Biopharma Consulting

PDE determination for health based limits

Determination of a PDE (Permitted Daily Exposure) for XXXXXXXX in Relation to Calculation of a Health-Based Exposure Limit

Chemical Structure


CAS number: AB-CD-E

Alternative name: XXXXXXXXXXX


Search Strategy

The main sources of information are:

·         UK SmPC:

·         FDA label:

·         CPDB:

·         NTP studies (1989):

·         WHO assessment:


The methodology employed for PDE determination is as described in the appropriate EMA guidance on setting of health-based exposure limits:


In the conversion of the mg/kg PDE to exposure in a typical patient, a bodyweight of 50 kg is assumed (as recommended in the above guidance).



PDE Determination Strategy


Company Name: XXXXXXXX


Company Address: XXXXXXXX

Expert Name and Signature: David J Snodin



Date: XX January 2017


Assessment Review Date: January 2019


Chemical Name/s: XXXXXXXXX

Hazards Identified


YES                NO           UNKNOWN

*Genotoxicant                                                                                                  X

**Reproductive developmental toxicant                        X                                                    

***Carcinogen                                                                                                 X

Highly sensitizing potential                                                                                   X

*Negative in Ames and multiple other in-vitro and in-vivo assays

** Animal studies indicate no adverse effects on fertility and no embryotoxicity apart from a reduction in ossification of fetuses derived from pregnant rats given high doses; SmPC advice is to avoid use in pregnancy

***Conventional rodent carcinogenicity bioassays negative


Basis for the PDE

XXXXX is used to treat a wide range of infections, the most intensive dosage regimen involving the administration of 4×500 mg/day for up to 30 days. Extremely high doses can be given in conventional toxicity studies, generally with no adverse effects, apart from vacuolization of liver cells and bone marrow atrophy noted in the rat at 1250 and 2500 mg/kg bw/day over 13 weeks (NOAEL = 625 mg/kg/day). In a 2-year study in the dog no adverse effects were noted at doses up to 250 mg/kg/day. This is used as a NOAEL for PDE determination. Assessment factors are: F1=2 (dog allometric factor) F2=10 (standard safety factor); F3=5 (2-year study in nonrodent); F4=10 (reproductive toxicity at doses that are not particularly toxic); F5=1 (NOAEL established). Hence PDE = 250/2x10x5x10x1 = 250/1000 = 0.25 mg/kg/day, equivalent to 12.5 mg in a 50 kg patient.




Publication(s) used to identify the critical effect and dose.

·         UK SmPC:

·         CPDB:

·         NTP studies (1989):

·         WHO assessment:




Summary of the Expert’s CV