Hi everybody,
I am working with the EMA guideline on setting health based exposure limits. The procedure to calculate permitted daily exposure ( PDE) includes:
(i) hazard identification by reviewing all relevant data,
(ii) identification of “critical effects”,
(iii) determination of the no-observed-adverse-effect level (NOAEL) of the findings that are considered to be critical effects, and
(iv) use of several adjustment factors to account for various uncertainties.
I'm not clearly about the third step. How can we choose critical effects for each API? Could you please give me an example?
Thank you very much!
Critical Effect of each API
The API products of each group will be selected based on the following:
1) The product containing the least soluble material.
2) The product containing the most toxic and potent material.
3) The product deemed “hard to clean” by production/laboratory staff.
The above-mentioned criteria [1), 2) and 3)] will be assessed to select critical effects of individual APIs. Refer to Table A below for a listing of key physical characteristics of each active ingredient. Refer to Table B for legend description of solubility nomenclature.
See attachment Ong.
Hope this helps a bit.
You will require to do solubility and toxicity of each API. Maybe not, if you are lucky you can get all that info from the C of A for each API. (Certificate of Analysis = C of A).
Acetaminophen
VSS (1)
rat = 1944
mouse = 338
80
ASA
VSS (3.3)
rat = 891
mouse = 480
325
Caffeine
SP.S (21)
rat = 192
mouse = 127
15
Chlorpheniramine Maleate
VS (250)
rat = 188
mouse = 133
2
Codeine Phosphate
FS (400)
mice = 300
8
Dextromethorphan HBr
SP.S (15)
rat = 350
mouse = 165
15
Dimenhydrinate
SP.S (3)
rat = 1320
mouse = 203
50
Diphenhydramine HCL
FS (1000)
rat = 500
mouse = 164
25
Doxylamine Succinate
VS (1000)
mouse = 470
6.25
Guaifenesin
I in cold water (50)
rat = 1510
mouse = 690
100
Methocarbamol
SP.S (25)
rat = 1320
mouse = 812
hamster=1410
400
Pamabrom
FS
rat = 940
25
Pseudoephedrine HCL
VS (250)
mouse = 371
30
Pyrilamine Maleate
VS (2000)
rat = 365
mouse = 220
The worst-case products (API) of each group will be selected based on the following:1) The product containing the least soluble material.2) The product containing the most toxic and potent material.3) The product deemed “hard to clean” by production staff. The above-mentioned criteria [1), 2) and 3)] will be assessed to select one worst-case product representing all scenarios. You must create a Table Active Ingredients (OTC’s)Solubility in Water (mg/mL)Oral LD 50 (mg/kg)Smallest Therapeutic Dose (mg)
Active Ingredients (OTC’s)
Solubility in Water (mg/mL)
Oral LD 50 (mg/kg)
Smallest Therapeutic Dose (mg)
Acetaminophen
VSS (1)
rat = 1944
mouse = 338
80
ASA
VSS (3.3)
rat = 891
mouse = 480
325
Caffeine
SP.S (21)
rat = 192
mouse = 127
15
Chlorpheniramine Maleate
VS (250)
rat = 188
mouse = 133
2
Codeine Phosphate
FS (400)
mice = 300
8
Dextromethorphan HBr
SP.S (15)
rat = 350
mouse = 165
15
Dimenhydrinate
SP.S (3)
rat = 1320
mouse = 203
50
Diphenhydramine HCL
FS (1000)
rat = 500
mouse = 164
25
Doxylamine Succinate
VS (1000)
mouse = 470
6.25
Guaifenesin
I in cold water (50)
rat = 1510
mouse = 690
100
Methocarbamol
SP.S (25)
rat = 1320
mouse = 812
hamster=1410
400
Pamabrom
FS
rat = 940
25
Pseudoephedrine HCL
VS (250)
mouse = 371
30
Pyrilamine Maleate
VS (2000)
rat = 365
mouse = 220
15
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