Official Journal of the European Communities), Skin Corrosion, Rat 
Skin TER and Human Skin Model Assay. OJ L 136, June 8, 2000. 
Available: http://embryo.ib.amwaw.edu.pl/invittox/prot/1_13620000608en00010089.pdf [cited July 19, 2001].
    Anon. Scientific Committee for Cosmetic Products, and Non-food 
Products intended for Consumers. Excerpts of the Outcome of 
Discussions Record of the 6th Plenary Meeting (SCCNFP) Brussels, 
Belgium. January 20, 1999. Available: http://europa.eu.int/comm/food/fs/sc/sccp/out50_en.html [cited July 19, 2001].
    Balls M, Corcelle G. ``Statement on the scientific validity of 
the Rat Skin Transcutaneous Electrical Resistance (TER) Test (an in 
vitro test for skin corrosivity) and Statement of the scientific 
validity of the EPISKINTM test (an in vitro test for skin 
corrosivity),'' dated April 3, 1998. Statement from the European 
Commission Joint Research Centre, Environment Institute, Ispra (VA), 
Italy presenting the results of the 10th ECVAM Scientific Advisory 
Committee (ESAC) meeting on March 31 (1998). Available: http://www.iivs.org/news/ratskin-episkin.html [cited July 19, 2001].
    Balls M, Hellsten E. ``Statement on the application of the 
EpiDermTM human skin model for corrosivity testing,'' 
dated March 20, 2000. ECVAM Scientific Advisory Committee meeting, 
Ispra, Italy, March 14-15 (2000).
    Barratt, MD, Brantom PG, Fentem JH, Gerner I, Walker AP, Worth 
AP. The ECVAM international validation study on in vitro tests for 
skin corrosivity. 1. Selection and distribution of the test 
chemicals. Toxicology In Vitro 12:471-482 (1998).
    Fentem, JH, Archer GEB, Balls M, Botham PA, Curren RD, Earl LK, 
Esdaile DJ, Holzhutter H-G, Liebsch M. The ECVAM international 
validation study on in vitro tests for skin corrosivity. 2. Results 
and evaluation by the management team. Toxicology In Vitro 12:483-
524 (1998).
    Interagency Center for the Evaluation of Alternative Methods 
(ICCVAM). Procedures for test methods that have been endorsed by 
ECVAM (April 20, 2001). http://iccvam.niehs.nih.gov.
    Liebsch M, Traue D, Barrabas C, Spielmann H, Uphill P, Wilkins 
S, McPherson JP, Wiemann C, Kaufmann T, Remmele M, Holzhutter HG. 
The ECVAM prevalidation study on the use of EpiDerm for skin 
corrosivity testing. ATLA-Alternatives to Laboratory Animals 28:371-
401 (2000).
    Organization for Economic Co-operation and Development (OECD). 
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 the Working Party 
on Chemicals, OECD, Paris, France. (November 1998) http://www.oecd.org/ehs/Class/HCL6.htm
    OECD. OECD Revised Proposals for Updated Test Guidelines 404 and 
405: Dermal and Eye Corrosion/Irritation Studies. [OECD ENV/JM/TG 
(2001)2]. OECD Environment Directorate, Joint Meeting of the 
Chemicals Committee and the Working Party on Chemicals, Pesticides 
and Biotechnology. Test Guidelines Programme. Circulated in 
preparation for the 13th Meeting of the Working Group of the 
National Coordinators of the Test Guidelines Programme, OECD, Paris, 
France. (2001a)

    Dated: September 21, 2001.
Samuel H. Wilson,
Deputy Director, National Institute of Environmental Health Sciences.
[FR Doc. 01-24371 Filed 9-27-01; 8:45 am]
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