ICH M7(R2) methodologyLinear extrapolationMW correction (Fine et al. 2023)Cohort of concern
Cohort of concern: N-nitroso compounds are classified under the ICH M7 cohort of concern
as high-potency mutagenic carcinogens. The default TTC of 1.5 µg/day may not be sufficiently protective.
Compound-specific risk assessment using carcinogenicity data (TD50 or BMDL10) is recommended.
1Carcinogenicity Data Input
TD50: Derived from carcinogenicity bioassay data. Use the most sensitive species and
tumour site. The TD50 represents the daily dose rate (mg/kg/day) that induces tumours in 50% of test
animals over a standard lifespan (linearised multistage model).
Use the most sensitive species (lowest value). If multiple tumour sites reported,
use the one giving the lowest TD50 or BMDL10.
2Risk Level & Body Weight
ICH M7 uses a lifetime excess cancer risk of 10⁻⁵ as the default threshold.
A 10⁻⁶ risk level may be appropriate for certain regulatory contexts or when
higher protection is warranted.
ICH M7 LTL principle: For treatment durations shorter than a lifetime, a higher
daily AI can be acceptable, provided the total cumulative intake does not exceed the lifetime
allowance (AIlifetime × 25,550 days).
4AI Results
Enter carcinogenicity data on the left and click "Calculate AI" to derive
the compound-specific acceptable intake.
5NDSRI Corrections (Fine et al., 2023)
When compound-specific carcinogenicity data are unavailable for an NDSRI, a molar
potency correction can be applied. Both approaches below can be calculated independently
for comparison. Use the "Use as AI" button on whichever result you wish
to carry forward to the concentration limit calculation.
5a) Molar Scale Correction
Uses the default molar dose threshold of 163 pmol/day (Fine et al., 2023)
when no surrogate-specific AI is available.
AI (ng/day) = molar threshold (pmol/day) × MW_NDSRI (g/mol) / 1000
Regulatory note: This molar-based correction is a published scientific approach (Fine et al., 2023)
whose regulatory acceptance for nitrosamines has not yet been established. Verify
acceptance with the relevant authority before use in submissions.
5b) MW Correction from Surrogate
Extrapolates from a known surrogate nitrosamine AI to the NDSRI of interest
using molecular weight ratio.
AI_NDSRI = (AI_surrogate / MW_surrogate) × MW_NDSRI
The surrogate AI calculated in Step 4 will be used
(not yet calculated).
Regulatory note: This molar-based correction is a published scientific approach (Fine et al., 2023)
whose regulatory acceptance for nitrosamines has not yet been established. Verify acceptance with the
relevant authority before use in submissions.
6Convert AI to Concentration Limit (ppm)
Converts the calculated AI into a maximum permissible concentration in the drug substance
or drug product, based on the maximum daily dose (MDD).
Calculate the AI first, then enter the MDD to derive the concentration limit in ppm.
ICH M7 Staged TTC Reference (Table 2)
For comparison, ICH M7 provides default staged TTC-based AI values for mutagenic impurities
(Class 2/3) when compound-specific data are unavailable:
Duration
AI (µg/day)
≤1 month
120
>1–12 months
20
>1–10 years
10
>10 years to lifetime
1.5
Important: The staged TTC values above apply to ICH M7 Class 2/3 mutagenic impurities
in general. For N-nitroso compounds (cohort of concern), compound-specific AI values derived from
TD50 or BMDL10 should be used instead, and these are typically much lower.