1. Basic information OEL & PBOEL-HHC for API & IPI
Level 1
Updated December 2010
- Information provided subject to the 'Conditions for Sharing Materials and Advice' -
- Information provided subject to the 'Conditions for Sharing Materials and Advice' -

2. Objective
To learn about exposure limits, particularly for Active Pharmaceutical Ingredient and Isolated Process Intermediates (APIs and IPIs)
To understand how exposure limits are derived
To know where you get the information you need and how you use it

3. Hazardous substances
Hazardous substances are substances that can have a harmful effect on health
Examples:
Chemicals – organic solvents, acids, pharmaceutical ingredients…
Dust – metal dust, wood dust, flour…
Fumes – welding, soldering…
Fibres – asbestos

4. Hazardous substances can enter the body
inhalation
dermal
ingestion

5. Acute effects – immediate reaction
Type of Health Effects
Acute effects – immediate reaction
Chronic effects – develop over years

6. Potency of Hazardous Substances
Snake poison – < 100mg can kill
Alcohol-2000mg gives effect
ten times that amount can kill
Nicotine- 2mg gives effect
50mg can kill

7. Occupational Exposure Limit OEL
Describing the hazard
We need to know how much of a hazardous substance a worker can breathe without harm
This is given by the
Occupational Exposure Limit
OEL

8. Occupational Exposure Limits
The OEL is the concentration in the air to which nearly all workers may be repeatedly exposed day after day without adverse health effects to themselves or their children.
Termed Threshold Limit Value TLV by ACGIH
(ACGIH is an American organisation for industrial hygiene)

9. OELs do not provide universal protection.
OELs - caution
OELs do not provide universal protection.
Adverse effects may occur despite adherence to the OEL due to reasons such as:
Individual sensitivity
pregnancy
pre-existing illness

10. Variation of exposure with time
Exposure patterns vary, some tasks give high exposure, others none. Some shifts give more exposure than others
Shift durations vary, typically between 8 and 12 hours
To compare exposures for different situations, we need a fixed reference period

11. OEL reference periods – 8 hours
8 hour reference period – (ACGIH descriptor TLV-TWA)
This is the main reference period and is concerned with chronic effects. When the worker exposure is measured, it is calculated what concentration it would be if the exposure was constant over 8 hours – called the 8 hour Time Weighted Average, or daily exposure
The 8 hour OEL is the 8 hour TWA exposure to which it is believed that nearly all workers may be repeatedly exposed, day after day, for a working lifetime, without adverse effect

12. OEL reference periods – 15 minutes and ceiling
15 minute reference period – called Short Term Exposure Limit (STEL)
Ceiling (TLV-C) – the concentration that should not be exceeded during any part of the working exposure
These are concerned with acute effects. The worker exposure is measured over the period when the exposure is greatest, and the 15 minute average or maximum level is determined. These are compared with the STEL and Ceiling limit respectively
The 15 minute TWA exposure should not be exceeded at any time during a work day, even if the 8 hour TWA is within the TLV-TWA. Exposures (re. 15 mins) above the TLV-TWA but below the TLV-STEL should not occur more than 4 times a day, with 60 minutes at least between successive exposures
The ceiling limit should not be exceeded during any part of the working exposure.

13. Who assigns Occupational Exposure Limits?
Who assigns OELs?
For common hazardous substances
Your national health and safety authority
ACGIH (called Threshold Limit Value, TLV)
For pharmaceutical ingredients
J&J corporate toxicologists

14. Order from www.acgih.org
ACGIH TLVs
Order from
The OEL set by your health and safety authority and ACGIH might be different
USE THE LOWER OEL

15. Examples of OELs set by ACGIH (values 2007)
Hazardous substance
Threshold Limit Value
TLV
8 hour
15 minute
Isopropyl alcohol
200ppm
400ppm
Benzene
0.5ppm
2.5ppm
Ammonia
25ppm
35ppm
Acrolein -
C 0.1ppm
Particles not otherwise specified
10 mg/m3
Cobalt
0.02 mg/m3
An instantaneous ceiling value that should not be exceeded
Source: ACGIH 2007

16. As the proportion of molecules
Concentration Units
As mass in unit volume 1m
1 mg /m3 is 1 mg in a cubic meter
1 μg /m3 is 1 μg in a cubic meter
1000 μg /m3 = 1 mg/m3
As the proportion of molecules
1 ppm is one part (molecule) in a million
1ppb is one part in a billion
1000 ppb = 1 ppm

17. OELs for APIs and IPIs
National and international bodies do not set OELs for APIs and IPIs
OELs for APIs and IPIs are set by the company that has developed them or are manufacturing them
API : Active Pharmaceutical Ingredients
IPI: Isolated Process Intermediates

18. Setting an OEL – what to consider
Sources of information
Animal studies
Pharmaceutical trials
These indicate the lowest active dose, or the dose where there is no observed adverse effect
Things that influence the effect on the body
Amount you breath in (10 m3 per day)
Body weight
How long the chemical stays in the body
Amount absorbed by body
Any hazardous substances formed in the body

19. Setting an OEL for APIs & APIs – how it is calculated
OEL (mg/m3) = NOEL (mg/kg/day) x BW (kg) V (m3/day) x S x UF x 
  NOEL = the no-observable-effect-level (mg/kg/day)
BW = average human body weight (50 kg)
V = volume of air breathed in an 8-hr work day (10 m3/day)
S = time, in days, to achieve a plasma steady state
UF = uncertainty factors
 (alpha) = % absorbed through inhalation

20. Typical Notes given with OELs
If carcinogenic, mutagenic or reproductive toxin
Skin: Substances which have the capacity to penetrate intact skin
Sensitization: where skin or respiratory sensitization could occur (that is, where intense response occurs to low concentrations after a person has become sensitised)
BEI: if a biological exposure index has been recommended for the substance

21. Acceptable Surface Limits
A surface limit is sometimes set. It is helpful :
if there might be significant exposure through the skin
if potent substances might be re-suspended and inhaled
to indicate contamination of surfaces

22. Acceptable Surface Limits
ASL
The ASL is the acceptable mass on a specified surface area
(typically 10 x 10 cm, the area of palms of hand)
Often set at 10 times the OEL for an area of 100cm2
Not as frequently used as OEL
Not set by ACGIH for any substance

23. What to do with the OEL …
Compare the results from your exposure monitoring surveys with the OEL to check if the exposure is OK

24. Evaluate exposure by comparing measured TWA exposure with OEL
Exposure exceeds OEL
Exposure as % of OEL
Exposure well below OEL

25. What to do with the OEL … Conc outside mask Conc inside mask =
If you use Respiratory Protection Equipment, compare the calculated exposure inside the mask with the OEL to check if the effective exposure is OK
Use the protection factor of the mask to get the concentration inside the mask
Conc inside mask =
Conc outside mask
Protection factor

26. What to do with the ASL…
Compare the measured surface concentration with the ASL to check that surface contamination levels are OK
Measure surface contamination on skin, if feasible, and compare result with ASL

27. J&J hazard classification for API & IPI
When drugs are in an early stage of development, there is not enough information available to set an OEL, but controls must be implemented
J&J uses a hazard classification system to group pharmaceutical ingredients according to their hazard called PbOEL-HHC (PbOEL- Health Hazard Categories)

28. OEL ranges of the PbOEL-HHCs
Categories
1A >1000 – 3000 g/m3
1B >100 – <1000 g/m3 
2 >20 – <100 g/m3
3A >5 - <20 g/m3
3B >.5 g/m3– <5 g/m3
4 < .5 g/m3

29. PbOEL-HHC versus OEL
A PbOEL-HHC is set at a very early stage in drug development, before there is enough information to set an OEL
Information is compiled in the PbOEL-HHC summary

30. Examples of OEL’s and PbOELs for API’s and IPI’s
Substance
OEL mg/m3
PbOEL category
Ketoconazole
0.2 1B
Nicotine
0.070 2
Nebivolol hydrochloride
0.015 3A
Risperidone
0.0025 3B
Fentanyl
0.0001 4
Remark: These values can change - always consult the most recent global PbOEL-HHC OEL list for actual information!

31. OEL monographs
When corporate toxicologists assign exposure limits, they publish an OEL monograph. This document contains useful information such as:
PbOEL-HHC / OEL / ASL / notations (e.g. sensitizer)
Description of substance
Toxicology of substance
How the substance acts in the body
Relevant data from laboratory tests, field trials or epidemiological studies
How the OEL was derived
References

32. Summary
The hazard associated with an API/IPI is quantified by a PbOEL-HHC, an OEL and sometimes an ASL
APIs/IPIs are assigned to one of the 6 PbOEL-HHCs, depending on how hazardous they are. PbOEL-HHC 1A is the least hazardous, PbOEL-HHC 4 is the most hazardous category
An OEL is a limit for the exposure to hazardous substances by inhalation. The reference periods are 8 hours and/or 15 minutes
An ASL is a limit for the dermal exposure to hazardous substances. The reference area is typically 100cm2. This is only assigned if the dermal route is a significant exposure path
PbOEL-HHCs/OELs /ASLs for APIs/IPIs are set by J&J
The OEL monograph contains these limits and other useful information
Use these limits as the input for the risk assessment to design controls and to monitor their effectiveness