How does one decide if a given compound is too hazardous to manufacture at a particular site? The answer to this question is much harder to arrive at than you might imagine.  It is very easy to spout glib, hand waving statements about risk analysis and risk based process safety. It is quite another matter to actually conceive of experiments to tease out the safety data and compile it into knowledge based practice.  For the manufacturer there are two kinds of operating hazards to contend with- 1) physical hazards, and 2) regulatory hazards.  Getting into trouble with either can bring your operation to a halt.

In general, there are two kinds of GO / NO GO approaches to the question of going forward with any given material. One method applies some kind of quantitative risk analysis based on accumulated knowledge combined with hazard thresholds defining acceptable risk. Regulatory compliance and insurance issues may apply, or not.

The other general approach is simply a management decision. The board of directors or CEO decrees that we’ll go forward and do what it takes to operate safely. Or management decrees that we will not go forward with the manufacture. We’ll let someone else have that plum.

I recall being at a propellants conference a few years ago where a representative from a solid propellants manufacturer asked me if we would consider making lead styphnate. I paused for a moment, as if to be carefully weighing my answer, and replied with a flat ‘no’.  The fellow wasn’t surprised and went on his merry way. This was the exercise of an informal method of process safety. Decline to make the obviously hazardous materials.

The threshold for the definition of hazardous materials varies considerably within industries and between them. The spread of hazard types across the manufacturing world is large and perhaps confusing.  Two of the broad types of manufacturing hazards are hazardous energy and toxicity.  Hazardous energy is found in operations with high pressure, flammable materials, mechanical energy, chemical reactivity, electrical energy, and explosive materials which is a combination of chemical reactivity and mechanical energy.

Toxicity

Toxic hazards are a group that cover a wide range of physiological effects and modes of dosing. Toxicity issues relating to manufacture can be a very complex matter and it is best to involve experienced hands to sort out the good sense fom the nonsense. To a large extent, the maufacture of toxic materials is covered by the proper application of personal protection equipment (PPE), good plant hygiene, and a process that keeps toxic materials contained to the greatest extent possible. The pharma people know all about this activity. But in the specialty chemicals business, a good deal of the chemical intermediates that go out the door have poorly understood toxicology.  

Products that are made for dispersal into the environment are subject to much greater oversight by EPA. But the same is not true for a great many chemical intermediates. Chemical intermediates flow through different  regulatory pipelines with some under thorough regulatory scrutiny and others considerably less so. Pharmaceutical intermediates may or may not be covered under FDA GMP rules. Very early intermediates may be items of commerce and not subject to the Byzantine ways of GMP. Later intermediates may have FDA requirements that handcuff you to the bedpost.  It is possible to have a very prosperous career outside of the GMP world.

Chemicals that are not for pharmaceutical or pesticide use may be listed under TSCA.  Chemical Abstracts Service maintains the list and access to entries is had through the CASRN, or the CAS registry number. TSCA is a type of oversight promulgated by the EPA and is intended to provide scrutiny in regard to worker exposure and environmental release during the execution of a chemical process. EPA does consider the toxicology and environmental  literature and is able to model the fate of a release into the air or water by calculation.

While specialty chemicals are subject to TSCA regulations and an approval by EPA, only cursory toxicological examination is customarily performed. TSCA approval is either in the form of a listing or through a low volume exemption. PSM regulations promulgated by OSHA provide regulatory crossfire on the manufacturer in that OSHA regulations require enough safety testing as to provide a safe working environment.  So together, OSHA and EPA cover a great deal of area in manufacturing safety. The rules are meant to be proactive, but they also provide substantial penalties for infractions. There is much more depth to TSCA and PSM than I have mentioned here, obviously. It is important to have people on staff who specialize in regulatory affairs.

Testing for toxicological effects is time and resource consuming. Much planning must go into such testing and it must be started well in advance of plant operations. Substances that pose a potential risk to workers via chronic occupational exposure during manufacture and handling are good candidates for such testing. However, if the substance is not a commodity chemical and if the substance is made only during infrequent campaigns for a limited group of users, it is less than likely that it will have been tested.  The best approach to manufacturing a substance with little data available on toxicity is through the use of precautionary guidelines with layers of protection for the operators. That is, design a process that prevents exposure of the workers to the product and offers redundancy in engineering and administrative controls. The coverage must include production operators, maintenance crews, warehouse workers, chemists, and engineers.

Hazardous Energy

Reactive hazards and hazardous energy issues can and should be investigated by the manufacturer to the greatest extent possible. While such activity can be farmed out to commercial labs, it is very important for management to grasp the benefis of in-house expertise.  Depth of knowledge is important in understanding and preventing  upset conditions. But the accumulation of such depth of knowledge is expensive and subject to throttling by management. It always involves accruing more information than is apparently needed, at least initially.

Science is to a large extent about understanding boundary conditions. In the same way, chemical safety requires understanding the conditions for the release of hazardous energy, decomposition, or other undesirable attributes.  What you’ll find quite often is that a single measurable attribute is not enough to assemble a complete picture of reactive hazards. Most reactive hazards are understood by assemblig a composite of several kinds of experimental results for a more complete appreciation of the dimensions of the reactivity.

To find such boundary conditions one needs to conceive of experiments to tease out the effects. Some kinds of information relating to safety issues can be obtained by instrumentation. Differential Scanning Calorimetry (DSC) is one such technique that gives a quantitative picture of the heat evolution of a substance while it is being heated over a planned temperature range. Thermogravimetric Analysis (TGA) of a test substance gives an indication of mass loss as a function of temperature. Accelerating Rate Calorimetry (ARC) shows heat flows into or out of a sample while recording sample cell pressure.  ARC goes a bit further than DSC in that the evolution of non-condensable gases can be inferred by the shape of a derived Anton curve. ARC also gives an indication of time to maximum rate (TMR), which is a useful parameter in determining the maximum temperature or residence time for a reactive material or mixture. Reaction Calorimetry (RC1)  shows the heat flux profile of an actual reaction mixture over the course of reagnt dosing. RC1 may be used to look for the accumulation of energy in a reactor. There are other tests available, but I cannot attest to them on the basis of personal experience.

Explosivity

Noninstrumental methods of safety appraisal include the tests for explosive properties. There are well defined protocols for explosive testing and they are applied in layers. It is very important for people handling new materials that may have explosive properties to understand the various assays for explosivity. 

Explosivity (or explosability) may be manifested in many ways and there are tests to tease out sensitivity to a measured stimulus. The key point I’m trying to make is that explosivity is a composite property sensitive to multiple kinds of stimulus and physical circumstances. Many materials are explosive only according to a few kinds of tests.

Safety testing for materials that may be energetic include BOM (Bureau of Mines) or BAM fall hammer tests and the BAM friction test. These tests do as the names suggest- look for thresholds for sensitivity to impact or friction.

The Koenen test  looks for explosivity when a material is heated under partial confinement, i.e., material is packed in a metal tube with a small hole in the end. Materials that are merely flammable will decompose and vent through the orifice. Compounds that are explosive may cause the Koenen tube to burst.

The time/pressure test is used in DOT classification and consists of a pressure vessel fitted with nichrome wire and a pressure sensor. The sample is heated with the nichrome wire or flame and the pressure is monitored. A pressure rise from 100 to 300 psi in 30 msec or less is regarded as having rapid deflagration properties and an qualifies as a positive indication for explosivity for transportation purposes. For the process chemical industry, this test gives an indication of the potential for rapid gas formation and the unwanted PV work it may do on your equipment.

There is a  series of tests used for DOT classification of explosive properties that will give useful insight for those who propose to manufacture intended or unintended energetic materials. It is useful to have material tested to assemble the composite picture of the materials sensitivity.  Questions to ask are: 1) does the material show any positive indications at all? 2) If explosive indications are found, is confinement required? 3)  Does the material show any detonability at all? 4) Can you fnd any sensitizers or catalysts to explosivity? 5) Does the material transition from deflagration to detonation? 6)  Is the material sensitive to stimulus by electrostatic discharge (ESD)? 7) What temperature gives a time to maximum rate (TMR) of 24 hours? 8) Do the decomposition products contain non-condensable gases?   There are more questions to ask. Remember not to confuse detonation with explosion.

For the chemist interested in manufacturing a product that has known reactive hazards associated with it, it is useful to have collated the data. The application of knowledge of reactive hazards depends greatly on the kind of equipment to be used and the kind of chemistry to be performed. It is possible nonetheless to make a few useful generalizations.

Accumulation of Hazardous Energy

The execution of a chemical process usually requires that two or more substances be put into physical contact in a solvent. This is a point at which hazardous energy may be evolved. Obviously, for promptly reacting systems the rate of heat generation must be less than the rate of heat removal to avoid a runaway situation. But special care must be taken for reactions that are not prompt and that might allow for the accumulation of unreacted material in the vessel. This unreacted material in a reation vessel represents an accumulation of potentially hazardous energy. Good process R&D will identify reactions with latent periods or reactions that are particularly slow to start. Problematic reactions require good in-process checks to ascertain the state of the rection. Very often, a heat kick is all you need to see to know the reatcion has begun.

Grignard reagent reactions are notorious for being slow to start, tempting operators to “goose” the reaction by adding more RX to the pot. Above about 10 % of RX over Mg, the potential for a runaway initiation is very high.  It is best to limit RX addition to a maximum of 5 %. If no initiation is observed after a reasonable attempt, the chemist must be awakened and hauled to the plant to provide on the spot guidance. Generally, initiation is a matter of time. But but sometimes parlor tricks must be used to activate the Mg. These are well known. It is always best to use these activation tricks prior to addition RX to the pot because otherwise a rapid consumption of RX may occur.

Solids Handling

It is always more desirable to handle sensitive or reactive materials in solution. They can be piped around under inert atmosphere and generally protected from environmental problems. However, sometimes there is no way to avoid the handling of reactive solids. That is, solids that are sensitive to O2 and/or water. The sensitivity may only go as far as quality control and specification problems. Or reactive hazards may be in play.

Solids handling is problematic in certain operations. Charging a reactor with reactive solids requires specialized solids handling equipment. Even non-reactive solids present a problem in handling. Dumping solids into an open manway can result inan  incendive electrostatic disharge. It’s made more serious if there is a flammable solvent in the vessel. Here is th rule- you don’t add solids into a reactor manway of there is the possibility of explosive dusts or flammable solvent in the pot.

Filtration is another problematic operation. Well, let’s say that opening the filter with reactive materials in it is a problem. If you use BuLi orRMgX, you probably have to do a  filtration at some point. Unless you quench the BuLi or RMgX in the pot, you are likely to have a hot filter cake.  While I cannot divulge any particular methods here, I can say that managers have to address this issue one way or another. It is especially exciting if the hot cake is wet with a flammable solvent. So, ESD and other ignition sources must be delt with when the filter is opened. Operators must be grounded and all locations for possible charge isolation must be accounted for.  It is best to open a filter in a location where having a hot cake fire is acceptable.

Filter cakes may be waste or product, depending on the circumstance. Drying operations in the filter must account for the accumulation of electrostatic energy as the material dries. It is important to have decay times for the solids if they are potentially energetic. Energetic materials that accumulate static must be allowed to decay their charge prior to handling. Of course, the prevention of charge accumulation is best. Propellant folks will coat granulated or pelletized product with charcoal or grapite to render the solids conductive.

Packaging

Chemists really hate to have to worry about packaging, but I can attest this is an activity that attracts quality control problems. Obviously reactive materials must be compatible with the  package materials of construction. Containers must seal properly.  Steel drums are useful for many kinds of materials, but the bungs can and do leak with temperature changes, so they can pull in moist air.  In terms of reactive hazards associated with containment, usually some choices have to be made. What kind of leak scenario is plausible and does the proposed container pose any special weaknesses? Drums are notoriously susceptable to being speared by forklifts. Cylinders too. 

What hazards are present for a workman who opens the drum with the hazardous material? Does the operator have to open the drum and put in a dip tube for pumping out the material? Perhaps a cylinder with a built in dip tube is safer.

Another matter to consider, especially with solids, is the issue of static charge generation during filling operations. Is the container or liner  conductive or dissapative? Are ESD procedures in place for safe handling?  Liquids can generate considerable static energy, especially when low dielectric constant liquids travel through a plastic pipe.  Transfer of flammable organic fluids should take place in grounded or bonded conductive pipe to the greatest extent possible to avoid charge isolation.

All equipment should be grounded or bonded via a ground that is periodically tested for integrity. Everything should be at the same potential as the ground.  Cement floors are dissipative, but painted cement floors are not. Wooden pallets and fibreboard packaging are dissipative when sitting on bare concrete.

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