Ferric pyrophosphate is a commonly used food nutrient fortifier and raw material for iron supplements. Its toxicity studies and safety assurance measures are core bases for evaluating the feasibility of its application, which can be elaborated from the following two aspects:
I. Toxicity Studies
Toxicity studies on ferric pyrophosphate mainly focus on acute toxicity, subchronic toxicity, chronic toxicity, and special toxicity (such as genotoxicity and reproductive developmental toxicity), showing an overall characteristic of "low toxicity and high safety":
1. Acute Toxicity
Existing animal experiments (e.g., oral acute toxicity tests on rats) show that ferric pyrophosphate has extremely low acute toxicity, and its median lethal dose (LD₅₀) is much higher than the conventional application dose. Even when animals ingest ferric pyrophosphate in a single dose far exceeding the daily supplementary dose for humans, no obvious acute poisoning symptoms (such as vomiting, diarrhea, or organ damage) are observed. Only under extremely high doses may transient gastrointestinal discomfort occur due to local irritation, with no irreversible damage. This indicates high safety of ferric pyrophosphate in acute exposure scenarios.
2. Subchronic and Chronic Toxicity
Long-term animal feeding experiments (e.g., 3–12 month subchronic toxicity tests on rats and dogs, and longer-term chronic toxicity observations) show that within the dose range consistent with the recommended human intake (calculated based on iron content), ferric pyrophosphate does not exert adverse effects on the growth and development, blood routine, liver and kidney functions, or organ morphology (e.g., liver, kidney, and gastrointestinal tract) of animals. Only when the dose far exceeds the safe range (e.g., the daily iron intake reaches more than 10 times the recommended human dose), some animals may exhibit mild hepatic iron accumulation (without inducing liver damage) or gastrointestinal reactions (such as constipation and abdominal distension). Moreover, the accumulation can be gradually alleviated after discontinuing intake, with no long-term toxic residues.
3. Special Toxicity
The results of genotoxicity tests (e.g., bacterial reverse mutation test, mammalian cell chromosome aberration test, and mouse bone marrow micronucleus test) are all negative, indicating that ferric pyrophosphate has no mutagenicity and will not cause DNA damage or chromosomal abnormalities. Reproductive developmental toxicity tests (e.g., rat reproductive capacity tests and embryonic developmental toxicity tests) show that at conventional doses, ferric pyrophosphate does not affect the reproductive function of parental animals, nor does it cause developmental abnormalities such as malformation or growth retardation in offspring, further confirming its non-toxic effect on the reproductive system.
4. Human Tolerability
Clinical studies show that humans have good tolerability to oral ferric pyrophosphate. Compared with other iron preparations (e.g., ferrous sulfate), it causes less irritation to the gastrointestinal mucosa. Due to the slow release of iron ions, it is less likely to trigger discomfort symptoms such as nausea, vomiting, or abdominal pain. Only a small number of people with sensitive gastrointestinal tracts may experience mild constipation when taking high-dose supplements, which can be alleviated by adjusting the dose or taking it with food. No serious adverse reactions have been reported.
II. Safety Assurance Measures
To ensure the safety of ferric pyrophosphate in production, application, and consumption, a multi-dimensional assurance system needs to be established covering raw material control, production standards, dose management, and application restrictions:
1. Raw Material and Production Process Control
For the production of ferric pyrophosphate, raw materials (such as phosphoric acid and iron hydroxide) that meet food-grade or pharmaceutical-grade standards must be used to avoid the introduction of heavy metals (e.g., lead, arsenic, and mercury), harmful microorganisms, or other impurities. The production process must comply with the National Food Safety Standard General Hygienic Specification for the Production of Food Additives (GB 14881) or Good Manufacturing Practice (GMP) for pharmaceuticals. Through strict control of reaction temperature, pH value, and purity testing (e.g., detecting impurity content via high-performance liquid chromatography and atomic absorption spectrometry), the purity of the final product is ensured to meet standards (e.g., the iron content of food-grade ferric pyrophosphate must reach the specified range, and the heavy metal content must be below the limit), thereby reducing safety risks from the source.
2. Strict Definition of Application Scope and Dosage
Food safety regulatory authorities in various countries (e.g., the National Health Commission of the People’s Republic of China, the U.S. Food and Drug Administration (FDA), and the European Food Safety Authority (EFSA)) have clearly stipulated the application scope and maximum dosage of ferric pyrophosphate. For example, in China, it can be used in infant formula food, follow-up formula food for older infants and young children, children’s solid drinks, and adult nutritional supplements. Strict limits on iron content are set for different food categories (e.g., the iron content in infant formula food usually does not exceed 10 mg per 100 g of product) to prevent excessive iron load in the human body due to over-addition.
3. Establishment of Dose Guidance Standards
Targeting differences in iron nutritional needs among different populations (e.g., infants, children, adults, pregnant women, and lactating women), personalized supplementary dose standards are formulated. For instance, the Chinese Nutrition Society recommends a daily iron intake of 12 mg for adult men, 20 mg for adult women (of childbearing age), and 24–29 mg for pregnant women. When ferric pyrophosphate is used as a supplement, the single or daily iron supplementary dose must comply with this recommended range to avoid toxic reactions caused by blind supplementation. At the same time, the "Tolerable Upper Intake Level (UL)" is specified—for example, the daily UL of iron for adults is 42 mg. The application of ferric pyrophosphate must be strictly below this limit to prevent iron accumulation poisoning caused by long-term over-intake.
4. Safety Adaptation to Application Scenarios
When ferric pyrophosphate is used in food or pharmaceuticals, its compatibility with other ingredients must be considered to avoid safety risks caused by component interactions (e.g., co-administration with certain tannic acid components may affect iron absorption but causes no toxic reactions). For special populations (e.g., patients with iron deficiency anemia or hepatic/renal insufficiency), it must be used under the guidance of doctors or nutritionists, and the dose should be adjusted according to individual health conditions to avoid adverse reactions caused by differences in metabolic capacity. When used in infant food, it is also necessary to ensure that ferric pyrophosphate has fine particles and good solubility to avoid swallowing difficulties or gastrointestinal irritation caused by excessively large particle sizes.
5. Improvement of Quality Standards and Regulatory Systems
Unified quality standards for ferric pyrophosphate (e.g., China’s GB 1903.28-2022 National Food Safety Standard Food Nutrient Fortifier Ferric Pyrophosphate) are formulated, specifying requirements for purity, impurity content, and microbial indicators. Through regulatory measures such as market sampling inspections and unannounced inspections of production enterprises, compliance of products with standards is ensured. Meanwhile, an adverse reaction monitoring mechanism is established. If abnormal reactions caused by ferric pyrophosphate (such as severe allergies or organ damage due to long-term over-intake) are detected, risk assessment and recall procedures are initiated in a timely manner to protect consumer safety.
