Dear Ms. Mette-Marie T. Johansen,

1998.3.5

Thank you for sending me a WD of Rev. ISO 10993-10.
The following is our tentative comments for that.
I would be happy if this could help to improve the ISO.

���@We think it basically fine to include the clause 4. "General principles, step-wise approach".
    This approach may help to decrease animal testing and to increase the opportunity of careful
    selection of materials.  Please find the following comments on this part:

  # step c) says "At the present time there are no validated in vitro tests (other than simple
    screens) to detect irritants or sensitizers."  
    If so, there is no practical meaning of this clause.
    Nakamura recommend to add the following sentence at the end of this clause.
   "However, it can be at least said that negative cytotoxicity test results obtained by the methods
    given in ISO 10993-5 indicate no skin irritation."

  # step d)     
    It needs to clarify the meanings of the words of "acute toxicity" and "repeated exposure."
    It may serve the readers' understanding to add the lists of acute tests and repeated tests in
    Annex D.

  # step e)
    I agree to limit the human test only for skin irritation evaluation.
    FDA recently published the "Guidance on the Content and Format of Premarket
    Notification [510k] Submission for Testing for Skin Sensitization to Chemicals in 
    Latex Products (July 29, 1997)."  It includes human sensitization testing.
    However, I do not agree to include a similar approach into ISO 10993-10, because
    sensitization may not necessarily occur only by skin contacting but also by implantation.
    For the latter, human skin sensitization protocol may not be appropriate. 

���@Clause 5.4
    The first sentence should be revised as follows:
    "When compositional details are unavailble, only qualitative information is available, or
    new or unknown substances may be expected to be born during the manufacturing process,
    it may be necessary to undertake analysis of a material."
   [REASON] 
    We experienced that some dyestuff added in resorbable suture degraded with heat 
    during the process to produce a strong sensitizer.

��  General comment for animal irritation tests
    Frankly I feel doubt of the validity of irritation test methods given in the 
    original ISO 10993-10.  So, I strongly support the change to move most irritation tests
    to the informative Annex C.  It is quite reasonable.
    I recommend the following:
      1) Add the same sentence that I proposed for step c) starting from "However, ---" 
         before the sentence "In parallel with the search for alternative ----."
      2) Add the following sentence at the top of the clause 6.2:
        "Tissue irritation is usually caused by direct contact with medical devices.  
         It must therefore be noted that simulated use test on animals may be more 
         predictable than the proposed test methods described in this part applying 
         the extracts to animals.  Several appropriate use test methods are given in
         the relevant vertical ISO standards shown in Annex X."

���@Comments for sensitization test

Clause 7.3    
    Add the following at the end of this clause.
   "The relative sensitization potencies of substances can be defined in terms of the minimum
    (lowest) induction concentration required to induce a given level of sensitization."
   [REASON]
    This is included in the clause 6.1 of the original Part 10.

Clause 7.4.6
    Add a new paragraph shown below at the end of this clause:
   "The relative sensitization potency is determined with the value of the lowest induction
    concentration of the sample that induces a given level of sensitization in the animals."

Create a new clause between 7.4.2 and 7.4.3 as follows:
   7.4.3  Test concentration of material
   The concentration of test material shall be the highest possible without affecting the
   the ability to interpret the results.  Ten % concentration is often used as the highest
   when it does not cause irritation on animals.
   And renumber the following clauses.
   [REASON]
   The first sentence is from the clause 6.1 of the original Part 10.  The second one is
   from pragmatism.
    
���@Comments for Annex D

# p55 D.2  Add the following sentence before the final sentence of this Annex:
    "The risk, e.g., incidence and severity, of the allergic reaction to the product is 
    determined mainly with the following two factors: the sensitizing potency of the
    chemical allergen and its amount in the product.  The relative sensitizing potencies
    of chemicals can be defined in terms of the minimum induction concentration
    required to induce a given level of sensitization: the lower this concentration the more
    potent the sensitizer (Roberts, 1987), and it was shown that the significant incidence
    of allergic contact dermatitis was found in users when the residue level of the allergen
    in the product exceeded its minimum induction concentration obtained by GPMT
   (Nakamura, et al., 1994).

   Roberts, D.W. Structure-activity relationships of skin sensitization potential of 
   diacrylates and dimethacrylates, Contact Dermatitis, 17:281-289, 1987
  
   Nakamura, A., Momma, J., et al.  A new protocol and criteria for quantitative
   determination of sensitization potencies of chemicals by guinea pig maximization
   test, Contact Dermatitis, 31:72-85, 1994.

# D.2 p54 para2, line 7
   Add the following after ",however, mild sensitizers responding in the GPMT was not
   identified (Basketter and Scholes, 1992).":

  "A new experimental design of sensitive mouse lymph node assay was developed 
  (Ikarashi, Y., et al., 1993) and validated using thioureas and disperse dyes (Ikarashi, Y.,
  et al., 1994 and 1996).

  Ikarashi, Y., Tsuchiya, T., Nakamura, A.  A sensitive mouse lymph node assay with two
  application phases for the detection of contact allergens, Arch. Toxicol., 67:626-636, 1993.

  Ikarashi, Y., Ohno, K., Momma, J., et al.  Assessment of contact sensitivity of two thiourea
  rubber accelerators: comparison of two mouse lymph node assays with the guinea pig
  maximization test, Food Chem. Toxicol., 32:1067-1072, 1994

  Ikarashi, Y., Tsuchiya, T., Nakamura, A., Application of sensitive mouse lymph node assay
  for detection of contact sensitization capacity of dyes, J. Appl. Toxicol., 16:349-354, 1996.


Yours sincerely,

Akitada Nakamura