Griseofulvin NOEL

GOOD VALIDATION PRACTICE (cGVP) CLEANING VALIDATION
1

I can not find a NOEL value for Griseofulvin, can anyone help? What other value can I use?

2

Dear nols,

the NOEL value can be calculated as 1/10th of the lowest therapeutic dose (
http://www.rxlist.com/gris-peg-drug.htm
). As stated in this link, the pediatric dose is 3,3 mg/pound of body weight, for children from 2 years up. So the NOEL is 0,33 mg/pound or 0,73 mg/kg of body weight. To calculate the ADI, worst case is the body weight of a 2 year old girl (11,5 kg according to WHO (
http://www.who.int/childgrowth/publi.../en/index.html
), equivalent to 25,4 pounds, so the lowest therapeutic dosage is 3,3 mg/pound * 25,4 pounds = 84 mg, and the ADI is then 8,4 mg. Hope I made no mistake.

Best regards

Alfred

3

Thanks Alfred,

Just to clarify, the NOEL is 8.4mg/11.5kg therefore 0.73mg/kg?
Or is the NOEL 8.4mg/kg?

Thanks

Nolene

4

Dear Nolene,

you are right, the NOEL is 0,73 mg/kg. The other figure, 8,4 mg, is the ADI. I will edit my previous answer in order not to let an unclear answer remain there forever.

Best regards

Alfred

5

Thanks Alfred,

I was also wondering if it is possible to calculate the NOEL from an LD50 value? I require to make the information comparable.

Thanks

Nolene

6

Dear Nolene,

A Piece of Advice for all those who are involved in the estimation of acceptance criteria for cleaning validation studies:
Use the alternate approaches for the estimation of ADI (acceptable daily intake) values only when all the necessary information (i.e. as required for using a direct approach) is not available. Let me explain you what do I mean by that? For example in your case you are interested in knowing NOEL value for Griseofulvin, which I think you want to use for the estimation of ADI and hence CV acceptance criterion. The direct approach for this is to use either a published or estimated (by your company for the product) NOEL value (as obtained from animal studies) for the calculation of ADI. Now, the alternate approach (or indirect approach) for the estimation of NOEL is using lowest therapeutic dose or LD50 values, which I strongly feel should be used only when the value from direct approach is not possible/available.

Now coming back to your query regarding griseofulvin. Griseofulvin is a known/proven carcinogen for which the NOEL shouldn’t be estimated using alternate approaches. Griseofulvin has a carcinogenic potency (TD50 value) of 13.8 mg/kg/day (Reference:
http://potency.berkeley.edu/chempages/GRISEOFULVIN.html
). I have managed to find ADI values for griseofulvin from two resources, you may use them directly for the estimation of CV acceptance criterion:
[LIST=1]

  • [b]50 µg/day[/b] (Reference: No Significant Risk Levels for Carcinogens, report by California Environmental Protection Agency, available here http://oehha.ca.gov/prop65/pdf/tb0194r2.pdf ), and
  • [b]0.036 mg/kg bw/day[/b] {Reference: Evaluation of the potential risks to consumers from indirect exposure to veterinary medicines (FINAL REPORT) by The Institute of Environment and Health (Cranfield University), available here http://randd.defra.gov.uk/Document.aspx?Document=VM02130_4772_FRA.doc}.

    Thanks.

    Ovais

    • 7

    Dear ovais,

    I agree completely with you. It is important to keep in mind that all these conversions (LD50 in NOEL and ADI) are only estimations, and that they should be the last resource if there are really no other data available.

    Best regards

    Alfred