Dear Dr. Keller,
 
Attached please find the Japanese Vote for ISO/CD 10993-3
"Tests for genotoxicity, carcinogenicity, and reproductive toxicity."

Formal voting sheet will be sent separately by air mail soon.

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We do not agree to the circulation of the draft as a DIS.
The reasons are as follows:

[REASONS]

# Concerning GENOTOXICITY TESTS

1. As described in the bottom line in p9, ICH Guidance for Genotoxicity
  Tests was developed.  We propose TC194 to adopt the principles of this
  guidance.

The Guidance basically recommends two in vitro and one in vivo tests:
(1) gene mutation test,
(2) clastogenicity test such as chromosome abberation test, and
(3) in vivo micronucleus test. 

Therefore, the 1st paragraph of Clause 4.1 General should be better to
be revised as follows:
"When the genetic toxicity of a medical devices has to be experimentally
assessed, a series of tests shall be used.  This series shall include at
least three assays: (1) in vitro gene mutation assay, (2) in vitro 
clastogenicity assay, and (3) in vivo micronucleus assay."

2. The clause 4.4.1 of the revised part 3 requires three in vitro tests
such as bacterial gene mutations, gene mutation in mammalian cells, and
clastogenicity test in mammalian cells.  
However, it must be pointed out that there is a good correlation 
between the results obtained by mouse lymphoma assay, the most frequently
used mammalian gene mutation assay method, and by chromosome abberation 
test, an in vitro clastogenicity assay.  Thus, we consider it redundant
to perform these two tests.

# Concerning CARCINOGENICITY TEST

"Introduction" says "For example the biological significance of solid
state carcinogenesis is poorly understood."  Nevertheless the clause
5. adopts IMPLANTATION PROTOCOL.  There are many descriptions that may
cause confusion among readers, i.e,  

OECD TEST GUIDELINES 451 and 453 are for assessing chemicals not for
solid materials.  There is no meaning to assess solid state carcinogenesis
in terms of mg/kg/body weight.

"The negative controls will generally include polyethylene(PE) implants
or other materials whose lack of carcinogenic potential is demonstrated
in a comparable form and shape."  It is obvious that PE gave the
high incidence of tumor formation by 2-years implantation.
There is no material of absolutely negative in implantation study.

Thus, we think it necessary to reconsider the whole part of 
clause 5 including the state-of -the-art.

Dr Tsuchiya should like to present a short lecture about her work
on Implant Carcinogenesis in the next meeting in Alexandria.

Sincerly yours,

Akitada Nakamura, Ph.D.
Leader, Japanese Committee for ISO/TC194