Enzacamene: When Scientists Say "No Safe Concentration Exists"

Twenty Years of "Safe" Use

For most of its commercial life, 4-MBC seemed like a reasonable UV filter choice. It absorbs UVB radiation (280-320 nm) with peak absorption around 300 nm. It's lipophilic, making it easy to formulate. It was permitted in the EU at up to 4% in leave-on sunscreen products.

The 2008 SCCP opinion (SCCP/1184/08) had calculated a Margin of Safety of just 42.5 - below the standard 100 threshold. But they accepted this based on a "toxicokinetic adjustment," arguing that rats are more sensitive to thyroid perturbation than humans.

Then the endocrine data started accumulating.

The Thyroid Problem

4-MBC disrupts the thyroid axis. This isn't subtle or controversial - it's well-documented across multiple studies:

The mechanism is clear: 4-MBC inhibits iodide uptake via the sodium-iodide symporter (NIS), decreases T4 production, triggers compensatory TSH elevation, and induces a hypothyroid-like state. In five-day gavage studies, effects appeared at just 33 mg/kg/day.

The Estrogenic Problem

Thyroid disruption wasn't the only concern. 4-MBC also shows estrogenic activity:

The 2008 Hofkamp study is particularly striking: fetal exposure to just 7 mg/kg/day of 4-MBC increased prostate and accessory sex gland volume by up to 69%, with increased ductal branching in the ventral prostate. This is low-dose endocrine disruption during a critical developmental window.

Found in 75% of Breast Milk Samples

Biomonitoring data confirmed that 4-MBC was reaching populations who should never be exposed to endocrine disruptors:

When a compound with documented developmental toxicity is found in most breast milk samples, the regulatory calculus changes dramatically.

The SVHC Designation

In 2022, ECHA added 4-MBC to the Candidate List of Substances of Very High Concern under REACH Article 57(f) for "endocrine disrupting properties for human health."

This designation carries significant regulatory implications:

• Triggers supply chain communication requirements
• May lead to eventual authorization requirements under REACH
• Signals intent for broader restrictions
• Carries reputational implications for brands

The SCCS Verdict: No Safe Concentration

The SCCS 2022-2023 reassessment reached an unusually definitive conclusion:

This is as close to an absolute rejection as regulatory science gets. They didn't set a lower limit. They didn't recommend 1% or 0.5% or 0.1%. They said no concentration is acceptable.

Why the MoS Calculation Failed

The updated exposure modeling destroyed any remaining safety margin:

The 2008 calculation already showed an inadequate MoS of 42.5, which they accepted only through creative adjustment of safety factors. When realistic aggregate exposures were modeled using updated dermal absorption data, even that insufficient margin disappeared.

The FDA Never Approved It

Americans were protected from 4-MBC not by precautionary regulation, but by bureaucratic inertia. The FDA's position:

• 2003: FDA granted "Time and Extent Application" eligibility - meaning it could be considered for approval
• 2015: Proposed order declaring enzacamene "not GRASE and misbranded"
• Current status: Remains "not GRASE" - effectively prohibited in US OTC sunscreens

No US-marketed sunscreens contain enzacamene because it was never approved in the first place.

The EU Ban Timeline

Following the SCCS opinion, the Commission moved to prohibition:

The UK Follows Suit

Post-Brexit, the UK's Scientific Advisory Group on Chemical Safety independently evaluated 4-MBC and reached the same conclusion: it cannot be considered safe for cosmetic use. The UK plans to:

• Remove 4-MBC from Annex VI (permitted UV filters)
• Add it to Annex II (prohibited substances)
• Deadlines: July 15, 2026 (no placing on market) / January 15, 2027 (no availability)

Sensitization: A Minor Concern

For completeness, 4-MBC is not a significant contact allergen. Patch test data shows about 0.5% positive reactions (6 positives in 1,233 patients tested). Some rare cases of photoallergic contact dermatitis have been documented.

But sensitization was never the regulatory concern. Endocrine disruption drove the ban.

The Bottom Line

Enzacamene's story is a cautionary tale about:

• Accepting marginal safety margins - MoS 42.5 was never adequate
• Delayed recognition of endocrine effects - decades of data accumulation preceded action
• Exposure during critical windows - found in breast milk means fetal/neonatal exposure
• The SVHC pathway - formal endocrine disruptor designation triggers broader restrictions
• Regulatory divergence - EU used it for 20+ years; US never approved it

When the scientific committee says "no safe concentration exists," it's time to reformulate. The alternatives (zinc oxide, titanium dioxide, bemotrizinol, other modern filters) don't carry this baggage.

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References

1. SCCP (2008). Opinion on 4-Methylbenzylidene Camphor. SCCP/1184/08. European Commission.
2. SCCS (2022-2023). Opinion on 4-Methylbenzylidene Camphor (4-MBC). SCCS/1658/23.
3. Schmutzler C, et al. (2007). Endocrine Disruptors and the Thyroid Gland - A Combined in Vitro and in Vivo Analysis. Environ Health Perspect, 115(Suppl 1):77-83. DOI: 10.1289/ehp.9369
4. Hofkamp L, et al. (2008). Region-Specific Growth Effects in the Developing Rat Prostate Following Fetal Exposure to Estrogenic Ultraviolet Filters. Environ Health Perspect, 116(7):867-872. DOI: 10.1289/ehp.10983
5. Mueller SO, et al. (2003). Activation of estrogen receptor alpha and ERb by 4-methylbenzylidene-camphor. Toxicol Lett, 142(1-2):89-101. DOI: 10.1016/S0378-4274(03)00016-X
6. Schauer UMD, et al. (2006). Kinetics of 3-(4-methylbenzylidene)camphor in rats and humans after dermal application. Toxicol Appl Pharmacol, 216(2):339-346. DOI: 10.1016/j.taap.2006.05.011
7. Schlumpf M, et al. (2008). Developmental toxicity of UV filters and environmental exposure: a review. Int J Androl, 31(2):144-151. DOI: 10.1111/j.1365-2605.2007.00856.x
8. ECHA (2022). Candidate List of Substances of Very High Concern. 3-(4-Methylbenzylidene)camphor addition.
9. FDA (2015). Over-the-Counter Sunscreen Drug Products - Regulatory Status of Enzacamene. 80 FR 10027.