Setting Elemental Impurity Limits for Different Types of Products

Lead, arsenic, cadmium and mercury turn up in almost everything we make: in mined excipients, botanical ingredients, catalysts, steel equipment and packaging. The question is never whether they are present. It is how much is acceptable, and that answer depends on what kind of product you are making. A tablet, a protein powder, a herbal capsule and a lipstick can each be held to a different standard, set by a different body, using a different logic. This guide walks through the main frameworks and shows how to turn a daily exposure limit into a number you can put on a specification.

Why One Limit Does Not Fit All

Elemental impurity limits come from two different philosophies. The first is toxicology-based: set a tolerable daily intake for each element and route, then make sure the patient or consumer never exceeds it. ICH Q3D, USP <2232> and most supplement and natural health product limits work this way. The second is feasibility-based: ask what level good manufacturing practice can reasonably achieve and treat anything above it as avoidable. Cosmetics regulation in Canada and Europe leans this way.

The unit matters too. A toxicology limit is a dose, expressed in µg/day. A specification is a concentration, expressed in µg/g (ppm). Moving between them requires the maximum daily intake of the product, which is why the same element can carry very different ppm limits in two products with the same PDE.

Drug Products: ICH Q3D(R2) and USP <232>/<233>

ICH Q3D sets PDEs for 24 elements across oral, parenteral and inhalation routes (ICH Q3D(R2), 2022). Elements are grouped by toxicity and likelihood of occurrence:

• Class 1. Arsenic, cadmium, mercury and lead. Highly toxic, little or no use in manufacturing, and must be assessed for every route.
• Class 2A. Cobalt, nickel and vanadium. Relatively likely to occur, so they are assessed for all routes even when not intentionally added.
• Class 2B. Ten elements including palladium, platinum, silver, gold and selenium. Low natural abundance, so they are assessed only if intentionally added, for example as catalysts.
• Class 3. Seven elements including barium, chromium, copper, lithium and tin. Low oral toxicity, so they are assessed for parenteral and inhalation products but generally not for oral ones.

Route makes a large difference. Oral PDEs are 5 µg/day for lead and cadmium, 15 µg/day for arsenic and 30 µg/day for mercury. By inhalation, the mercury PDE drops to 1 µg/day and arsenic to 2 µg/day. The R2 revision, adopted at ICH Step 4 in April 2022, corrected values for gold, silver and nickel and added Appendix 5 on the cutaneous and transcutaneous route (GMP Publishing, 2022). During its development, the working group derived cutaneous PDEs from parenteral PDEs adjusted for limited skin absorption, and added concentration limits for skin sensitizers such as nickel (PQRI, 2020).

The guideline is built on risk assessment, not blanket testing. You identify potential sources (excipients, drug substance, water, equipment, container closure), evaluate likely levels, and compare them with the PDE. If an element is consistently below the control threshold of 30% of the PDE, additional controls are generally not needed. In the US, USP <232> (limits) and <233> (ICP-OES and ICP-MS procedures) apply to compendial products, and FDA expected risk assessments for existing approved products by 1 January 2018 (FDA/USP workshop materials, 2016).

Four Options for Converting a PDE

• Option 1. A common concentration limit for all components, calculated with a default daily intake of 10 g. Simple and conservative.
• Option 2a. A common concentration limit calculated with the product’s actual maximum daily dose.
• Option 2b. Different limits for different components, provided the summed contribution stays within the PDE.
• Option 3. Test the finished product and compare the measured amount at the maximum daily dose with the PDE.

Dietary Supplements: USP <2232> and Proposition 65

USP <2232> sets daily limits for supplements: 15 µg/day inorganic arsenic, 5 µg/day cadmium, 5 µg/day lead, 15 µg/day total mercury and 2 µg/day methylmercury. Its individual component option, for products taken at up to 10 g/day, gives 0.5 µg/g for lead and cadmium (USP <2232>, USP 38).

For products sold in California, the binding constraint is often Proposition 65. Lead’s Maximum Allowable Dose Level for reproductive toxicity is 0.5 µg/day, ten times lower than the USP figure (OEHHA). Prop 65 does not ban the product. It requires a warning if exposure exceeds the safe harbour level, and exposure depends on serving size and frequency of use (Eurofins).

Food rules are tightening as well. Under its Closer to Zero initiative, FDA issued final guidance in January 2025 with lead action levels of 10 ppb for most processed foods for babies and young children and 20 ppb for single-ingredient root vegetables and dry infant cereals (FDA, 2025).

“The PDE is set by toxicology. Your specification is set by your dose, your market and your customer.”

Natural Health Products in Canada

Health Canada’s Quality of Natural Health Products Guide sets limits for arsenic, cadmium, lead and mercury, expressed per day and per kilogram of body weight. A draft version 4.0, published for consultation in July 2026, proposes adult oral limits of less than 5.0 µg/day for lead and cadmium, 15.0 µg/day for total and inorganic arsenic, 15.0 µg/day for total mercury and 2.0 µg/day for methylmercury. It points to ICH Q3D for calculating concentration limits and to USP <2232> or <233> for test methods (Health Canada, 2026 draft).

Two details deserve attention. Products for people under 18 must be recalculated using the lowest body weight in the target population. Topical NHPs get separate ppm limits based on a 10 g daily dose.

Cosmetics: Technically Avoidable Levels

Health Canada’s 2012 guidance treats heavy metals above these levels as technically avoidable: lead 10 ppm, arsenic 3 ppm, cadmium 3 ppm, mercury 1 ppm (lowered from 3 ppm under the Minamata Convention) and antimony 5 ppm (Health Canada). The guidance is not law, but products above the limits are assessed case by case.

In the EU and UK, Regulation (EC) No 1223/2009 lists these metals in Annex II as prohibited. Article 17 allows small, non-intended traces only when they are technically unavoidable under good manufacturing practice and the product remains safe. There is no harmonized EU number. Germany’s BVL publishes non-binding orientation values, such as 2.0 mg/kg for lead in general cosmetics (UK OPSS, 2023).

Framework	Products	Lead Limit	Basis
ICH Q3D(R2) / USP <232>	Drugs (oral)	5 µg/day	Toxicology (PDE)
USP <2232>	US supplements	5 µg/day	Toxicology (PDE)
Proposition 65	Products sold in California	0.5 µg/day	Warning trigger (MADL)
FDA action levels	Foods for babies	10–20 ppb	Closer to Zero
Health Canada NHP (2026 draft)	Oral NHPs	<5 µg/day	Toxicology (proposed)
Health Canada cosmetics	Cosmetics	10 ppm	Technically avoidable
German BVL (EU)	Cosmetics	2.0 mg/kg	Technically avoidable

What This Means for Product Developers and Quality Teams

Start by deciding which frameworks apply. A product sold in several markets, or one that moves between categories (a supplement reformulated as an NHP, a topical drug versus a cosmetic), may face several limits at once.

• Know your dose. The maximum daily intake drives every concentration limit. Use labelled maximums, not typical use.
• Assess before you test. A documented risk assessment of ingredients, equipment and packaging is what regulators expect under Q3D, and it focuses testing where it matters.
• Qualify suppliers on data. Botanical, marine and mined ingredients vary by lot and origin. Ask for element-specific results, not a total heavy metals test.
• Use validated methods. ICP-MS or ICP-OES procedures meeting USP <233>, verified for your matrix, are the expected standard.

Terraforme Biosciences helps drug, supplement, natural health product and cosmetic companies build elemental impurity risk assessments, set defensible specifications and prepare for regulatory review. Learn more about our regulatory guidance services. For method set-up, see our guide to compendial analytical method verification.

The Bottom Line

Elemental impurity control is one calculation applied under several rulebooks. Get the PDE right, get the daily dose right, and know which market rule is the tightest.