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Hazard Analysis and Risk-Based 

Preventive Controls for Human Food: 

Draft Guidance for Industry1

This draft guidance, when finalized, will represent the current thinking of the Food and Drug 

Administration (FDA or we) on this topic. It does not establish any rights for any person and is 

not binding on FDA or the public. You can use an alternative approach if it satisfies the 

requirements of the applicable statutes and regulations. To discuss an alternative approach, 

contact FDA’s Technical Assistance Network by submitting your question

at https://www.fda.gov/Food/GuidanceRegulation/FSMA/ucm459719.htm.

Chapter 3: Potential Hazards Associated with the 

Manufacturing, Processing, Packing, and Holding of Human 

Food 

Table of Contents

3.1 Purpose of this Chapter

3.2 Potential Hazards

3.3 Biological Hazards

3.3.1 Characteristics of Vegetative Foodborne Pathogens

3.3.2 Characteristics of Spore-Forming Foodborne Pathogens

3.3.3 Potential Ingredient-Related Biological Hazards

3.3.4 Potential Process-Related Biological Hazards

3.3.4.1 Bacterial pathogens (vegetative and sporeforming) that survive after 

treatment

3.3.4.2 Bacterial pathogens that grow and/or produce toxin

3.3.4.3 Bacterial pathogens in ingredients added after process controls

 1 This guidance has been prepared by the Office of Food Safety in the Center for Food Safety and 

Applied Nutrition at the U.S. Food and Drug Administration. Underlined text in yellow highlights 

represents a correction from the draft Chapter 3 that we issued for public comment in August 2016.
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3.3.4.4 Bacterial pathogens introduced after packaging due to lack of container 

integrity

3.3.5 Potential Facility-Related Biological Hazards

3.3.5.1 Sources of facility-related biological hazards

3.3.5.2 Transient vs. resident facility-related environmental pathogens

3.3.5.3 Facility-related environmental pathogens associated with wet vs. dry 

processing environments

3.4 Chemical Hazards

3.4.1 Ingredient-Related Chemical Hazards

3.4.1.1 Pesticides

3.4.1.2 Animal drug residues

3.4.1.3 Heavy metals

3.4.1.4 Environmental contaminants

3.4.1.5 Mycotoxins and other natural toxins

3.4.1.6 Chemical hazards that may be intentionally introduced for purposes of 

economic gain

3.4.2 Chemical Hazards That Can Be Either Ingredient-Related or ProcessRelated

3.4.2.1 Food allergens

3.4.2.2 Food additives, color additives, and GRAS substances, including 

substances associated with food intolerance or food disorder

3.4.2.3 Process contaminants produced during heating

3.4.2.4 Radiological hazards

3.4.3 Facility-Related Chemical Hazards

3.5 Physical Hazards

3.6 References

3.1 Purpose of this Chapter

The guidance in this chapter is intended to help you consider the biological, chemical, and 

physical hazards that are commonly of concern in food plants and that should be addressed in a 

hazard analysis. It addresses ingredient-related hazards, process-related hazards, and hazards 

that may be introduced from the food-production environment (facility-related hazards). It does 

not provide an exhaustive compendium of hazards or details about each hazard. Where 

possible, we cite scientific literature, regulations, and/or guidance (issued by FDA or our food 

safety regulatory partners) that may provide useful detailed discussion or analysis of hazards of 

concern. See the definition of “hazard” in 21 CFR 117.3. 
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It is important for you to understand the potential hazards that may be associated with your 

products using the raw materials and other ingredients, processes, and equipment specific for 

those products, as well as the environment of your specific facility. If you identify hazards 

requiring a preventive control, you will then have to determine what preventive controls are 

needed to reduce food safety risks and ensure the safety of your products for human 

consumption. See 21 CFR 117.130 and 117.135. Although this chapter briefly describes the 

types of preventive controls that may be appropriate for you to implement to control certain 

hazards, see Chapter 4 and Chapters 6 through 13 of this guidance for more detailed 

discussion of applicable preventive controls. 

3.2 Potential Hazards 

Food products can become contaminated with biological, chemical (including radiological), or 

physical hazards. Table 3-1 provides examples of potential hazards and is not exhaustive. 

Table 3-1 Examples of Potential Hazards 

Hazard Category Hazard Sub-category Examples

Biological Bacteria • Bacillus cereus (B. cereus)

• Campylobacter jejuni (C. jejuni)

• Clostridium botulinum (C. botulinum)

• Clostridium perfringens (C. perfringens)

• Shiga-toxin producing Escherichia coli

such as O157:H7 (E. coli O157:H7)

• Listeria monocytogenes (L. 

monocytogenes)

• Salmonella spp.

• Shigella spp.

• Staphylococcus aureus (S. aureus)

Biological Protozoa and Parasites • Cryptosporidium parvum

• Cyclospora cayetanensis

• Giardia lamblia (G. intestinalis)

• Trichinella spiralis

Biological Viruses • Norovirus

• Hepatitis A

• Rotavirus

Chemical Pesticide residues • Organophosphates

• Carbamates 

• Chlorinated hydrocarbons

• Pyrethroids

Chemical Heavy Metals • Lead

• Arsenic

• Cadmium

• Mercury

Chemical Drug residues (veterinary 

antibiotics)

• Chloramphenicol

• Beta- Lactams
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Hazard Category Hazard Sub-category Examples

Chemical Industrial chemicals • Ammonia

Chemical Environmental contaminants • Dioxins

Chemical Mycotoxins • Aflatoxin

• Patulin

• Ochratoxin

• Fumonisin

• Deoxynivalenol

Chemical Allergens • Milk, eggs, fish, crustacean shellfish, tree 

nuts, peanuts, wheat, and soybeans

(commonly called “the Big 8”)

Chemical Unapproved colors and 

additives

• FD&C Red #4

• Melamine

Chemical Substances associated with a 

food intolerance or food 

disorder

• Lactose

• Yellow #5

• Sulfites

• Carmine and Cochineal

• Gluten

Chemical Radionuclides • Radium 226 and 228

• Uranium 235 and 238

• Strontium 90

• Cesium 137

• Iodine 131

Physical N/A • Metal

• Glass

• Hard plastic

As discussed in Chapter 2 of this guidance, when conducting your hazard analysis you must 

consider the potential for biological, chemical, and physical hazards to be related to raw 

materials and other ingredients (ingredient-related hazards), processes (process-related 

hazards), and the food-production environment (facility-related hazards) (21 CFR 117.130). In 

Chapter 2 we also provide examples of questions to be considered when identifying potential 

hazards in the following areas:

• Ingredients;

• Intrinsic factors; 

• Processing procedures; 

• Microbial content of the food; 

• Facility design; 

• Equipment design and use; 

• Packaging; 
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• Employee health, hygiene, and education; and

• Storage conditions between packaging and the end user.

Throughout this chapter, we discuss potential biological, chemical, and physical hazards from 

the perspective of ingredient-related hazards, process-related hazards, and facility-related 

hazards, considering the issues and factors listed immediately above.

3.3 Biological Hazards

You must conduct a hazard analysis to identify and evaluate known or reasonably foreseeable 

biological hazards, including microbiological hazards such as parasites, environmental 

pathogens, and other pathogens. See 21 CFR 117.130(b)(1)(i). When your hazard analysis 

identifies a known or reasonably foreseeable biological hazard that requires a preventive 

control, you must identify and implement a preventive control for the biological hazard. See 21 

CFR 117.135(a)(1). 

The biological hazards that are the focus of this guidance are bacterial pathogens (e.g., 

Salmonella spp., Listeria monocytogenes, Clostridium botulinum, and Shiga-toxin producing 

Escherichia coli (STEC) such as O157:H7) that may be associated with foods or food 

processing operations and can cause consumer illness or disease. The other biological 

hazards, viruses (e.g., norovirus and hepatitis A) and parasites (e.g., Cryptosporidium spp. and 

Giardia intestinalis), are also known to cause illness or disease, but these would generally be 

addressed by following Current Good Manufacturing Practice (e.g., worker hygiene and disease 

control) in facilities and our regulation entitled “Standards for the Growing, Harvesting, Packing, 

and Holding of Produce for Human Consumption” (21 CFR part 112) (e.g., worker hygiene and 

disease control, water safety) on farms that supply raw agricultural commodities to facilities. 

Food products can become contaminated with bacterial pathogens that can be:

• Ingredient-related hazards - i.e., introduced from raw materials and other ingredients; 

• Process-related hazards - e.g., if the pathogens:

o Survive processing that was intended to significantly minimize the pathogen;

o Increase in number due to lack of time/temperature control or due to the food’s 

formulation; or

o Selectively grow, and/or produce toxin, in a food as a result of using reduced oxygen 

packaging; 

• Facility-related hazards – e.g., if the pathogens are introduced from:

o Food processing equipment (e.g., insanitary equipment and utensils);

o Cross-contamination between raw and cooked products; 

o Air; or

o Contaminated water or sewage; or

• People-related hazards – e.g., due to people handling the product during packing or 

processing. (Such people-related hazards are sometimes controlled by following Current 

Good Manufacturing Practice (e.g., worker hygiene and disease control)).
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For further details on the sources of biological hazards that can be introduced into food 

products, see Tables 1A through1Q and Tables 3A through 3Q of Appendix 1 of this guidance.

Bacterial pathogens can be classified based on whether they form spores (“sporeformers”) or 

whether they only exist as vegetative cells and do not form spores (“non-sporeformers”). Spores 

are not hazardous as long as they remain in the spore state. Unfortunately, spores are very 

resistant to heat, chemicals, and other treatments that would normally kill vegetative cells of 

both sporeformers and non-sporeformers. As a result, when spores are a concern, the process 

steps used to kill them are often much more severe than those necessary to kill vegetative cells.

When spores survive a processing step designed to kill vegetative bacteria, they may become a 

hazard in the food if they are exposed to conditions that allow germination and growth as 

vegetative cells. This can be particularly serious when a processing step has removed most of 

their competition. Thus, other controls such as reduced pH or water activity (aw) or temperature 

control (refrigeration or freezing) may be needed to control sporeformers that remain after a kill 

step. 

Because the characteristics of foodborne pathogens differ, the preventive controls that you 

identify and implement to control specific pathogens should be based on the characteristics of 

those specific pathogens. In the remainder of this section on biological hazards, we briefly

review characteristics of common vegetative and sporeforming foodborne pathogens. For more 

detailed information, see FDA’s Bad Bug Book (FDA 2012c).

Table 3-2 is a Quick Reference Guide to help you identify potential pathogens by biological 

classification and potential sources or entry points in your facility. The potential hazards listed in 

Table 3-2 will not apply to all facilities. 

Table 3-2 Quick Reference Guide for Common Sources of Biological Hazards

Primary Source Bacteria Parasites Viruses

Ingredient-related (e.g., 

contamination of raw 

materials and other 

ingredients)

• Salmonella spp. (e.g., 

poultry, produce, nuts)

• E. coli O157:H7 & similar 

STEC (e.g., ruminant 

animals, dropped fruit, 

sprouts)

• Campylobacter spp. (e.g., 

poultry and raw milk)

• B. cereus (e.g., rice and 

other grains)

• C. botulinum (spores may 

be found in soil and on 

certain root crops.)

• C. perfringens (e.g., 

spices, may come in soil 

on produce)

• L. monocytogenes (e.g., 

raw agricultural 

commodities, other 

contaminated products

used as ingredients)

• Cryptosporidium 

parvum (contaminated 

water used as an 

ingredient)

• Cyclospora 

cayetanensis (berries)

• Toxoplasma gondii

(meat)

• Norovirus 

(produce, 

shellfish)

• Hepatitis A virus 

(produce, fruits)
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Primary Source Bacteria Parasites Viruses

Process-related (e.g., 

poor or ineffective 

process controls, 

including by a supplier)

• Salmonella spp. survive 

inadequate heat 

treatment

• C. perfringens (improperly 

cooled cooked foods)

• L. monocytogenes (raw 

agricultural commodities, 

contaminated products)

Cryptosporidium parvum

(contaminated water 

source)

N/A

Facility-related (may be 

caused by poor 

sanitation practices (e.g., 

inadequate cleaning and 

sanitizing of potential 

harborage sites), poor 

plant and equipment 

design, and poor pest 

management practices)

• L. monocytogenes (e.g., 

reservoirs include floors, 

cold wet areas, 

equipment, drains, 

condensate, coolers, and 

soil)

• Salmonella spp. (pests)

N/A Norovirus (only 

when active 

shedding occurs in 

facility through 

vomiting and 

diarrhea)

People-related 

(individuals who are 

carriers, showing no 

signs of disease, who 

are shedding the hazard, 

or who are infected and 

are actively ill)

• S. aureus 

• Shigella spp.

• Salmonella spp.

Cryptosporidium parvum • Hepatitis A virus 

• Norovirus

• Rotavirus

3.3.1 Characteristics of Vegetative Foodborne Pathogens 

Table 3-A in Appendix 3 of this guidance contains information on the physical conditions (i.e., 

aw, acidity (pH), temperature, and oxygen requirements) that will limit growth for most of the 

vegetative pathogens that are of greatest concern in food processing. Data shown are the 

minimum or maximum values - i.e., the extreme limits reported among the references cited. 

These values may have been obtained in laboratory media, which may be more favorable to 

growth than many foods. These values may not apply to your specific processing conditions.

Brucella spp. is the bacterium responsible for brucellosis. An estimated 840 foodborne cases 

of brucellosis occur annually in the United States (Scallan et al., 2011) When sheep, goats, 

cows, or camels are infected with the pathogen, their milk becomes contaminated with the 

bacteria. The most common way for humans to be infected is by eating or drinking 

unpasteurized/raw dairy products from infected animals. Brucella can also enter the body 

through skin wounds or mucous membranes following contact with infected animals. Symptoms 

include: fever; sweats; malaise; anorexia; headache; pain in muscles, joints and/or back; and 

fatigue. Some signs and symptoms may persist for prolonged periods of time or may never go 

away.

Campylobacter jejuni (C. jejuni) is the bacterium responsible for campylobacteriosis. An 

estimated 845,000 foodborne cases of campylobacteriosis occur annually in the United States

(Scallan et al., 2011). Symptoms include diarrhea, fever, abdominal pain, nausea, headache, 

and muscle pain. Symptoms start from 2 to 5 days after consumption of contaminated food and 

last from 7 to 10 days. A small percentage of patients develop complications that may be 
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severe. These include bacteremia and infection of various organ systems, such as meningitis, 

hepatitis, cholecystitis, and pancreatitis. Autoimmune disorders are another potential long-term 

complication associated with campylobacteriosis; for example, Guillain-Barré syndrome (GBS).

Everyone is susceptible to infection by C. jejuni. Campylobacteriosis occurs more frequently in 

the summer months than in the winter.

Pathogenic strains of Escherichia coli (E. coli) are responsible for four types of illness: 

gastroenteritis or infantile diarrhea, caused by enteropathogenic E. coli (EPEC); travelers’ 

diarrhea, caused by enterotoxigenic E. coli (ETEC); bacillary dysentery, caused by 

enteroinvasive E. coli (EIEC); and hemorrhagic colitis, caused by enterohemorrhagic E. coli

(EHEC). EHEC is the most severe, with potential for serious consequences such as hemolytic 

uremic syndrome, particularly in young children. An estimated 205,800 foodborne cases from 

all four types of E. coli occur annually in the United States (Scallan et al., 2011). Symptoms vary 

for the different forms of illness, but include abdominal pain, diarrhea, vomiting, fever, chills, 

dehydration, electrolyte imbalance, high body fluid acidity, and general discomfort. Symptoms 

start from 8 hours to 9 days after consumption of contaminated food and last from 6 hours to 19 

days, with both periods varying significantly between the illness types. Everyone is susceptible 

to all forms of infection from E. coli, but EPEC is most commonly associated with infants, and all 

types tend to result in more severe symptoms in the very young and elderly. 

Listeria monocytogenes (L. monocytogenes) is the bacterium responsible for listeriosis. An 

estimated 1,600 foodborne cases of listeriosis occur annually in the United States (Scallan et 

al., 2011). L. monocytogenes produces mild flu-like symptoms in many individuals. However, in 

susceptible individuals, including pregnant women, newborns, and the immunocompromised, it 

can result in more severe symptoms, including septicemia, meningitis, encephalitis, 

spontaneous abortion, and stillbirth. Symptoms start from 3 days to 3 weeks after consumption

of contaminated food. Mortality is high (approximately 25%) in those that display the more 

severe symptoms.

Salmonella spp. is the bacterium responsible for salmonellosis. An estimated 1,029,000 cases 

of foodborne salmonellosis occur annually in the United States (Scallan et al., 2011). Symptoms 

include: nausea, vomiting, abdominal cramps, diarrhea, fever, and headache. Symptoms start 

from 6 hours to 2 days after consumption of contaminated food and generally last from 4 to 7

days. The most severe form, typhoid fever, is caused by Salmonella Typhi. Everyone is 

susceptible to infection by Salmonella spp., but symptoms are most severe in the elderly, 

infants, and the infirmed. Infections by Salmonella spp. and other closely related bacterial 

pathogens, such as Shigella spp., E. coli, and Yersinia enterocolitica, can lead to chronic 

reactive arthritic symptoms in pre-disposed individuals.

Shigella spp. is the bacterium responsible for shigellosis. Shigella infections may be acquired 

from eating contaminated food. Foods may become contaminated by infected food handlers 

who do not wash their hands before handling food. An estimated 131,000 foodborne cases of 

shigellosis occur annually in the United States (Scallan et al., 2011). Symptoms include: 

abdominal pain; cramps; diarrhea; fever; vomiting; blood, pus, or mucus in stools; continuous or 

frequent urges for bowel movement; and death. Symptoms start from 12 hours to 2 days after 

consumption of contaminated food and last from 1 to 2 weeks. Everyone is susceptible to 

infection by Shigella spp.

Staphylococcus aureus (S. aureus) is a common bacterium found on the skin and in the 

noses of many healthy people and animals. The bacterium is responsible for producing toxins 

as it grows in foods, causing staphylococcal food poisoning. An estimated 241,000 foodborne 
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cases of staphylococcal food poisoning occur annually in the United States (Scallan et al., 

2011). Symptoms include: nausea, vomiting, diarrhea, abdominal pain, and weakness. 

Staphylococcal toxins are fast acting and can cause illness in as little as 30 minutes. Symptoms 

usually start within one to six hours after eating contaminated food. Everyone is susceptible to 

intoxication by S. aureus toxin, with more severe symptoms, including occasional death, 

occurring in infants, the elderly and debilitated persons. 

3.3.2 Characteristics of Spore-Forming Foodborne Pathogens 

Table 3-A in Appendix 3 contains information on the conditions that will limit growth for most of 

the spore-forming pathogens that are of greatest concern in food processing. Data shown are 

the minimum or maximum values – i.e., the extreme limits reported among the references cited. 

These values may have been obtained in laboratory media, which may be more favorable to 

growth than many foods. These values may not apply to your processing conditions.

Bacillus cereus (B. cereus) is the bacterium responsible for B. cereus food poisoning. An 

estimated 63,400 foodborne cases of B. cereus food poisoning occur annually in the United 

States (Scallan et al., 2011). There are two forms of illness, associated with two different toxins.

In one form of illness, B. cereus produces an emetic toxin in the contaminated food; the emetic 

toxin causes nausea and vomiting, starting from 30 minutes to 6 hours after consumption of the 

food. In the other form of illness, associated with an infection due to high numbers of B. cereus

in the contaminated food, B. cereus produces a diarrheal toxin in the intestines of the affected 

consumer after the consumer ingests food; the diarrheal toxin causes diarrhea, starting from 6 

to 15 hours after consumption. Symptoms in both forms of illness last about 24 hours. Everyone 

is susceptible to B. cereus food poisoning.

Clostridium botulinum (C. botulinum) toxin is the toxin responsible for a severe paralytic 

illness called botulism. C. botulinum is found in soil and grows best in low oxygen conditions. 

The bacteria form spores that can survive in a dormant state until exposed to conditions that 

support their germination and growth, such as in inadequately processed low-acid canned 

foods. Foodborne botulism is caused by eating foods that contain the botulinum toxin, which is 

formed during growth of C. botulinum. There are seven types of botulism toxin designated by 

letters A through G; only types A, B, E and F have caused botulism in humans. An estimated 55

foodborne cases of botulism occur annually in the United States (Scallan et al., 2011). 

Symptoms include: weakness; vertigo; double vision; difficulty in speaking, swallowing, and 

breathing; abdominal swelling; constipation; paralysis; and, possibly, death. Symptoms start 

from 18 to 36 hours after eating a contaminated food, but can occur as early as 6 hours or as 

late as 10 days after exposure. Everyone is susceptible to intoxication by C. botulinum toxin; 

only a few micrograms of the toxin can cause illness. Mortality is high; without the antitoxin and 

respiratory support, death is likely. 

Clostridium perfringens (C. perfringens) is the bacterium responsible for perfringens food 

poisoning. C. perfringens causes illness when large numbers of the bacteria are consumed in

contaminated food. The bacterium then produces enough toxin in the intestines to cause illness. 

C. perfringens spores can survive high temperatures. During cooling and holding of food at 

warm temperatures, the spores germinate and the resulting vegetative cells of the bacteria 

grow. An estimated 966,000 foodborne cases of perfringens food poisoning occur annually in 

the United States (Scallan et al., 2011). Symptoms include: abdominal cramps and diarrhea. 

Symptoms typically start from 8 to 12 hours after eating a contaminated food, but can occur as 

early as 6 hours after exposure and last for about a day. Everyone is susceptible to perfringens 
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food poisoning, but it is more common in the young and elderly, who may experience more 

severe symptoms lasting for one to two weeks.

3.3.3 Potential Ingredient-Related Biological Hazards 

See Table 3-2 in this chapter and Tables 1A through 1Q in Appendix 1 of this guidance for 

information that can help you identify potential ingredient-related biological hazards that may be 

associated with specific food products. See Chapter 4 – Preventive Controls, as well as 

Chapters 6 through 13, for recommendations on control of some specific ingredient-related 

biological hazards. 

3.3.4 Potential Process-Related Biological Hazards

The purpose of this section is to help you identify potential process-related biological hazards 

for the foods that you produce. See Chapter 4 – Preventive Controls, as well as Chapters 6 

through 13, for recommendations on control of some specific process-related biological 

hazards.

Some process-related biological hazards can occur if something goes wrong with a process 

control. For example, pathogens that you intend to control by cooking could survive if your 

product is undercooked during application of a heat treatment; pathogens that you intend to 

control by refrigeration could multiply and/or produce toxin if there is a lack of proper 

refrigerated holding during product assembly; and pathogens that you intend to control by aw

could multiply and/or produce toxin if the product is not properly formulated (e.g., too little sugar 

is used, resulting in an increase in the aw). Other process-related biological hazards are not 

related to something going wrong with a process control. For example, if you plan to use 

reduced oxygen packaging (ROP) to prevent the growth of spoilage organisms and extend the 

shelf life of the product, the extended shelf life provides more time for toxin production or 

pathogen growth if pathogens are present and temperatures are suitable for growth. As another 

example, if you manufacture a product by adding spices after a process control that would 

significantly minimize pathogens, pathogens in the added spices could introduce pathogens to 

the treated product. As yet another example, pathogens could be introduced to a treated 

product after packaging if there is a lack of container integrity.

In the following sections on process-related biological hazards, we describe examples of these 

kinds of process-related biological hazards.

3.3.4.1 Bacterial pathogens (vegetative and sporeforming) that survive 

after treatment 

If a process that you design to kill bacterial pathogens and/or their spores does not work as 

intended, the bacterial pathogens and/or their spores that you intended to control can be 

present in your food product. The primary pathogens of concern are L. monocytogenes, 

Salmonella spp., S. aureus and C. jejuni, pathogenic strains of E. coli, Yersinia enterocolitica (Y. 

enterocolitica), B. cereus C. perfringens, and C. botulinum. See Appendix 3 of this guidance for 

limiting conditions for growth of bacterial pathogens. 

See Chapter 4 of this guidance for an overview of recognized and established processing 

conditions to control pathogens and for factors to consider when designing your process to 

prevent problems. For example:
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• Some foods heat faster than others. Bacterial pathogens in the cold spot of the food will be 

inactivated more slowly than those at the surface because those in the cold spot are 

subjected to less heat. If the minimum process for lethality is not achieved at the cold spot, 

pathogens may survive the treatment.

• Certain characteristics of food make it either easier or harder to destroy bacterial pathogens, 

if present. For example, pathogens are more easily destroyed in foods with an acidic pH; 

sugars and oils tend to shield pathogens from the effects of heat; and the presence of 

moisture, both in and surrounding the food, make destruction easier. If these have not been 

taken into account in designing the process, pathogens may survive the treatment.

• Spores of bacterial pathogens are more heat tolerant than the vegetative cells of the same 

pathogen and different bacterial pathogens have different heat resistances (see Appendix 3 

of this guidance). If the process is not designed to control the most resistant pathogen of 

concern in the food, pathogens may survive the treatment.

See also Chapter 6 – Use of Heat Treatments as a Preventive Control for more detailed 

recommendations to control process-related biological hazards through heat treatments.

3.3.4.2 Bacterial pathogens that grow and/or produce toxin

3.3.4.2.1 Due to lack of proper time/temperature control

Bacterial pathogens that are introduced from contaminated ingredients into a product that does 

not undergo a lethality process, or that survive a lethality process as a result of a problem with a 

process control, can multiply (“grow”) and, depending on the pathogen, produce toxin as a result 

of time and temperature abuse of food products. Certain bacterial pathogens (e.g., E. coli

O157:H7, S. aureus, and L. monocytogenes) grow well in time- and temperature-abused food.

Time and temperature abuse occurs when a product is allowed to remain at temperatures 

favorable to bacterial pathogen growth for sufficient time to result in unsafe levels of the 

pathogens or their toxins in the product. Most bacterial pathogens will grow well in cooked foods 

that are temperature-abused if their growth is not otherwise controlled by means such as drying, 

salting, or acidification, because competing bacteria are significantly reduced by the cooking 

process. Uncooked foods that have high water activities and pH, such as batters, which are 

subjected to time/temperature abuse (e.g., using room-temperature batter for several hours), 

can support growth and toxin production by pathogens such as S. aureus. 

Vegetative pathogens may grow in products during processing steps and may be ultimately 

destroyed by a lethal step such as cooking. However, too much bacterial growth before the 

lethal step may render the lethal process inadequate. Moreover, if the time and temperature 

abuse allows production of toxin, such as toxin production from S. aureus in temperatureabused custard pies, this toxin will not be destroyed by a heat step later in the process.

In evaluating the potential for bacterial pathogens to grow and/or produce toxin in your food 

products, you should consider the following factors: 

• The types of pathogenic bacteria that are known or reasonably likely to be present; 

• Whether those pathogens can grow in the food; 

• The infective dose of the pathogenic bacteria;

• The expected initial level of the pathogenic bacteria in the food.
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See Chapter 4 of this guidance for an overview of processing conditions to minimize pathogen 

growth by controlling temperatures to prevent pathogen growth and time of exposure to 

temperatures at which growth can occur. See also Chapter 7 – Use of Time/Temperature 

Control as a Process Control for more detailed recommendations to control process-related 

biological hazards through time/temperature controls. Tables 3-A and 3-B (Appendix 3 of this 

guidance) provide the limiting temperature conditions for growth of vegetative and sporeforming 

bacterial pathogens. 

3.3.4.2.2 Due to lack of proper cooling after heat treatments

Depending upon the food and ingredients, heat treated foods can still possibly have viable 

forms (i.e., spores) of pathogenic bacteria present. Sometimes, vegetative cells that are 

particularly heat tolerant, (like Listeria monocytogenes) survive the cooking process; however, 

this should not be the case if the appropriate target pathogen was selected to be controlled by 

the applied process. More often, it is spores that survive the cooking process if they are present, 

and they begin to germinate when the product temperature begins to drop below 140°F. In 

addition, they will be present in the food during storage. Some spores such as those from 

pathogens such as non-proteolytic C. botulinum and some strains of B. cereus have the ability 

to germinate and grow at refrigeration temperatures, although long times are required. Other 

spores that remain in the food remain dormant until the product is temperature abused. In such 

an event, pathogenic spores that may be present are able to germinate, grow and possibly 

produce toxin due to the fact that most spoilage bacteria have been eliminated by the reduction 

step.

See Chapter 4 of this guidance for an overview of processing conditions to minimize pathogen 

growth by controlling temperatures during cooling after cooking. See also Chapter 7 – Use of 

Time/Temperature Control as a Process Control for more detailed recommendations to control 

process-related biological hazards through time/temperature controls.

3.3.4.2.3 Due to poor formulation control

Products most susceptible to biological hazards due to problems with formulation are RTE 

products that either do not receive a kill step in their process or that receive a kill step for 

vegetative pathogens but not spores and that may require refrigeration for safety during their 

manufacture and shelf life. For this category of products, product formulation can play a 

significant role in significantly minimizing or preventing hazards. For example, a naturally acidic 

product with a pH below 4.6 may rule out C. botulinum as a hazard requiring a preventive 

control, since this pH will prevent spore germination, growth, and toxin production. Formulation 

parameters such as pH, aw, use of preservatives, and oxygen availability, can work in concert to 

establish an ecosystem that is designed to inhibit the growth of the pathogens that may be 

present. If not, just as described for foods that have been time and temperature abused, 

bacterial pathogen growth and toxin formation can result due to this lack of inhibition and 

control.

In determining the potential for a process-related hazard due to poor formulation control, we 

recommend that you know the formulations or ingredient lists of your incoming products, as well 

as the equilibrated pH, titratable acidity, aw, percent moisture, percent sodium and percent

sugar, as appropriate, of the finished combined product. Many of the products susceptible to 

biological hazards due to problems with formulation are made up of multiple ingredients, each 

with their own specific set of formulation parameters. Any one individual component not 

meeting the required formulation criteria to ensure that the designed preventive control system 
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is achieved may result in a food that does not inhibit the growth or toxin formation of a pathogen 

that may be present in the food. 

In determining the potential for a process-related biological hazard due to poor formulation 

control, we also recommend that you consider the interactions that may occur among the 

various products, raw materials, and other ingredients when combined. Layering product 

components of significantly different pH or aw values alters the microenvironments at the 

interfaces of the components. A simple example is an éclair filled with a cream filling. The pH 

and aw at the interface of the pastry and the filling will be affected by the difference between the 

higher pH and lower aw of the pastry and the potentially lower pH and higher moisture content of 

the filling, potentially resulting in an environment favorable to microbial growth. A microorganism 

that is in the filling may not grow due to the pH, but the pH of the pastry may favor growth of a 

microorganism at the interface during the product’s shelf life. Characteristics such as oxygenreduction (redox) potential and the effectiveness of antimicrobials are also likely to differ at 

component interfaces and may impact pathogen survival and growth.

In determining the potential for a process-related hazard due to poor formulation control, we 

also recommend that you consider how the equilibrium pH and aw of the finished product 

compares to that of the individual components. If a finished formulated product is a more 

homogeneous mixture of the components, then the resulting final equilibrium pH and aw may be 

significantly different from that of the individual components. A good example is hummus, which 

is typically made from chick peas (garbanzo beans), which may be rehydrated from a dry state,

blended with acidifying agents, oils and spices and then pureed. The final product with a smooth

texture will have an equilibrium pH, and possibly aw, different from the original ingredients. If a 

topping of pine nuts, or oil, or diced red peppers is added to the top in the container as 

“decoration” then those additions could then significantly change the microenvironment at the 

interface and may require a control (such as acidification).

See Chapter 4 of this guidance for an overview of formulation-based controls. See Chapter 8 –

Use of Formulation as a Preventive Control for more detailed recommendations to control 

process-related biological hazards through product formulation.

3.3.4.2.4 Due to reduced oxygen packaging (ROP)

From a food safety standpoint, packaging serves two functions: (1) It prevents contamination of 

the food; and (2) it makes possible, or extends the effectiveness of, food preservation methods. 

For example, packaging can maintain the atmosphere in a controlled or modified atmosphere 

package or a vacuum package, or it can prevent rehydration of a dried food. All of these 

different packaging methods are grouped into a category that we call ROP. ROP is used to 

prevent the growth of spoilage organisms, thereby extending the shelf life of the product. There 

are some other product quality benefits as well, such as reductions in rancidity, shrinkage, and

color loss.

However, ROP does not control the growth of all bacterial pathogens and can create a processrelated biological hazard. The extended shelf life provides more time for toxin production or 

pathogen growth if pathogens are present and temperatures are suitable for growth. Lower 

oxygen levels favor pathogens that can grow in the absence of oxygen over the aerobic 

spoilage organisms that require oxygen for growth. For this reason, you may get toxin 

production before you get spoilage - something that is less likely to happen in traditional 

packaging.
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The major concern with ROP is C. botulinum, although there may also be concerns with other 

pathogens such as L. monocytogenes, particularly in refrigerated RTE foods. You should not 

use ROP unless barriers for C. botulinum are present. These barriers include: aw below 0.93; 

pH below 4.6; salt above 10%; thermal processing in the final container; and freezing with 

frozen storage and distribution. Each of these barriers by itself can be effective in the control of 

C. botulinum growth. Refrigeration below 38°F (3.33°C) can prevent growth of all strains of C. 

botulinum, but because temperatures above this are commonly employed for refrigeration, 

temperature should not be relied on as the only control. Combinations of barriers that 

individually would not control growth of C. botulinum can work together to prevent growth.

For a further discussion on the potential for ROP to create a process-related biological hazard, 

see Annex 6 of the 2013 Food Code (FDA, 2013b).

3.3.4.3 Bacterial pathogens in ingredients added after process controls 

The manufacture of certain RTE products involves, by design, the addition of ingredients after 

any process controls are applied. For example, the production of some fresh vegetable salad 

kits includes the addition to the final product, prior to packaging, of various ingredients such as 

nuts, dried berries, and seeds. The process control for the salad components (e.g., chlorine 

wash) is applied to the various fresh cut vegetables that are mixed in preparation for packaging, 

while the nuts, berries, and seeds are added just prior to packaging. As another example, the 

production of some fresh-baked pastry products includes the addition of toppings, such as 

frostings, nuts, dried fruit, confections (e.g., sprinkles). A facility that produces products 

containing ingredients added after a process control should consider the potential for the added 

components to be a process-related biological hazard as part of its hazard analysis.

3.3.4.4 Bacterial pathogens introduced after packaging due to lack of 

container integrity

Food manufactured and processed (e.g., heat treated) in a container and/or clean-filled after 

treatment can become contaminated if its container forms a leak or loses seal integrity, thereby 

exposing the processed food to a variety of biological hazards. The primary pathogens of 

concern include C. botulinum, L. monocytogenes, pathogenic strains of E. coli, Salmonella spp., 

S. aureus, and B. cereus.

The primary causes of recontamination of foods after a process control step and packaging are 

defective container closures and contaminated cooling water. Poorly formed or defective 

container closures can increase the risk of bacterial pathogens entering the container through 

container handling that occurs after the product has been filled and the container has been 

sealed. This risk is a particular concern during container cooling performed in a water bath. As 

the product cools, a vacuum is drawn in the container. Contaminated cooling water can enter 

through the container closure, especially if the closure is defective. 

3.3.5 Potential Facility-Related Biological Hazards

Foodborne illnesses due to commercially produced foods have been traced to post-process 

contamination due to the poor implementation of CGMPs, such as by exposure or contact with 

contaminated equipment during processing such as conveying, holding, chilling or packaging. 

Examples of events and foodborne illness outbreaks due to contamination of RTE foods are 

quite extensive and readily available in scientific literature. Typically in these events, foods that 

were processed by some means (e.g., cooked, pasteurized, dried) to reduce the presence of 
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microorganisms, in particular pathogens identified as hazards requiring a preventive control, 

were subsequently exposed to the environment where they were recontaminated with 

pathogens. As discussed in the following sections on facility-related biological hazards, there 

are challenges to prevent this from happening.

Table 3-3 provides a list of examples, adapted in part from ICMSF Book 7, Chapter 11 (ICMSF, 

2002) and from FDA documents that highlight the public health impact of contamination of RTE 

foods with environmental pathogens.

Table 3-3. Examples of Pathogens Identified from Outbreaks Attributed to Contamination 

with Environmental Pathogens 

Product Environmental 

Pathogen Details Reference

Chocolate S. Napoli Possibly contaminated water used 

in double-walled pipes, tanks and 

other equipment

Gill, et. al. (1983)

Chocolate S. Eastbourne From processing environment Craven, et. al.

(1975)

Butter (from 

pasteurized cream)

L. monocytogenes From processing environment Lyytikainen et. al.

(2000)

Peanut butter S. Tennessee From processing environment FDA (2007a, 

2007b)

Peanut butter Salmonella spp. From processing environment Cavallaro et al. 

(2011); FDA 

(2009b, 2009c)

Whole white pepper S. Rissen From processing environment FDA (2009d)

Cantaloupes L. monocytogenes From processing environment FDA (2012a)

Peanut butter S. Bredeney From processing environment FDA (2012b)

Soft cheeses (from 

pasteurized milk)

L. monocytogenes From processing environment FDA (2013c)

Soft cheese (from 

pasteurized milk)

L. monocytogenes From processing environment FDA (2014a)

The PCHF requirements specify that your hazard evaluation must include an evaluation of 

environmental pathogens whenever a ready-to-eat food is exposed to the environment prior to

packaging and the packaged food does not receive a treatment or otherwise include a control 

measure (such as a formulation lethal to the pathogen) that would significantly minimize the

pathogen. (See 21 CFR 117.130(c)(1)(ii).) Effectively designed and implemented CGMPs are 

key to keeping biological hazards out of your food products. However, experience has shown 

that application of CGMPs – even in combination with a HACCP plan - cannot guarantee that 
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contamination of a processed food from the environment will not occur. This is one reason why 

the PCHF requirements specify that sanitation controls include procedures, practices, and 

processes to ensure that the facility is maintained in a sanitary condition adequate to 

significantly minimize or prevent hazards such as environmental pathogens (21 CFR 

117.135(c)(3)). In addition, the PCHF requirements specify that, as appropriate to the facility, 

the food, and the nature of the preventive control and its role in the facility’s food safety system, 

you must conduct activities that include environmental monitoring, for an environmental 

pathogen or for an appropriate indicator organism, if contamination of an RTE food with an 

environmental pathogen is a hazard requiring a preventive control, by collecting and testing 

environmental samples.

In the following sections, we provide information to help you determine whether an 

environmental pathogen is a hazard requiring a preventive control in your facility. Although 

Table 3-3 includes some examples of outbreaks of foodborne illness caused by facility-related 

biological hazards other than environmental pathogens, we do not discuss those other facilityrelated biological hazards in this chapter.

3.3.5.1 Sources of facility-related biological hazards

The likelihood of product contamination with a facility-related environmental pathogen increases 

as the prevalence of the environmental pathogens in the processing environment increases. 

The prevalence of the environmental pathogens in the processing environment can be 

influenced by the raw materials used in the process, the type of process, and the hygienic 

practices applied to keep to keep the processing area clean and hygienic. Table 3-4 is a quick 

reference guide to help you identify some of the most common sources for facility-related 

hazards that can contaminate the food processing environment; Table 3-4 does not provide an 

exhaustive list of such pathogens.

Table 3-4. Quick Reference Guide for Common Sources of Facility-Related Biological 

Hazards

Source Examples

Raw agricultural commodities • Raw milk

• Cocoa beans

• Fruits and vegetables

• Nuts

• Unprocessed spices

Food handlers and maintenance 

personnel

• Transfer of biological hazards from one point to another 

on, for example, shoes and other clothing

• Improper hand washing 

• Transfer of biological hazards to foods through improper 

handling or maintenance practices

Air and water • Lack of appropriate air filtration for cooling, drying, air 

conveying

• Improper air flow from “raw” to RTE areas

• Aerosols from improper cleaning practices

Insects and pests • Flies

• Cockroaches

• Rodents
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Source Examples

Transport equipment • Forklifts

• Trolleys

• Racks 

• Carts

With these varied sources for potential contamination, it is easy to understand how a failure of 

one or more steps in your CGMPs can lead to contamination of the processing environment 

and, ultimately, your food products with facility-related biological hazards.

3.3.5.2 Transient vs. resident facility-related environmental pathogens

Once bacterial pathogens have been introduced into the processing environment, experience 

has shown that pathogens may be present as “transient” contamination or “resident” 

contamination within the facility.

3.3.5.2.1 Transient contamination 

Bacterial pathogens, including environmental pathogens, are typically introduced into the 

processing facility through, for example, incoming raw materials, personnel, or pests. It is 

important to ensure that these microorganisms remain transient and do not become established 

in the environment where they can grow and multiply. Transient contaminants can, however, 

result in a diversity of pathogens in the processing environment that can show up in the 

processing lines and finished product. This phenomenon is typical for food operations using a 

wide variety of ingredients, in particular raw commodities, because these materials can contain 

very diverse microflora. Generally though, the proper application of cleaning and sanitizing in 

accordance with CGMPs is adequate to control the transient bacteria in the processing facility. 

So, contamination detected from day-to-day may be found to be quite diverse.

3.3.5.2.2 Resident contamination

Bacterial pathogens causing resident contamination can also be introduced into the processing 

facility, where the pathogens then become established in a harborage site, multiply, and persist 

for extended periods of time, even years. A harborage site, or niche, is a site in the environment 

or on equipment (e.g., junctions, cracks, holes, and dead-end areas) that enables the 

accumulation of residues (food debris, dust, and water) and permits the growth of 

microorganisms such as L. monocytogenes and Salmonella. These sites may be difficult to 

inspect or access and therefore can protect environmental pathogens during routine cleaning 

and sanitizing. Thus, while common cleaning and sanitation practices are adequate to control 

the presence of transient contaminants, such practices do not control the presence of resident 

contaminants once they have become established. Sanitation controls, including proper 

personnel practices and equipment and facility design, are key to preventing transient bacterial 

pathogens from becoming resident strains. Once an environmental pathogen has become 

established as a “resident strain,” there is a persistent contamination risk for foods processed in 

that facility. The facility will need to use intensified sanitation procedures to eliminate the 

contamination. Of all the bacterial pathogens, Salmonella and L. monocytogenes have the most 

extensive history of being able to set up residence in a processing facility. Although not as likely, 

the potential exists for the other pathogens discussed previously in this chapter to become 

established as resident contaminants. 
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Key determinants for the pathogens to become established in a food processing environment 

are: 1) The temperature at which the food processing environment is maintained; 2) the

available moisture in the food processing environment; and 3) the availability of nutrients for 

growth. For processed foods, this typically translates into two primary categories of food 

processing environments by the nature of the products that are manufactured and packaged in 

a facility:

• Frozen/refrigerated and wet 

• Warm/ambient and dry

In both cases, proper cleaning is needed to minimize nutrient availability. The pathogen most 

often associated with cold and wet processing environments is L. monocytogenes, and the 

pathogen most often associated with warm and dry processing environments is Salmonella

(Scott et. al., 2009; ICMSF, 2005).

3.3.5.3 Facility-related environmental pathogens associated with wet vs. 

dry processing environments 

Food processing operations can typically be classified into one of two simple categories – wet 

processing environments or dry processing environments (Table 3-5). This very simple 

distinction has significant implications for the strategy that must be applied to control food 

contamination from environmental pathogens. 

Table 3-5. Some Examples of Foods Processed in Wet and Dry Processing 

Environments

Processing Environment 

Conditions

Examples of Foods

Wet • Ice Cream

• Refrigerated Dairy Products

• Refrigerated Deli Salads

• Refrigerated and Frozen Meals

• Refrigerated Beverages (non-juice)

Dry • Chocolate and Confections

• Milk Powders

• Baked Goods

• Dehydrated Soups

• Powdered Beverages

• Nut/nut products

3.3.5.3.1 Wet process environments

The most effective strategy to prevent the contamination of finished products with L. 

monocytogenes is to maintain an environment as dry as possible. Wet environments have some 

very obvious characteristics that lead to problems with contamination by L. monocytogenes, 

such as:
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• Wet floors due to constant wet cleaning will facilitate the transfer of Listeria spp., including L. 

monocytogenes, from an environmental source to food contact surfaces;

• Wet floors can create harborage sites if they are not well maintained and have 

broken/cracked grout or tiles. These structures may provide protected harborage to 

environmental pathogens even when the floors are cleaned and sanitized.

• Condensation on overhead structures as a result of air temperature and humidity control 

issues and from use of water in cooking and cooling operations creates a means of transfer 

of Listeria spp., including L. monocytogenes, from non-food-contact surfaces to exposed 

product and equipment food-contact surfaces. 

• Frost formation due to condensation at freezer entry and exit points provides an opportunity 

for moisture accumulation and a constant source of water for Listeria spp. to multiply.

• Inadequate sanitation practices on floor freezer and cooler units may provide the moisture to 

support Listeria spp., including L. monocytogenes, if water sources are not properly 

plumbed to hygienically designed drains.

Wet floors can serve as vectors for spreading Listeria spp. via the movement of people and 

equipment and material handling items such as totes and pallets. Wet floors can also serve as 

vectors for pathogen transfer when personnel walk through standing water on poorly designed 

floors and drains and during cleaning. L. monocytogenes does not spread alone through the air; 

however, in wet environments, aerosols from high pressure water hoses used during cleaning 

operations help spread L. monocytogenes throughout the environment and from one surface 

(e.g., floors) to another surface (e.g., food contact surfaces, such as conveyors, tables, and 

product containers). In many facilities, certain processing operations are inherently wet, such as 

product debagging, raw material preparation, mixing and formulation of liquid product 

components, cooking, and blanching. In these cases, the best that can be done is to control the 

personnel, equipment traffic, and cleaning practices that are involved with the specific operation. 

The intent is to minimize water accumulation and aerosol formation to prevent in-process and 

finished product recontamination.

We recommend that wet processing areas be dried out as much as possible. This continues to 

be an ongoing challenge for the food industry that has for many years depended upon the 

unlimited use of water for equipment and facility cleaning practices.

3.3.5.3.2 Dry process environments

Moisture control is critically important in preventing Salmonella contamination in low-moisture 

products (ICMSF, 2005). Water in the dry processing environment is one of the most significant 

risk factors (perhaps the single most important factor) for Salmonella contamination, because

water allows for pathogen growth, significantly increasing the risk for product contamination. 

Water, present even in very small amounts for short, sporadic time periods, may allow 

Salmonella to grow in the environment. At times, moisture is obvious in the form of water 

droplets or puddles from wet cleaning or from other not-so-apparent sources such as high 

relative humidity or moisture accumulating inside of equipment. 

Salmonella can, to varying degrees, be introduced into low-moisture product manufacturing 

facilities and become established in those environments. Harborage sites may develop and 

become a source of product contamination, unless the sites are identified and eliminated (CAC, 

2008). 
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Growth of Salmonella is only possible in the presence of water. Because food particles and dust 

are normally expected to be present in processing areas, adequate nutrients are always 

available to microorganisms. Growth cannot occur, however, if the plant environment is 

sufficiently dry. The potential Salmonella harborage sites become more important when water is 

present for a sufficient period of time. The presence of water in the dry processing environment 

can result from improper use of water during cleaning, which has been linked to the occurrence 

and spread of Salmonella (CAC, 2008). Other events resulting in the presence of water in a dry 

area include condensate formation, leaking water or steam valves, infiltration of water following 

heavy rains (e.g., leaky roofs) and the use of water showers in the case of fire emergencies. 

(CAC, 2008). We recommend that you remove water immediately from the primary Salmonellacontrolled hygiene areas (areas where RTE food is exposed to the environment) following such 

events in order to keep the plant environment as dry as possible. 

You should maintain dry conditions at all times in primary Salmonella-controlled hygiene areas, 

except for the occasions when you have determined that controlled wet cleaning is necessary. 

Potential problems arise when there is visible water present in the dry areas or when there are 

areas in which standing water has dried out. Salmonella may be found both in wet spots and in 

spots where standing water has dried (Zink, 2007). The latter situation may present an 

additional risk of spread via the generation of airborne contaminated dust.

3.4 Chemical Hazards

You must conduct a hazard analysis to identify and evaluate known or reasonably foreseeable 

chemical hazards. See 21 CFR 117.130(b)(1)(ii). When your hazard analysis identifies a known 

or reasonably foreseeable chemical hazard that requires a preventive control, you must identify 

and implement a preventive control for the chemical hazard. See 21 CFR 117.135(a)(1).

The chemical hazards that are the focus of this section of this chapter include ingredient-related 

chemical hazards (i.e., pesticide and drug residues, heavy metals, environmental contaminants,

histamine due to decomposition, natural toxins (e.g., mycotoxins), radiological hazards, 

unapproved food and color additives, food allergens, and substances associated with a food 

intolerance or food disorder) and process-related chemical hazards (i.e., food allergens, 

substances introduced by misformulation and the introduction of industrial chemicals or other 

contaminants from the food processing environment). 

Food products can become contaminated with chemical hazards that are introduced at any 

stage in food production and processing. Some ingredient-related chemical hazards are natural 

components of food, such as food allergens, or are produced in the natural environment, such 

as mycotoxins, whereas other ingredient-related hazards (e.g., pesticides, drug residues, heavy 

metals, environmental contaminants) are contaminants of raw materials and other ingredients. 

Some process-related chemical hazards may be included in product formulation (e.g., sulfites 

that are a hazard for those consumers who are sensitive to them), whereas other processrelated chemical hazards may be unintentionally introduced into food, such as industrial 

chemicals that are used in a facility for purposes other than food production. Process 

contaminants may also form during heating (e.g., acrylamide).

2

 For further details on the 

 2 Some processing contaminants are formed during the heating of certain ingredients or finished foods 

(e.g., acrylamide). We have not included such contaminants in Table 3-6 as potential process-related 

chemical hazards that may require a preventive control as part of a food safety plan under part 117 

because we believe that more information is needed regarding appropriate levels and effective controls. 

As stated in our “Guidance for Industry: Acrylamide in Foods” (FDA, 2016a), we recommend that 
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sources of ingredient-related and process-related chemical hazards, see Tables 2A through 2Q 

and Tables 3A through 3Q of Appendix 1 of this guidance.

A chemical hazard may cause immediate effects, or may be associated with potential long-term 

effects after chronic exposure to the chemical. One example of an immediate effect is 

gastrointestinal illness such as nausea, which can be caused by elevated levels of industrial 

chemicals (such as caustic cleaning compounds). Caustic cleaning compounds can also cause 

burning of the mouth and esophagus. Ammonia in food contaminated by a refrigerant leak has 

caused gastrointestinal illness (stomachache and nausea) and headaches (Dworkin, et al. 

2004). Sulfites have resulted in diarrhea, headache, difficulty breathing, vomiting, nausea, 

abdominal pain and cramps in sulfite-sensitive individuals (Timbo et al. 2004). Examples of 

long-term effects include impaired cognitive development in children chronically exposed to 

relatively low levels of lead (e.g., in contaminated candy) (FDA, 2006a) and liver cancer

resulting from chronic exposure to the mycotoxin, aflatoxin (Williams et. al, 2004 and Shephard, 

2008).

FDA has set action levels and tolerances for some contaminants (FDA, 2015f). They represent 

limits at or above which FDA will take legal action to remove products from the market. Where 

no established action level or tolerance exists, FDA may take legal action against the product at 

the minimal detectable level of the contaminant. Action levels and tolerances are established 

based on the unavoidability of the poisonous or deleterious substances and do not represent 

permissible levels of contamination where it is avoidable. For example, FDA has established an 

action level of 3 ppm polychlorinated biphenyl (PCB) residues in red meat on a fat basis (FDA, 

1987). FDA also has issued for public comment a draft guidance for industry that would, when 

finalized, establish an action level of 100 ppb for inorganic arsenic in infant rice cereal (FDA 

2016). FDA has established tolerances for polychlorinated biphenyls (PCB's) in foods such as 

milk and other dairy products, poultry, eggs, and infant and junior foods (see 21 CFR 109.30).

Further, under the Federal Food, Drug, and Cosmetic Act (FD&C Act), certain substances, such 

as food additives, color additives, new animal drugs, and pesticides require premarket approval 

before they may be legally used. 

FDA also has issued guidances to provide information to industry on methods to reduce levels 

of specific chemicals in foods. For example, FDA has issued guidance providing information to 

help growers, manufacturers, and food service operators reduce acrylamide levels in certain 

foods (FDA, 2016a). Similarly, the Codex Alimentarius Commission has established a number 

of codes of practice for controlling mycotoxins, heavy metals, and other chemicals in foods 

(CAC, 2012).

Chemical residues in a food are not always considered hazards and their occurrence may be 

unavoidable. Because the particular chemical and its levels in the food determine whether it is a 

hazard, and because mechanisms whereby a chemical hazard can be introduced into a food 

product are both varied and dependent on the nature of the chemical, the preventive controls 

that you identify and implement to control specific chemical hazards should be based on the 

characteristics of those chemicals and the mechanisms whereby they could be introduced into 

your food product. In the following sections on chemical hazards, we describe some common 

preventive controls for controlling chemical hazards. For additional information on the control of 

 

manufacturers evaluate approaches to acrylamide reduction that may be relevant to their particular 

processes and consider adopting approaches, if feasible, that reduce acrylamide levels in their products.
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chemical hazards, see Chapter 4 – Preventive Controls and Chapter 12 – Preventive Controls 

for Chemical Hazards.

In the remainder of this section on chemical hazards, we briefly describe characteristics of some 

chemical hazards that are of concern in foods and processing environments, including 

mechanisms whereby they can be introduced into a food product. We do not discuss seafood 

toxins in this guidance because seafood is exempt from the PCHF requirements; for a 

discussion of seafood toxins see our Fish and Fishery Products Hazards and Controls Guidance 

(FDA, 2011). 

Table 3-6 is a quick reference guide to help you identify some of the most common sources of 

chemical hazards; Table 3-6 does not provide an exhaustive list of such hazards

Table 3-6. Quick Reference Guide for Common Sources of Chemical Hazards

Source Examples

Ingredient-related chemical hazards • Pesticide residues on produce raw agricultural 

commodities

• Drug residues in milk

• Heavy metals in or on produce raw agricultural 

commodities

• Environmental contaminants (e.g., dioxins)

• Mycotoxins in grains

• Histamine in some aged cheeses

• Radiological hazards in foods from areas after a nuclear 

accident

• Unapproved food or color additives

• Food allergens and substances associated with a food 

intolerance or food disorder (e.g., sulfites, gluten)

Process-related chemical hazards • Undeclared food allergens due to mislabeling or crosscontact

• Improper addition of substances associated with a food 

intolerance (e.g., sulfites) 

• Improper use of a color additive such as Yellow No. 5

• Contamination with industrial chemicals such as cleaners 

or sanitizers

• Radiological hazards from use of contaminated water 

supply

Facility-related chemical hazards • Heavy metals due to leaching from equipment, containers,

or utensils 

3.4.1 Ingredient-Related Chemical Hazards

3.4.1.1 Pesticides 

Pesticide residues may be of concern in food crops and in foods of animal origin (as a result of 

pesticide residues in animal food). The term pesticide is used for products such as insecticides, 

fungicides, rodenticides, insect repellants, herbicides or weed killers, and some antimicrobials 

that are designed to prevent, destroy, repel, or reduce all types of pests (See EPA “Setting 
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Tolerances for Pesticide Residues in Foods”) (EPA, 2015). Three federal government agencies 

share responsibility for the regulation of pesticides. Pesticides that have been registered (i.e., 

approved) with the U.S. Environmental Protection Agency (EPA) may be applied according to 

label directions directly to raw agricultural commodities or food (see 40 CFR 180). For a 

registered pesticide that could potentially result in residues in or on food, the EPA establishes a 

tolerance, which is the maximum amount of residue that is permitted in or on a food. FDA is 

responsible for enforcing pesticide tolerances for foods other than meat, poultry, and certain egg 

products, which are the responsibility of the U.S. Department of Agriculture Food Safety and 

Inspection Service (USDA FSIS) (FDA, 2012d). A detailed description of how FDA enforces 

pesticide residues in animal food is available in CPG Sec. 575.100 Pesticide Residues in Food 

and Feed – Enforcement Criteria (FDA, 2015e). If pesticide residues are present in food in the 

absence of, or in excess of, a tolerance, the food is deemed adulterated under section 

402(a)(2)(B) of the FD&C Act (21 U.S.C. 342(a)(2)(B)). The most common reasons for 

adulteration of food products with pesticide residues are the improper treatment of raw materials 

with registered pesticides, and raw materials being exposed to prohibited pesticides. 

Fruits and vegetables that have been grown in the United States usually are in compliance with 

EPA’s pesticide tolerance regulations. If you obtain produce from a foreign country you should 

take steps to ensure that the imported produce will be in compliance with U.S. pesticide 

tolerance regulations, such as by considering pesticide residues to be chemical hazards that 

warrant preventive controls, such as supply-chain controls with a supplier verification program. 

3.4.1.2 Animal drug residues

Animal drug residues may be of concern for foods of animal origin, including muscle meat, 

organ meat, fat/skin, eggs, honey, and milk. In the United States, animal drugs require approval 

by FDA before they can be administered to food-producing animals. Depending on the 

chemical property of the drug, residues of certain drugs can become concentrated during food 

manufacturing and processing. For example, if a fat-soluble, heat-stable drug residue is present 

in raw milk, the drug can get concentrated when the milk is converted to full fat cheese

(Cerkvenik et al., 2004; Imperiale et al., 2004). Potential effects of drug residues range from 

short-term effects as a result of acute allergic reactions (e.g., penicillin) to long-term effects from 

drug resistant bacteria (Dayan, 1993). An example of an unapproved drug residue that has 

adulterated food is fluoroquinolone, which is an antibiotic that has not been approved for use on 

honey bees in the United States and has been detected in honey products from certain regions 

outside the United States (FDA, 2015a).

Drug residues in a food derived from an animal (such as milk) are considered a hazard if a 

tolerance has not been established for the particular drug-food combination, or if the tolerance 

level has been exceeded. Animal drugs used according to labeled directions should not result in 

residues in meat, poultry, milk, or egg products. When your hazard analysis identifies drug 

residues that require a preventive control, supply-chain controls with a supplier verification 

program could be an appropriate preventive control to manage the potential risk.

3.4.1.3 Heavy metals

Heavy metals, including lead, cadmium, arsenic, and mercury, may be of concern in certain 

foods as a result of agricultural practices (e.g., use of pesticides containing heavy metals or 

because crops are grown in soil containing elevated levels of heavy metals due to industrial 

waste), or the leaching of heavy metals from equipment, containers or utensils that come in 

contact with foods. Consumption of heavy metals in foods can lead to adverse health 
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consequences. For example, lead exposure can impair cognitive development in children (FDA, 

2006a). Consumption of inorganic arsenic has been associated with cancer, skin lesions, 

developmental effects, cardiovascular disease, neurotoxicity, and diabetes in humans (JEFCA, 

2010). 

When your hazard analysis identifies a heavy metal that requires a preventive control, the type 

of control would depend on how the heavy metal could get into your food product. In some 

cases, high levels of heavy metals may result from the environment (e.g., high lead levels in 

carrots that were grown in lead-contaminated soil). If your food product contains a food crop that 

is known to have been contaminated with a heavy metal through contaminated soil, a preventive 

control such as a supply-chain control with a verification program to ensure that the grower 

conducts an assessment of the growing region prior to its use for agriculture may be 

appropriate. In other cases, an unsafe level of a heavy metal such as lead could be introduced 

into a food product as a result of a food-contact surface constructed with lead solder. CGMP 

controls, such as the controls on equipment and utensils in 21 CFR 117.40, generally can 

control chemical hazards such as heavy metals that can leach from food-contact surfaces. 

3.4.1.4 Environmental contaminants 

Environmental contaminants may be of concern in certain foods as a result of their presence in 

the environment. When your hazard analysis identifies an environmental contaminant that 

requires a preventive control, the type of control would depend on how the environmental 

contaminant could get into your food product. In some cases, high levels of environmental 

contaminants (e.g., dioxin) may result from accidental contamination of animal feed (WHO, 

2014). In 2008, pork meat and pork products were recalled in Ireland when up to 200 times the 

safe limit of dioxins were detected in samples of pork, although risk assessments indicated no 

public health concern. The contamination was traced back to contaminated feed. In 1999, high 

levels of dioxins were found in poultry and eggs from Belgium and in several other countries. 

The cause was traced to animal feed contaminated with illegally disposed PCB-based waste 

industrial oil. Because dioxins tend to accumulate in the fat of food-producing animals, 

consumption of animal-derived foods (e.g., meat, poultry, eggs, fish, and dairy products) is 

considered to be the major route of human exposure, and FDA has developed a strategy for 

monitoring, method development, and reducing human exposure (FDA, 2002). 

3.4.1.5 Mycotoxins and other natural toxins

Natural toxins, such as mycotoxins, histamines and other biogenic amines, and plant-produced 

substances (such as the toxin hypoglycin A found in the tropical fruit ackee) are well recognized 

as hazards in raw or processed agricultural commodities (FDA, 2005a; FDA 2005b; FDA, 

2005c; FDA, 2005d).

Mycotoxins are a common group of natural toxins that include aflatoxin, fumonisin, 

deoxynivalenol (vomitoxin), ochratoxin, and patulin (see Table 3-7). Mycotoxins are toxic 

metabolites produced by certain fungi (i.e., molds) that can infect and proliferate on agricultural 

commodities (e.g., grains such as wheat and corn, peanuts, fruits, and tree nuts) in the field and 

during storage. Mycotoxins may produce various toxicological effects. Some mycotoxins are 

teratogenic, mutagenic, or carcinogenic in susceptible animal species and are associated with 

various diseases in domestic animals, livestock, and humans in many parts of the world. The 

occurrence of mycotoxins in human and animal foods is not entirely avoidable; small amounts of 

these toxins may be found on agricultural commodities. Occurrence of these toxins on 

commodities susceptible to mold infestation is influenced by environmental factors such as 
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temperature, humidity, and the extent of rainfall during the pre-harvesting, harvesting, and postharvesting periods. The molds that produce mycotoxins typically grow and become established 

in the agricultural commodity during stressful growing and holding conditions, such as insect 

damage to the crop, drought stress, and wet storage (e.g., from condensation). Although 

mycotoxins are not a hazard requiring a preventive control during times and locations with good 

growing and harvest conditions, a preventive control such as supply-chain controls with a 

supplier verification program may be appropriate if you use agricultural commodities susceptible 

to mycotoxin formation, because growing and harvest conditions vary from year to year. 

Table 3-7 Common Mycotoxins Associated with Commodities

Mycotoxins Commodities Associated with Mycotoxins

Aflatoxin Peanuts, dried corn, tree nuts

Ochratoxin Coffee, raisins, cereal grains

Fumonisins Dried corn

Deoxynivalenol Wheat, barley

Patulin Apples

Histamines and other biogenic amines are produced from the breakdown of amino acids by 

bacteria in animal-derived foods (e.g., histamine is produced from the amino acid histidine). 

Effects of foodborne histamines or other biogenic amines generally are acute effects, including 

headache, nausea, heart palpitations, facial flushing, itching, urticaria (hives), and 

gastrointestinal upset. Consumption of certain cheeses, especially aged cheeses, has been 

associated with illness from histamines (Taylor and WHO, 1985; Stratton et. al, 1991). If you 

determine that cheeses you use as a raw material present a histamine hazard, you must identify 

and implement a preventive control (see 21 CFR 117.135(a)). If you purchase such cheeses, 

we recommend a supply-chain control with a supplier verification program as well as 

temperature controls to minimize growth of histamine-producing microorganisms. 

An example of a natural toxin produced by a plant is hypoglycin A, a heat stable toxin found in 

the tropical fruit ackee. The level of hypoglycin A in the edible portion of the ackee fruit 

decreases as the fruit ripens. Only properly ripened and processed ackee products with 

hypoglycin A at negligible levels are safe for consumption (FDA, 2015f). Although some persons 

consume unripe ackee with no adverse effects, other persons who consume unripe ackee with 

hypoglycin A exhibit symptoms that range from mild (e.g., vomiting) to severe (e.g., vomiting 

with profound hypoglycemia, drowsiness, muscular exhaustion, and possibly coma and death). 

3.4.1.6 Chemical hazards that may be intentionally introduced for 

purposes of economic gain 

The PCHF requirements specify that you must consider, as part of your hazard identification, 

known or reasonably foreseeable hazards that may be intentionally introduced for purposes of 

economic gain (21 CFR 117.130(b)(2)(iii)). We recommend that you focus on circumstances 

where there has been a pattern of such adulteration in the past, suggesting a potential for 
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intentional adulteration even though the past occurrences may not be associated with the 

specific supplier or the specific food product. Table 3-8 is a quick reference guide listing 

circumstances where there has been a pattern of such adulteration in the past. Additional 

resources include a free on-line food fraud database made available by the U.S. Pharmacopeial 

Convention (USP)3 (USP, 2014 and USP, 2016), a report from the Congressional Research 

Service (Congressional Research Service, 2014), and a report that identifies 137 unique 

incidents in 11 food categories (Everstine et al., 2013).

Table 3-8. Quick Reference Guide for Hazards That May Be Intentionally Introduced for 

Purposes of Economic Gain

Food Containing the 

Hazard Hazard Details Reference

Milk Melamine Milk firms in one country added 

melamine, a nitrogen-rich industrial 

by-product, to diluted dairy 

products to increase the apparent 

protein content

FDA, 2008

Turmeric Lead chromate A chemical with a vibrant yellow 

color that has been used as an 

adulterant in turmeric to change 

the color of the spice to suggest 

that it is of a higher quality

FDA, 2013d

Paprika Lead oxide A red chemical that has been used 

as an adulterant in paprika to 

change the color of the spice to 

suggest that it is of a higher quality

Lead Action 

News, 1995

Chili powder Sudan I An orange-red powder that had 

been added to chili powder as a 

coloring agent, but is now banned 

in many countries because the 

International Agency for Research 

on Cancer has classified it as a 

category 3 carcinogen (not 

classifiable as to its carcinogenicity 

to humans)

United Kingdom 

Food Standards 

Agency, 2005

In determining whether a hazard that may be intentionally introduced for purposes of economic 

gain is a hazard requiring a preventive control, we recommend that your hazard analysis 

consider both the country of origin of an ingredient that may contain the hazard and any specific 

supplier associated with an ingredient containing that hazard. For example, one example listed 

 3 USP is a scientific nonprofit organization that sets standards for the identity, strength, quality, and purity 

of medicines, food ingredients, and dietary supplements manufactured, distributed and consumed 

worldwide. 
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in Table 3-8 is a widespread incident of economically motivated adulteration in which some milk 

firms in one country added melamine, a nitrogen-rich industrial by-product, to diluted dairy 

products to increase the apparent protein content (FDA, 2008). This adulteration resulted in 

significant public health consequences, with more than 290,000 ill infants and 6 deaths in that 

country. In light of this incident, we recommend that you include in your hazard analysis the 

potential for melamine to be an economically motivated adulterant in your food products when 

using milk products from a country where melamine adulteration has occurred and, based on 

the outcome of that hazard analysis, determine whether melamine is a hazard that must be 

addressed in your food safety plan. At present, we do not expect you to consider the potential 

for melamine to be a significant hazard when using domestic milk products, or milk products 

from other countries when there is no history of melamine adulteration associated with those 

countries.

If you determine through your hazard analysis that a hazard that may be intentionally introduced 

for purposes of economic gain is a hazard requiring a preventive control, we recommend that 

you address that hazard through your supply-chain program. 

3.4.2 Chemical Hazards That Can Be Either Ingredient-Related or ProcessRelated 

3.4.2.1 Food allergens

Researchers estimate that up to 15 million Americans and more than 17 million Europeans have 

food allergies (FARE, 2015). A number of foods contain allergenic proteins, which are natural 

constituents of the food that can pose a health risk to certain sensitive individuals. The 

symptoms of food allergies can include a tingling sensation in the mouth, swelling of the tongue 

and throat, nausea, difficulty in breathing, chest pain, hives, rash, itchy skin, vomiting, 

abdominal cramps, diarrhea, sudden drop in blood pressure, loss of consciousness, and, in 

severe cases, death. Symptoms of a food allergy usually come on suddenly, can be triggered by 

a small amount of food, and happen every time the food is eaten. The symptoms are the result 

of the body’s immune system reacting to a specific food or an ingredient in the food. 

Allergic consumers must avoid allergens to prevent potentially life threatening reactions. 

Undeclared food allergens are chemical hazards that can get into food because either: (1) The 

food manufacturer did not properly declare a food allergen ingredient on the product label; or (2) 

unintended (and, thus, undeclared) food allergens are present in a food due to incorrect labeling 

or due to allergen cross-contact. 

This section of this chapter provides a general discussion of food allergen hazards and common 

mechanisms to control them. For more detailed information, see Chapter 11 – Food Allergen 

Controls, which provides a comprehensive guide to food allergen control. An additional 

resource is “Managing Allergens in Food Processing Environments,” a publication of the 

Grocery Manufacturer’s Association (GMA, 2009). 

3.4.2.1.1 The “Big Eight” food allergens

The Food Allergen Labeling and Consumer Protection Act (FALCPA) of 2004 amended the 

FD&C Act and defined the following eight foods and any ingredients that contain protein derived 

from these eight foods (with certain exemptions noted in section 201(qq)(2) of the FD&C Act (21 
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U.S.C. 321(qq)(2)) as major food allergens: milk, eggs, fish, crustacean shellfish, tree nuts, 

peanuts, wheat, and soybeans. The eight foods or food groups cause more than 90% of the 

food allergies in the United States (FDA, 2015c) and are commonly referred to as “the big eight” 

food allergens. FDA has published guidance on labeling the food allergens identified in 

FALCPA – See “Guidance for Industry: Questions and Answers Regarding Food Allergens, 

including the Food Allergen Labeling and Consumer Protection Act of 2004” (FDA, 2006b). 

Immediately below, we provide more information about each of “the big eight food allergens.”

• Crustacea: The class of Crustacea, or shellfish, includes shrimp, crab, lobster, and crayfish. 

Crab and shrimp are the most commonly consumed shellfish in the United States. The major 

shellfish allergen is tropomyosin, a muscle protein that accounts for 20% of the dry weight of 

shrimp (GMA, 2009).

• Egg: Most egg allergic proteins are found in the egg white (albumin) rather than the yolk.

• Fish: Different fish species (e.g., bass, cod, and flounder) have been found to have 

structurally-related proteins, and this may explain why individuals with a fish allergy are 

allergic to multiple types of fish. Cooking may reduce the allergenicity of fish, but it does not 

eliminate it.

• Milk (Dairy): Cow’s milk contains a number of different proteins that are grouped into two 

categories: caseins, which constitute 80% of the total protein, and whey proteins, which 

make up 20%. 

• Peanut: Peanut seeds contain an average of about 29% protein, classified as albumins or 

globulins. 

• Soy: Globulins are the major proteins in soybeans. 

• Tree Nuts: Tree nuts include almonds, Brazil nuts, cashews, filberts/hazelnuts, macadamia 

nuts, pecans, pine nuts, pistachios, and walnuts. FDA lists the nuts considered “tree nuts” 

in its 2006 “Guidance for Industry: Questions and Answers Regarding Food Allergens, 

including the Food Allergen Labeling and Consumer Protection Act of 2004 (Edition 4)”

(FDA, 2006b) and its 2013 Guidance for Industry: A Food Labeling Guide (FDA, 2013a).

• Wheat: Wheat proteins include the globulins, prolamins (i.e., glutenin and gliadin), and 

glutelins. About 25% of wheat-allergic children react to other cereal grains (i.e., barley, oats, 

or rye). Gluten is a mixture of proteins that occur naturally in wheat, rye, barley and 

crossbreeds of these grains. It is associated with celiac disease, which affects as many as 3 

million people in the United States by the body's natural defense system attacking the lining 

of the small intestine and preventing the proper absorption of nutrients (FDA, 2015(d)). 

3.4.2.1.2 Undeclared food allergen hazards due to incorrect label design

FALCPA also amended section 403 of the FD&C Act (21 U.S.C. 343) to prescribe certain 

requirements for what you must declare on the product label for any food product that contains 

any of the “big eight allergens,” including allergenic whole foods (such as milk) and any 

ingredients that contain protein derived from these foods (such as casein derived from milk). 

See section 403(w) of the FD&C Act (21 U.S.C. 343(w)) and our guidance entitled “Guidance for 

Industry: Questions and Answers Regarding Food Allergens, including the Food Allergen 

Labeling and Consumer Protection Act of 2004” (FDA, 2006b). 
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An undeclared food allergen (including a food allergen contained in flavorings, colorings, and 

incidental additives) due to an incorrect label design that does not address all of the labeling 

requirements of FALCPA is a chemical hazard. See 21 CFR 117.130(b)(1)(ii).

3.4.2.1.3 Undeclared food allergen hazards due to incorrect application or 

use of a product label

If you apply the wrong label to a food, or use the wrong packaging (e.g., using packaging for 

“chocolate ice cream” rather than for “chocolate ice cream with almonds”), consumers who have 

a food allergy could purchase a food that would cause an allergic reaction. An undeclared food 

allergen due to applying the incorrect food label to a product, or using the wrong packaging, is a 

chemical hazard. See 21 CFR 117.130(b)(1)(ii).

3.4.2.1.4 Undeclared food allergen hazards due to allergen cross-contact

Cross-contact results from the unintentional incorporation of undeclared allergens into foods 

that are not intended to include those allergens. Cross-contact can occur either between foods 

that contain different food allergens or between foods with and without food allergens. 

Introduction of an allergen through cross-contact may occur during receiving, handling, 

processing and storage of ingredients and foods, utensils, and packaging; through improper 

handling and cleaning of equipment, utensils, and facilities; and through improper facility design. 

An undeclared food allergen due to allergen cross-contact is a chemical hazard. See 21 CFR 

117.130(b)(1)(ii). Allergen cross-contact can result from: 

• Failure to schedule the production of two different products appropriately, resulting in an 

allergen-containing product contaminating a product without food allergens.

• Failure to adequately clean between two different formulations of a product that do and do 

not contain allergens, resulting in an allergen-containing product contaminating a product 

without the allergen. 

• Failure to store allergen-containing ingredients separately from ingredients that do not 

contain allergens, where leakage of allergen-containing materials results in contamination of 

the non-allergen containing product.

• Failure to handle powdered allergens in a way that prevents particles from blowing onto 

foods or food contact surfaces for foods that do not contain that allergen. 

3.4.2.2 Food additives, color additives, and GRAS substances, including 

substances associated with food intolerance or food disorder

Under sections 201(s) and 409 of the FD&C Act (21 U.S.C 321(s) and 348, respectively), a 

substance that is added to food requires premarket review and approval as a food additive 

unless it satisfies the statutory exclusion from the definition of "food additive" for a substance 

that is generally recognized as safe (GRAS) under the conditions of its intended use (section 

201(s) of the FD&C Act or is otherwise excepted from the statutory definition of food additive 

(e.g., as a color additive, as a dietary ingredient intended for use in a dietary supplement, or as 

a new animal drug).

Under sections 201(t) and 721 of the FD&C Act (21 U.S.C 321(t) and 379(e), respectively), a 

color additive requires premarket review and approval; there is no statutory GRAS exclusion 

applicable to a color additive.
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Generally, a food additive, color additive, or GRAS substance is known to be safe for use in 

food only under specific conditions of use, such as a maximum level of use or use only in 

certain food categories. The potential risk to consumers increases when these substances are 

not properly controlled, such as exceeding the usage rates or accidentally introducing an

additive into a food for which it was not approved.

For some consumers, certain substances (including substances that are lawfully used in food as 

food additives, color additives, GRAS substances, and components of whole foods such as 

milk) can cause hypersensitivity reactions because the substance irritates the stomach, or the 

body cannot properly digest it. The symptoms include nausea, abdominal pain, diarrhea, 

vomiting, gas, cramps or bloating, heartburn, headaches, irritability, or nervousness. Symptoms 

of food intolerance usually occur gradually, in comparison with the sudden onset from an 

allergic reaction, and may only occur when a lot of a food is consumed or the food is consumed 

often. 

• Lactose: Some people are intolerant to lactose, a sugar that is a component of milk, 

because they lack the enzyme to digest lactose. The symptoms include abdominal pain, 

diarrhea, vomiting, gas, cramps or bloating. People who have a lactose intolerance avoid 

milk or milk products and rely on the allergen labeling for milk to identify the types of 

products that may cause them problems. 

• Sulfiting agents: Sulfiting agents are used as chemical preservatives in various products. 

People sensitive to sulfiting agents can experience symptoms that range from mild to lifethreatening reactions. As noted previously, sulfites have resulted in diarrhea, headache, 

difficulty breathing, vomiting, nausea, abdominal pain and cramps in sulfite-sensitive 

individuals (Timbo et al. 2004). 

• The sulfiting agents permitted in foods that must be listed on the ingredient label, unless 

they are added to food as an “incidental substance,” are: sulfur dioxide (21 CFR 182.3862), 

sodium sulfite (21 CFR 182.3798), sodium bisulfite (21 CFR 182.3739), sodium metabisulfite 

(21 CFR 182.3766), potassium bisulfite (21 CFR 182.3616), and potassium metabisulfite (21 

CFR 182.3637). Sulfiting agents are considered to be incidental only if they have no 

technical effect in the finished food and are present at less than 10 parts per million (ppm) 

(21 CFR 101.100(a)(4)). The quantity of sulfiting agents added to food should not exceed 

the amount necessary to achieve the intended technical effect(s).

• Yellow No. 5: Yellow No. 5 (tartrazine) is a color additive subject to color certification under 

section 721(c) of the FD&C Act. (21 U.S.C. 379e) People sensitive to Yellow No. 5 can 

experience symptoms that range from mild to moderately severe. For example hives occur 

in some intolerant individuals, but in asthmatic individuals Yellow No.5 can trigger allergictype reactions (including bronchial asthma). To help protect people who are sensitive to 

Yellow No. 5, FDA’s regulation for Yellow No. 5 states that any food for human use that 

contains Yellow No. 5 must specifically declare the presence of the color additive by listing it 

as an ingredient (21 CFR 74.705(d)(2)). If Yellow No. 5 is added but is not declared, the 

product would be both misbranded under section 403(m) of the FD&C Act (21 U.S.C. 

343(m) and adulterated under section 402(c) of the FD&C Act (21 U.S.C 342(c)). 

• Cochineal extract and carmine: Cochineal extract and carmine are color additives 

permitted for use in foods in the United States under conditions of safe use listed in 21 CFR 

73.100. For sensitive consumers, cochineal extract and carmine can cause severe allergic 

reactions, including anaphylaxis (74 FR 207, January 5, 2009). Although the color additives 

cochineal extract and carmine cause allergic reactions, they are not included in the eight 
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major food allergens identified in FALCPA. As a result, the color additives cochineal extract 

and carmine are not included in the definition of “food allergen” in part 117 and are not 

subject to the food allergen controls specified in the PCHF requirements. In addition, FDA’s 

specific labeling requirement in the color additive listing for cochineal extract and carmine 

(21 CFR 73.100(d)(2)), rather than the more general labeling requirements of FALCPA, 

govern the food labeling requirements cochineal extract and carmine. All human foods 

containing cochineal extract or carmine are required to declare the presence of the color 

additive by listing its respective common or usual name, “cochineal extract” or “carmine,” in 

the statement of ingredients ((21 CFR 73.100(d)(2)). Additional information on the labeling 

requirements for these two color additives can be found in FDA industry guidance, 

Cochineal Extract and Carmine: Declaration by Name on the Label of All Foods and 

Cosmetic Products That Contain These Color Additives; Small Entity Compliance Guide

(FDA, 2009a). Control strategies for cochineal extract and carmine are similar to those 

applied to food allergen labeling controls.

In addition, some consumers have celiac disease, which is a hereditary, chronic inflammatory 

disorder of the small intestine triggered by the ingestion of certain storage proteins (referred to 

as gluten) occurring in wheat, rye, barley, and crossbreeds of these grains. As discussed in 

section 3.4.2.1.1 of this chapter, celiac disease affects as many as 3 million people in the United 

States (FDA, 2015(d)).

3.4.2.2.1 Unapproved food additives and color additives 

A substance (other than a food contact substance subject to a notification under section 409(h)) 

that is a food additive or a color additive must be used in accordance with a food additive 

regulation permitting that specific use or a color additive listing. Otherwise, the presence of that 

substance in food would make the food adulterated under section 402(a)(2)(C) of the FD&C Act

(21 U.S.C. 342(a)(2)(C)). Under the PCHF requirements, an unapproved food or color additive 

is a chemical hazard (see 21 CFR 117.130(b)(1)(ii)). 

Some food and color additives are specifically prohibited from use in food because we have 

determined that the chemical additive poses a potential risk to public health (see 21 CFR part 

189 and 21 CFR 81.10). Examples of such food and color additives are coumarin, safrole, and 

FD&C Red No. 4 (Red No. 4) (FDA, 2015b). We consider a prohibited food additive or color 

additive to be an unapproved food additive or color additive for the purposes of the PCHF 

requirements and, thus, to be a chemical hazard. You should consult 21 CFR if you have 

questions about the regulatory status or safety of a particular additive when formulating your 

food products. An additional resource for you is the Food Additive Status List on our website 

(FDA, 2014b).

3.4.2.2.2 Chemical hazards due to misformulation 

A food ingredient can be a chemical hazard if it is added in excess of a maximum use level, 

regardless of whether the maximum use level is established due to food intolerance (such as for 

sulfites) or is otherwise a condition of safe use of a food additive, color additive, or GRAS 

substance. Control strategies to prevent misformulation of substances generally include 

process controls to ensure that excessive amounts are not added. 
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3.4.2.2.3 Chemical hazards due to incorrect labeling of substances 

associated with food intolerance or food disorder

Although the mechanisms whereby persons experience food intolerance or food disorder are 

different from the mechanisms that cause food allergy, reactions due to food intolerance or food 

disorder can cause significant health problems for those affected, and the principal means that 

consumers have to avoid the symptoms of food intolerance are the same means that 

consumers use to avoid symptoms of food allergy – i.e., avoid foods containing the substance 

that causes the problem. For example, people who are intolerant to lactose, a sugar that is a 

component of milk, avoid food products containing milk to avoid the symptoms associated with 

lactose intolerance. In addition, people who have celiac disease avoid food products containing 

wheat and other sources of gluten.

Undeclared substances associated with a food intolerance or food disorder are chemical 

hazards that can get into food because either: (1) The food manufacturer did not properly 

declare the substance on the product label; (2) unintended (and, thus, undeclared) substances 

are present in a food due to incorrect labeling. Control strategies to prevent incorrect labeling of 

substances associated with a food intolerance or food disorder are analogous to those used to 

prevent incorrect labeling of food allergens and, thus, you may find Chapter 11—Food Allergen 

Controls helpful in preventing incorrect labeling of substances associated with a food 

intolerance or food disorder. The preventive controls in that comprehensive guide to food 

allergen control do not explicitly address substances associated with food intolerance or food 

disorder, but may nonetheless be useful in addressing chemical hazards due to incorrect 

labeling of such substances.

3.4.2.3 Process contaminants produced during heating

There are several process-related contaminants that are produced during heating of specific 

ingredients or finished foods that may be a health (e.g., cancer) concern. For example, 

acrylamide is formed during high-temperature cooking processes (including frying, roasting, or 

baking) due to interaction between sugars and amino acids that are naturally present in foods. 

Acrylamide is found mainly in foods made from plants, including potato products, grain products, 

and coffee. 

As noted in footnote 8, we have not included such contaminants in Table 3-6 as potential 

process-related chemical hazards that may require a preventive control as part of a food safety 

plan under part 117 because we believe that more information is needed regarding appropriate 

levels and effective controls. We have published a guidance document, Guidance for Industry: 

Acrylamide in Foods (FDA, 2016a) to help growers, manufacturers, and food service operators 

reduce acrylamide levels in certain foods. Control strategies to reduce acrylamide in food may

include controlling temperatures during cooking and ingredient substitution.

3.4.2.4 Radiological hazards

Radiological hazards rarely occur in the food supply; however, when they do occur, these 

hazards can present a significant risk when exposures occur over a period of time (WHO, 

2011). Consuming food contaminated with radionuclides will increase the amount of 

radioactivity a person is exposed to, which could have adverse health effects. The health effect 

depends on the radionuclide and the amount of radiation to which a person is exposed. For 

instance, exposure to certain levels of radioactive iodine is associated with increased risk of 

thyroid cancer (WHO, 2011).
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Radiological hazards can become incorporated into food through the use of water that contains 

the radionuclides during food production or manufacture. There are areas in the United States 

where high concentrations of some radionuclides, such as radium-226, radium-228, and 

uranium, can be detected in well water (Ayotte et al., 2007; Focazio et al., 2001). You should be 

aware of the condition of the water used for production and manufacture in your facilities. For 

example, if your facility uses well water and there are elevated levels of radionuclides in the well 

water, you should not use the water. The CGMPs require that water that contacts food, foodcontact surfaces, or food-packaging materials be safe and of adequate sanitary quality (see 21 

CFR 117.37(a)).

Radiological hazards also may result from accidental contamination, e.g., contamination arising 

from accidental release from a nuclear facility or from damage to a nuclear facility from a natural 

disaster. In 2011, following damage to a nuclear power plant during an earthquake and tsunami 

in Japan, radioactivity was subsequently detected in foods, particularly milk, vegetables, and 

seafood produced in areas neighboring the plant (WHO, 2011). You should be vigilant 

regarding accidental releases of radiological hazards and their potential to contaminate your 

food product, either directly due to contamination of natural resources near your facility or as a 

result of raw materials and other ingredients that you obtain from a region that has experienced 

an accidental release of radiation. 

3.4.3 Facility-Related Chemical Hazards 

Industrial chemicals or other contaminants from the food processing environment can 

contaminate food during production – e.g., if chemicals used to clean a production line are not 

adequately removed from the production line or if heavy metals are leaching from containers or 

utensils. In this guidance, we do not discuss preventive controls for facility-related chemical 

hazards such as cleaning chemicals and the leaching of heavy metals from containers or 

utensils, because such hazards are usually addressed through CGMPs. 

3.5 Physical Hazards 

You must conduct a hazard analysis to identify and evaluate known or reasonably foreseeable 

physical hazards (such as stones, glass, and metal fragments). See 21 CFR 117.130(b)(1)(iii).

When your hazard analysis identifies a known or reasonably foreseeable physical hazard that 

requires a preventive control, you must identify and implement a preventive control for the 

physical hazard. See 21 CFR 117.135(a)(1).

Physical hazards are broadly classified as “hard/sharp” physical hazards and “choking” hazards. 

Both categories can cause injury to the consumer. These injuries may include dental damage, 

laceration of the mouth or throat, laceration or perforation of the intestine, and choking and may 

even lead to the death. Because physical hazards cover a broad range of contaminants, such 

as glass, metal, plastic, wood, and stones, such contamination can occur throughout the 

processing facility, including the receiving dock for ingredients and supplies. 

In this section of this guidance we describe common physical hazards – i.e., metal, glass, and 

hard plastic physical hazards. 

• Metal: Metal-to-metal contact during processing can introduce metal fragments into 

products. For example, metal fragments can break off during mechanical cutting and 

blending operations, and some metal equipment has parts that can break or fall off, such as 

wire-mesh belts. FDA’s Health Hazard Evaluation Board (FDA, 2005e; Olsen, 1998) has 
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supported regulatory action against products with metal fragments of 0.3 inches (7 mm) to 

1.0 inches (25 mm) in length. Such fragments have been shown to be a hazard to 

consumers. Metal hazards can be controlled by the use of metal detection devices or by 

regular inspection of at-risk equipment for signs of damage.

• Glass: Glass fragments can be introduced into food whenever processing involves the use 

of glass containers. Normal handling and packaging methods, especially mechanized 

methods, can result in breakage. Ingesting glass fragments can cause injury to the 

consumer. FDA’s Health Hazard Evaluation Board has supported regulatory action against 

products with glass fragments of the same size noted for metal. Most products packed in 

glass containers are intended to be a ready-to-eat (RTE) commodity. In your hazard 

analysis, you should consider the potential for glass fragments to originate from sources 

other than glass containers used in packaging. For example, some facilities that do not 

pack in glass prohibit the presence of glass in the production environment to reduce the risk 

of glass getting into the product. You can address glass fragments originating from sources 

such as overhead light fixtures through CGMPs.

• Hard Plastic: Hard plastic can be introduced into food when tools and equipment such as 

scoops, paddles, buckets or other containers develop fatigue, crack, and break as they 

wear. Hard plastic also can be introduced into food when plastic sieves and screens 

deteriorate. You should examine items to determine whether they are worn and remove

worn items before they break, especially if they cannot be effectively cleaned (e.g., because 

of small cracks). 

In general, there is overlap between facility-related physical hazards and process-related 

physical hazards. For example, equipment that has food-contact surfaces that break during 

food processing and result in physical debris being deposited in the food product can be 

considered a facility-related physical hazard (because the equipment is part of the facility) or a 

process-related physical hazard (because the equipment broke during processing). In general, 

in evaluating the potential for physical hazards in your food products, it does not matter whether 

you consider physical hazards to be facility-related or process-related. However, a few physical 

hazards can readily be classified as facility-related or process-related. For example, nuts and 

bolts used during maintenance procedures would be a facility-related hazard, but production 

equipment that has nuts and bolts that could fall out during production would be a processrelated hazard. 

Table 3-9 is a Quick Reference Guide to help you identify common sources of these physical 

hazards. See Chapter 13 – Preventive Controls for Physical Hazards for more detailed 

recommendations on control measures for physical hazards. In this guidance, we do not 

discuss ingredient-related physical hazards such as wood and stone, which are usually 

addressed through CGMPs or as a supply-chain control through your supplier program. 
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Table 3-9. Quick Reference Guide for Common Sources of Physical Hazards

Source Metal – Ferrous & NonferrousPlastic, Ceramic, and 

Glass

Other

Ingredient-related • Farm field debris

• Precut, ground, 

injected, sliced, items, 

where metal was not 

properly controlled by 

supplier. 

• Farm field debris, 

• Packaging materials

• Pits or pit fragments, 

shells

Facility-related and processrelated (processing/production 

environment, equipment, and 

pests (insects, birds, rodents, 

reptiles))

 

• Equipment

• Grinders, slicers, 

knives

• Sieves, screens, wiremesh belts

• Mixing paddles 

• Metal cans (shavings, 

lids) 

• Pumps

• Cook Kettles with 

swept surface 

paddles

• Drop buckets 

• Equipment (inspection 

belts, small wares, 

buckets)

• Facility (glass light 

fixtures, glass 

windows in doors, 

plastic strip curtains)

• Glass containers

• Scoops 

• Mixing paddles

• Buckets

• Incomplete removal 

of pits or pit 

fragments, shells

• Poor Design --

Particle size of food 

inappropriate for 

consumer –

choking hazard

People-related (actions or 

behaviors)

• Jewelry 

• Hair pins 

• Buttons 

• Zipper pulls

N/A

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