Category 4 or 5 Potent Compounds: Understanding the Risks

Here at Affygility Solutions, we often get asked the questions "What makes a Category 4 or Category 5 potent compound?" In addition, we often get asked, "What are some examples of Category 4 or Category 5 potent compounds?" In this article, Dr. Jim Damewood, Senior Director of Occupational Toxicology and Industrial Hygeine with Affygility Solutions and Dean M. Calhoun, CIH, President and CEO of Affygility Solutions discussed answers to these two questions.

What determines a Category 4 or 5 Potent Compound?

Dean Calhoun: Good afternoon, Jim. As you know, here at Affygility Solutions, we often get asked the question "What determines a Category 4 or 5 Potent Compound?" Can you provide some insight regarding this question?

Jim Damewood: Thanks Dean. The categorization of an active pharmaceutical ingredient into a Category 4 or 5 occupational health category is based on the toxicology of the compound. The evaluation of the toxicological profile considers many factors and is performed by expert review and there can be different reasons why a compound is placed in Category 4 or 5.

Pharmaceutical compounds in Category 4 or 5 may have very high acute toxicity, where even a limited, short-term exposure has the potential to cause harm. Or compounds in this category may have serious long-term consequences, like having a high probability of causing cancer. Pharmaceutical compounds in Category 4 or 5 may also have major effects on biochemical functions within us, such as hormonal balance. These potent chemicals can affect fertility and can have major influences on fetal development. Finally, what we don’t know can elevate a compound to higher categories. For example, genotoxic compounds can be associated with the development of cancer and birth defects. If we don’t know anything about the genotoxicity of a compound, as a precautionary measure, it may be placed in Category 4.

When classifying all compounds into categories we consider many factors. This is largely based on data from animal studies, but for pharmaceuticals in later stage development or on the market, human data may also be available. We consider the results of acute or short-term exposure to the compound as well as what is observed during longer term studies. We consider whether the compound is genotoxic or not.

Does the compound produce sensitization or allergic responses? What is known about the carcinogenic potential of the compound? What is the therapeutic target of the compound and does that suggest potential hazards for non-patients? Has the compound demonstrated the ability to affect fertility or the developing fetus? Is the compound a teratogen, meaning has it shown the ability to cause malformations in offspring? Does the compound expected to clear a worker’s system by the start of the next shift, or does it have the possibility of having an ever-increasing exposure throughout the week? Are there known side effects such as cardiovascular effects or neurological effects that need to be considered beyond the therapeutic indication?

Not all Category 4 or 5 compounds demonstrate hazards in all of these areas, but across the board, all Category 4 or 5 compounds demonstrate or have the potential to demonstrate considerable hazards.

Category 4 and 5 compounds might also offer little warning signs when over exposure occurs, depending on their hazard profile and medical attention could, in some cases, be immediately required.

DC: All right, thank you. Now that we have answered the questions on what determines a Category 4 or Category 5 potent compound, what is the impact on a company when their compound is assigned to a Category 4 or Category 5 control band?

JD: These are compounds that are going to require very special handling. Companies will have an isolation suite with the proper containment devices and engineering controls, administrative procedures, and personal protective equipment.

DC: Do you ever see a case where a compound was initially assigned to be a Category 4 or Category 5 compound, where after more clinical data comes in, is lowered to a Category 3 compound?

JD: It is certainly possible. Some studies are often not undertaken until later in a drug discovery program such as developmental studies. During an early evaluation a compound may have a profile that includes a mechanism of action known to often lead to developmental issues. Until those experiments are completed, the assumption will be that the compound could be a developmental hazard. Once completed, it may be discovered that the compound is not, in fact, a developmental hazard. Depending on the rest of the profile for the compound, this could result in a lowering of the Category.

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Examples of Category 4 and Category 5 Potent Compounds

DC: Great, that answers that question. Now, can you provide a few examples of Category 4 and Category 5 potent compounds and what characteristics makes those types of compounds?

JD: Sure. Ethinyl Estradiol is a good example. It is a semisynthetic estradiol that is used as an oral contraceptive. It is considered to be a carcinogen by the International Agency for Research on Cancer (IARC), and it has been found to be genotoxic in a number of assays. Its mechanism of action is to affect reproduction, a desired outcome for the patient, but not for the general worker. Compounds with strong estrogenic activity such as ethinyl estradiol can also have significant effects on development. Like hormones themselves, it is extremely potent, with a recommended dose as low as 0.01 mg/day.

Another example is Thiotepa. This anticancer compound is a cytotoxic alkylating agent that stops tumor growth by crosslinking DNA bases. Thiotepa is genotoxic, carcinogenic, causes reproductive effects and causes myeloid suppression. In addition to these toxicological hazards, thiotepa is also capable of explosive decomposition on contact with acid or when heated above 40 oC.

Finally, another great example is lactase. Lactase is the enzyme that is responsible for breaking lactose into simple sugars. Lactase is an enzyme and in powdered for it is a powerful sensitizer. Sensitization is an allergic response and it is very difficult to predict how any given individual will react. The reaction can be extremely serious, however, so for lactase and other enzymes in powdered form, the accepted occupational exposure level is at nanograms per cubic meter.

DC: Well that was really good and we are almost out of time, so is there anything else that you would like to say before we end?

JD: Thanks Dean, only that please feel free to contact us at Affygility Solutions if you would like more information on occupational toxicology, industrial hygiene in the pharmaceutical industry, control banding, or potent compound safety.

Published May 16, 2011 , Updated August 28, 2019