Nitrosamines Testing for Elastomers

Understanding

What are nitrosamines?

Nitrosamines (more precisely, N-nitrosamines) are a class of organic compounds containing a nitroso group (–N=O) bonded to the nitrogen of an amine (chemical motif N–N=O). They form when secondary or tertiary amines react with nitrosating agents such as nitrites, typically under acidic conditions. Well-known examples include N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA).

Are nitrosamines dangerous?

Many nitrosamines are potent genotoxic (DNA-reactive, mutagenic) carcinogens in animal studies and are classified by regulators as probable human carcinogens. Under the ICH M7(R2) guideline they belong to the “cohort of concern,” meaning the standard threshold of toxicological concern (TTC) of 1.5 µg/day used for ordinary mutagenic impurities does not apply; instead, much lower substance-specific acceptable intake (AI) limits must be set. Regulatory AI limits are derived to approximate an excess lifetime cancer risk of not more than 1 in 100,000 assuming daily lifetime exposure. NDMA and NDEA are among the most potent and best-characterized members of the class. The 2018 discovery of NDMA in valsartan, and subsequently in other sartans, ranitidine, metformin and further products, triggered worldwide recalls and today’s regulatory framework.

Where are nitrosamines commonly found?

Nitrosamines occur at trace levels in many places: cured and processed foods (e.g., cured meat, smoked fish, beer), tobacco smoke, drinking water (as disinfection by-products), cosmetics (notably NDELA in certain formulations), rubber and elastomer articles (formed from amine-based vulcanization accelerators workplace atmospheres in the rubber industry, and pharmaceuticals (introduced via contaminated raw materials/solvents, reaction of amines with nitrites during synthesis or formulation, or degradation over shelf life).

Requirements

Do I need nitrosamine testing for my elastomer product?

Rubber/elastomer articles for infants and children in the EU – teats and soothers (Directive 93/11/EEC) and toys for children under 3 or intended to be placed in the mouth (Toy Safety Directive 2009/48/EC) are subject to binding migration limits, which requires compliance testing. (3) Certain food-contact rubber articles – e.g., per national rules and recommendations such as Germany’s BfR Recommendation XXI. If your product contains vulcanized rubber/latex, secondary amines plus nitrosating agents, or is a drug product/API, a nitrosamine risk assessment – and usually testing – is warranted.

What industries require nitrosamine testing?

Verified regulatory testing/assessment requirements exist for the pharmaceutical industry (APIs and finished drug products), the rubber/elastomer industry supplying childcare articles (teats, soothers, drinking accessories) and toys in the EU, and food-contact rubber articles under national provisions. In addition, standardized test methods exist for condoms (ISO 29941, migration of nitrosamines from natural rubber latex condoms) and for cosmetics (ISO 10130 and ISO 15819 for NDELA determination; nitrosamines are prohibited substances under the EU Cosmetics Regulation framework). Occupational-health rules for carcinogenic nitrosamines also apply in the rubber industry (e.g., Germany’s TRGS 552; in the US, specific nitrosamines such as NDMA are regulated under OSHA 29 CFR 1910.1003). Food and drinking-water sectors monitor nitrosamines as process contaminants, though limits there are jurisdiction-specific.

What are acceptable limits for nitrosamines?

There is no single universal limit; limits are product- and jurisdiction-specific. For pharmaceuticals, limits are expressed as acceptable intake (AI) in ng/day and converted into a concentration limit via: acceptable concentration (ng/g) = AI (ng/day) ÷ maximum daily dose (g/day). Key verified values:

Context	Limit	Source
NDMA (pharma)	96 ng/day AI	FDA / EMA / Health Canada
NDEA (pharma)	26.5 ng/day AI	FDA / EMA / Health Canada
NDSRIs, CPCA Category 1	26.5 ng/day (FDA); 18 ng/day (EMA/Health Canada)	FDA RAIL guidance (2023); EMA/HC CPCA
NDSRIs, CPCA Categories 2 / 3 / 4 / 5	100 / 400 / 1500 / 1500 ng/day	FDA RAIL guidance (2023)
EU teats & soothers (migration)	0.01 mg/kg total N-nitrosamines; 0.1 mg/kg total N-nitrosatable substances	Directive 93/11/EEC (tested per EN 12868)
EU toys (<3 yrs / mouth toys)	0.05 mg/kg N-nitrosamines; 1 mg/kg N-nitrosatables (migration)	Directive 2009/48/EC (tested per EN 71-12)
US rubber infant nipples	≤10 µg/kg per nitrosamine; ≤20 µg/kg total	ASTM F1313
Food-contact rubber (Germany)	≤1 µg/dm² nitrosamine migration	BfR Recommendation XXI

For nitrosamines without an established compound-specific AI, regulators apply a class-specific default: Health Canada and EMA use a nitrosamine-class TTC of 18 ng/day, while FDA recommends 26.5 ng/day for products marketed in the US. FDA and Health Canada each maintain continuously updated online tables of compound-specific AI limits, which should always be consulted for the current value.

Execution

How do labs test for nitrosamines?

Because regulatory limits are in the low ng/g (ppb) range, testing relies on highly sensitive and selective trace analysis. For rubber articles, some testing is migration-based: the article is immersed in an artificial saliva test solution under standardized conditions and the released nitrosamines (and, after nitrosation of the migrate, the nitrosatable substances) are quantified. The harmonized methods are EN 12868 (teats/soothers, implementing Directive 93/11/EEC), EN 71-12 (toys), ASTM F1313 (US rubber nipples) and ISO 29941 (condoms).

What methods are used?

GC-MS/MS suits volatile small nitrosamines such as NDMA and NDEA. In the rubber field, gas chromatography is the classical detection technique referenced in the standards, alongside GC-MS.

What materials are at risk (rubber, latex)?

Highest-risk materials are: vulcanized rubber and natural rubber latex (nitrosamines form from secondary-amine vulcanization accelerators such as thiurams and dithiocarbamates – relevant for teats, soothers, balloons, gloves, condoms, seals, hoses and also rubber closures used in pharmaceutical primary packaging). Nitrosatable substances, amines that are not yet nitrosamines but can be converted into them, are regulated in their own right for EU childcare articles and toys.

Industry-Specific

What are nitrosamine testing requirements by industry?

Pharmaceuticals: mandatory risk assessment for all human medicinal products; confirmatory testing where risk is identified; control strategy/specifications and reporting of changes to the authority (FDA Rev. 2 guidance 2024; EMA Art. 5(3) Q&A; Health Canada guidance).

Childcare articles & toys (EU): migration testing of rubber/elastomer teats and soothers against Directive 93/11/EEC limits using EN 12868; children’s drinking accessories are covered by EN 14350 with the same limits; toys for under-threes and mouth toys against Directive 2009/48/EC limits using EN 71-12.

Food contact & food: rubber food-contact articles per national provisions (e.g., BfR Recommendation XXI, Council of Europe resolutions); no fully harmonized EU-wide migration limit exists for general food-contact rubber.

Condoms & cosmetics: standardized methods ISO 29941 (condoms) and ISO 10130/ISO 15819 (NDELA in cosmetics) support compliance testing.

Occupational health (rubber industry): workplace exposure rules for carcinogenic nitrosamines (e.g., TRGS 552 in Germany; OSHA 29 CFR 1910.1003 for listed nitrosamines in the US).

Nitrosamines in rubber products – compliance

Compliance for rubber products is driven by the intended use: teats and soothers placed on the EU market must not release more than 0.01 mg/kg total N-nitrosamines and 0.1 mg/kg total N-nitrosatable substances; the same limits are applied to children’s drinking accessories via EN 14350, and the UK implemented the Directive through its 1995 Safety Regulations). Toys made of elastomer for children under 36 months, or intended to be placed in the mouth (e.g., balloons), must meet 0.05 mg/kg (nitrosamines) and 1 mg/kg (nitrosatables) under Directive 2009/48/EC, tested per EN 71-12. In the US, ASTM F1313 sets ≤10 µg/kg per individual nitrosamine and ≤20 µg/kg total for rubber infant nipples. For food-contact rubber (gloves, hoses, seals, conveyor belts), German BfR Recommendation XXI (≤1 µg/dm² migration) is the commonly used reference in the absence of harmonized EU limits. Upstream, compliance is typically achieved by using “nitrosamine-safe” accelerator systems and confirmed by migration testing of the finished article.

Geography-Specific

Nitrosamine requirements for USA compliance

Pharmaceuticals: comply with the FDA framework described above, risk assessment for all products, confirmatory testing where indicated, AI-limit-based specifications (NDMA 96 ng/day; NDEA 26.5 ng/day; NDSRIs per CPCA, with 26.5 ng/day recommended for Category 1 for US-marketed products), and reporting of changes under 21 CFR 314.70 / 314.97 / 601.12 as applicable.

Consumer rubber articles: ASTM F1313 for rubber infant nipples (≤10 µg/kg individual, ≤20 µg/kg total).

Occupational: certain nitrosamines (e.g., NDMA) are OSHA-regulated carcinogens under 29 CFR 1910.1003.

Nitrosamine requirements for EU compliance

Pharmaceuticals: the Article 5(3) referral outcome (procedure EMEA-H-A5(3)-1490) and the EMA Questions & Answers for marketing authorisation holders govern the process “call for review” risk assessments, confirmatory testing, and changes to marketing authorisations; limits are set via Appendix 1 (established acceptable intakes) and Appendix 2 (CPCA), with an enhanced Ames test protocol (Appendix 3) available to de-risk compounds. EMA continues to update the Q&A and AI list as new NDSRIs are identified.

Consumer products: Directive 93/11/EEC (teats/soothers, 0.01 / 0.1 mg/kg migration limits, EN 12868), Toy Safety Directive 2009/48/EC (0.05 / 1 mg/kg for under-3 and mouth toys, EN 71-12), EN 14350 for children’s drinking equipment, and nitrosamine prohibitions in the cosmetics framework. Food-contact rubber follows national measures (e.g., BfR XXI) pending EU harmonization.

Nitrosamine requirements for other prominent regions

Canada: Health Canada’s “Nitrosamine impurities in medications: Guidance” (first published 2022, most recently updated August 1, 2025) mirrors the international framework: risk assessment, confirmatory testing, and CAPA implementation with timelines of up to 3 years from AI-limit publication (i.e., up to August 1, 2028 for limits published before August 1, 2025). It maintains an online Appendix 1 table of established AI limits, applies the CPCA (Appendix 4), and uses a class-specific TTC of 18 ng/day as the default where no compound-specific AI exists.

United Kingdom: the EU teats/soothers rules were implemented through the N-nitrosamines and N-nitrosatable Substances in Elastomer or Rubber Teats and Dummies (Safety) Regulations 1995.

International convergence: the CPCA and the ICH M7(R2) “cohort of concern” treatment of nitrosamines have been adopted consistently by FDA, EMA and Health Canada, so AI limits and methodology are largely aligned across these regions (with the noted Category-1 difference: 26.5 ng/day FDA vs. 18 ng/day EMA/Health Canada). Requirements of other national authorities (e.g., in Asia-Pacific or Latin America) follow similar principles but were not verified for this document and should be confirmed against the respective authority’s current guidance before relying on them.