Full Submission: VeganicSKN's Application to the TGA for the Removal of 4-Methylbenzylidene Camphor (4-MBC)

ASC Endorses Submission for the Removal of 4-MBC, Citing Overwhelming Toxicological Evidence and International Bans

The Australian Sunscreen Council is committed to ensuring that all sunscreen ingredients used in Australia meet the most stringent and current global safety benchmarks. In line with this core mission, we formally endorse the accompanying submission from our partner, VeganicSKN Pty Ltd, which calls for the complete removal of 4-Methylbenzylidene Camphor (4-MBC) from the Therapeutic Goods Administration's (TGA) list of permissible ingredients.

Authored by ASC expert panel member Dr. Abhinandan Chowdhury, this submission is grounded in conclusive and authoritative safety assessments from Comparable Overseas Bodies. It presents a compelling case based on:

• Significant Toxicity Concerns: Including well-documented endocrine-disrupting effects.

• Decisive Regulatory Action: 4-MBC is now prohibited for use in sunscreens across the European Union and the United Kingdom.

  
  

The Council believes the evidence is unequivocal. Retaining 4-MBC in Australian sunscreens represents an unacceptable divergence from international safety standards and poses an unnecessary risk to consumers. We fully support this submission and urge the TGA to act on its recommendations to safeguard public health.

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IN1 Application to Vary the Permissible Ingredients Determination

Substance: 4-Methylbenzylidene Camphor (4-MBC)

Updated Submission Category: IN1 (IN-2025-AP-000920)

Prepared by: VeganicSKN Pty Ltd

Dated: 23 July 2025

Contents

• Cover Letter – 4-Methylbenzylidene Camphor (4-MBC) Regulatory Submission

• Regulatory Submission – 4-Methylbenzylidene Camphor (4-MBC)

• Executive Summary

• Graphical Abstract

• Legislative Mandate for Review

• Chemical Overview

• Background and Context

• SCCS Review Summary

• Australian Exposure Context

• Engagement with TGA's Internal Review and Public Trust Concerns

• TGA Assessment Status

• Impurities

• Toxicokinetics

• Toxicodynamics

• Adverse Reactions

• TGA Gap Table

• Conclusion and Submission Request

• References

Cover Letter – 4-Methylbenzylidene Camphor (4-MBC) Regulatory Submission

To:The DelegateTherapeutic Goods AdministrationRegulatory and Product Submission DivisionCanberra, Australia

Date: 23 July 2025

Subject: Request to remove 4-Methylbenzylidene Camphor from the Permissible Ingredients Determination

Dear Delegate,

We respectfully submit this IN1 regulatory application recommending the removal of 4-Methylbenzylidene Camphor (4-MBC) from the Therapeutic Goods (Permissible Ingredients) Determination for use in therapeutic sunscreens in Australia. Although currently permitted for dermal use at concentrations up to 4%, 4-MBC has been comprehensively reviewed by multiple Comparable Overseas Bodies (COBs), all of which have now determined that no safe level of use can be established due to its systemic toxicity, endocrine-disrupting effects, and insufficient genotoxicity data.

This IN1 application is based entirely on the following internationally recognised safety assessments:

• The Scientific Committee on Consumer Safety (SCCS) concluded in its final opinion (SCCS/1640/21) that “no safe concentration of 4-MBC in cosmetic products can be established” due to the combination of endocrine activity and unresolved genotoxic potential (SCCS, 2022).

• The UK Scientific Advisory Group on Chemical Safety (SAG-CS) further confirmed these findings in its 2025 opinion, stating that 4-MBC meets the World Health Organization (WHO) definition of an endocrine disruptor, with insufficient data to derive a margin of safety and no robust reproductive or genotoxicity package available (SAG-CS, 2025).

• The substance has been officially prohibited in the European Union as of May 2025 under Regulation (EU) 2024/996, with its removal from Annex VI (UV filters) and inclusion in Annex II (banned substances).

• The United States Food and Drug Administration (FDA) does not recognise 4-MBC as GRASE (Generally Recognized As Safe and Effective) and has never authorised it for over-the-counter sunscreen use (FDA, 2022).

In addition to these COB assessments, the TGA’s own internal toxicology documents confirm longstanding awareness of these safety issues. Specifically, a 2005 TGA File Note, released under FOI (Document 11 AR), acknowledged the absence of reliable dermal and oral absorption data, the inability to define a NOAEL, and advised against taking regulatory action until the European SCCP had concluded its evaluation. The TGA’s senior toxicologist wrote:

“A major problem is the absence of reliable data to estimate the dermal and oral absorption… Based on these, there is no cause for urgent action and hence it is recommended that we wait for the outcome of the SCCP’s evaluation of 4-MBC” (TGA, 2005).

That evaluation is now complete, and the conclusion from the SCCS is that 4-MBC cannot be considered safe at any concentration. No new data have emerged that would overturn this conclusion. Despite this, the TGA has not updated its position or conducted a formal toxicological review. As confirmed in correspondence and internal summaries (Annex 3), the current listing of 4-MBC in the Determination reflects administrative retention, not evidence-based re-evaluation.

IN1 Category Justification

This application is submitted under the IN1 category, as defined in the TGA’s Mandatory Requirements for an Effective Application to Vary the Permissible Ingredients Determination (2023). It does not propose a new formulation, indication, or increased concentration, but rather seeks alignment with finalised decisions of Comparable Overseas Bodies under Appendix A.

The relevant COB reports—SCCS/1640/21 (European Commission) and SAG-CS Opinion 18 (UK OPSS)—address the full scope of toxicological requirements, including endocrine activity, systemic exposure, dermal absorption, and genotoxicity. These assessments conclude that 4-MBC presents an unacceptable risk, and no margin of safety can be calculated using current data (SCCS, 2022; SAG-CS, 2025).

A completed COB Checklist is attached to this application (Appendix 2), confirming that all applicable TGA assessment domains have been addressed or exceeded by the SCCS and SAG-CS reviews.

Request

Given:

• The clear consensus among international regulators that 4-MBC is not safe for use in cosmetic or therapeutic sunscreens,

• The TGA’s historical reliance on EU evaluation outcomes,

• And the absence of any published TGA toxicological safety assessment

We respectfully request that 4-Methylbenzylidene Camphor be removed from the Permissible Ingredients Determination, or assigned a 0% maximum concentration limit under the IN1 process. This action would bring Australian regulations in line with international standards and fulfil the Delegate’s obligation under section 26BE(2) of the Therapeutic Goods Act 1989 to consider “the safety and quality of the ingredient concerned.”

Thank you for considering this submission.

Sincerely,

Dr. Abhinandan Chowdhury (Rocky)

BSc (Biotechnology, AU) | MSc (Analytical Bioscience, UK) | PhD (Toxicology, AU)Head of Toxicology and Compliance VeganicSKN Australia

Regulatory Submission – 4-Methylbenzylidene Camphor (4-MBC)

Executive Summary

This IN1 submission seeks the removal of 4-Methylbenzylidene Camphor (4-MBC) from the Therapeutic Goods (Permissible Ingredients) Determination based on authoritative safety assessments conducted by Comparable Overseas Bodies (COBs), including the European Union Scientific Committee on Consumer Safety (SCCS) and the UK Scientific Advisory Group on Chemical Safety (SAG-CS).

The SCCS concluded in 2022 that no safe concentration of 4-MBC can be established in cosmetic products due to evidence of endocrine disruption and insufficient genotoxicity data (SCCS, 2022). This conclusion directly informed Regulation (EU) 2024/996, which removed 4-MBC from Annex VI and added it to Annex II of the Cosmetics Regulation, banning its use in all cosmetic products in the European Union from May 2025.

The SAG-CS independently reached the same conclusion in its 2025 review, noting that 4-MBC:

• Meets the World Health Organization definition of an endocrine disruptor;

• Shows evidence of thyroid and reproductive toxicity in vivo;

• Lacks a robust genotoxicity and reproductive toxicity database;

• Cannot support a standard Margin of Safety (MoS) of 100, and thus no safe level can be derived (SAG-CS, 2025).

In addition to these COB determinations, the Therapeutic Goods Administration’s own internal records reveal that the agency has not conducted a modern toxicological safety assessment of 4-MBC. In a 2005 file note (FOI 25-0009), the TGA’s senior toxicologist acknowledged that:

• No reliable NOAEL had been established;

• Dermal and oral absorption data were lacking;

• And regulatory action was deferred pending the outcome of the European SCCP review (TGA, 2005).

The EU has now completed that review, and the final determination is that 4-MBC should not be used in any cosmetic or sunscreen formulation. The UK and multiple other jurisdictions (e.g., the United States, Japan, Denmark) have aligned with this position.

Despite this, 4-MBC remains listed in the Australian Determination without updated toxicological validation, posing unnecessary and avoidable public health risk.

This application meets all requirements for an IN1 submission under the TGA’s Mandatory Requirements for an Effective Application to Vary the Permissible Ingredients Determination (2023):

• It relies solely on published COB decisions;

• It does not propose a new concentration, use, or formulation;

• It aligns with the public health protection intent of Section 26BE(2) of the Therapeutic Goods Act 1989.

Accordingly, we request the immediate removal of 4-Methylbenzylidene Camphor from the Permissible Ingredients Determination, or a restriction to 0% maximum allowable concentration, consistent with the positions of the SCCS and SAG-CS.

1. Legislative Mandate for Review

This application is made under the IN1 category of the Therapeutic Goods Administration’s (TGA) regulatory framework for varying the Therapeutic Goods (Permissible Ingredients) Determination, in accordance with Section 26BE(2) of the Therapeutic Goods Act 1989 and the accompanying Mandatory Requirements for an Effective Application to Vary the Permissible Ingredients Determination (2023).

Section 26BE(2) of the Act states that:

“In making a determination under this section, the Secretary must have regard to whether the ingredient is safe for use in the kind of therapeutic goods in which its use is proposed.”

This submission relies entirely on finalised evaluations by Comparable Overseas Bodies (COBs)—namely:

• The Scientific Committee on Consumer Safety (SCCS) of the European Commission, and

• The Scientific Advisory Group on Chemical Safety (SAG-CS) under the UK Office for Product Safety and Standards (OPSS).

Both of these COBs have concluded that no safe concentration can be established for 4-Methylbenzylidene Camphor (4-MBC) due to its endocrine-disrupting potential and unresolved genotoxicity profile (SCCS, 2022; SAG-CS, 2025).

Furthermore, under the TGA’s IN1 guidelines, the application satisfies all relevant requirements for reliance on COB decisions:

• No new use, formulation, or concentration is proposed;

• The ingredient is already included in the Determination but is now the subject of international prohibitions;

• The COB decisions used as the basis for this submission are final, publicly available, and scientifically comprehensive;

• A completed COB checklist is attached (Appendix 2) to demonstrate compliance with Appendix A of the TGA’s mandatory requirements.

In addition, the TGA has not published a full toxicological evaluation of 4-MBC. Internal documents obtained under FOI confirm that in 2005, the agency’s senior toxicologist explicitly recommended deferring further regulatory action until the European Scientific Committee on Cosmetic Products (SCCP) reached a conclusion:

“A major problem is the absence of reliable data to estimate the dermal and oral absorption… Based on these, there is no cause for urgent action and hence it is recommended that we wait for the outcome of the SCCP’s evaluation of 4-MBC” (TGA, 2005).

That evaluation is now complete. The SCCS has determined that 4-MBC cannot be considered safe at any concentration, and this position has now been implemented across Europe and the UK via Regulation (EU) 2024/996, with a full prohibition from 1 May 2025.

Given these developments, and in accordance with the TGA’s own commitment to international regulatory alignment and public health protection, this IN1 application seeks the removal of 4-MBC from the Determination, or restriction to 0% allowable concentration, consistent with global regulatory standards.

2. Chemical Overview

IUPAC Name: (3E)-1,7,7-trimethyl-3-[(4-methylphenyl)methylidene]bicyclo[2.2.1]heptan-2-one

CAS Number: 36861-47-9

Molecular Formula: C₁₈H₂₂O

Molecular Weight: 254.37 g/mol

Structure: Camphor derivative with a 4-methylbenzylidene substituent (The substance is also the subject of a United States Pharmacopeia (USP) Reference Standard, defining its quality, purity, and identity specifications)

Key Functional Groups: Aromatic ring, ketone, alkene

Photostability: Prone to photodegradation; low quantum yield for cis-trans isomerization

Regulatory Status:

• ❌ Not permitted in products intended for eye use

• ❌ Prohibited in the EU (listed in Annex II by Regulation (EU) 2024/996)

• ❌ Not considered GRASE by the FDA

• ✅ Permitted in Australia at a maximum concentration of 4% for dermal use only

Pharmacopeial Status

4-Methylbenzylidene Camphor (Enzacamene) is formally recognised under an active United States Pharmacopeia–National Formulary (USP–NF) monograph, official as of 1 December 2022 (USP, 2022). The monograph defines compendial specifications for identity, purity, and impurity control in dermally applied substances. These include:

• ✓ Identification: Infrared (IR) and ultraviolet (UV) spectroscopy

• ✓ Assay: 98.0%–102.0% purity (dried basis) by GC-FID

• ✓ Impurities: Quantification of total impurities and camphor content

• ✓ Loss on drying: Not more than 0.2%

In compliance with TGA’s IN1 submission requirements, a Certificate of Analysis (CoA) from a pilot-scale GMP batch has been provided to confirm the ingredient's conformance to pharmacopeial specifications. In addition, two supplementary CoAs from reputable manufacturers were reviewed to confirm analytical consistency across supply chains. Summary findings are as follows:

• ✓ Assay (GC-FID): 98.4% to 99.0%

• ✓ Loss on drying: 0.05% to 0.12%

• ✓ Total impurities: <0.1%

• ✓ Camphor content: Not Detected

• ✓ Identification (IR/UV): Conforms

• ✓ Appearance: White crystalline powder

Sources:

• ✓ Suzhou Greenway Biotech Co., Ltd. (Batch No. 20250516)

• ✓ Zhejiang Biosun Biotech Co., Ltd.

• ✓ Hangzhou Shield Biotech Co., Ltd.

These CoAs demonstrate the current manufacturing quality, regulatory-grade identity, and USP-aligned batch reproducibility of 4-MBC as used in therapeutic sunscreens.

3. Background and Context

4-Methylbenzylidene Camphor (4-MBC), also known as enzacamene, is currently permitted in Australia for dermal use only at concentrations not exceeding 4%, according to the TGA’s 16 May 2025 summary (TGA, 2025). However, despite this regulatory allowance, 4-MBC has come under significant international scrutiny due to mounting toxicological concerns. Over the past three years, multiple national and supranational regulatory bodies have re-evaluated 4-MBC and reached a shared conclusion: it cannot be considered safe for continued use in cosmetics or therapeutic sunscreens.

International Regulatory Status:

Major regulatory agencies across the EU, UK, US, and Asia have re-evaluated 4-MBC within the last three years and concluded that it cannot be considered safe.

The table below summarises the current status as of mid-2025:

Country / Agency	Regulatory Position	Year	Justification
European Union	Banned in all cosmetics (Annex II)	2024	Endocrine disruptor, MoS cannot be derived (Reg. 2024/996)
United Kingdom	Not safe for use in cosmetics	2025	SAG-CS Opinion 18: genotoxicity & ED concerns
United States (FDA)	Not GRASE for OTC use	2015 (unchanged in 2025)	Insufficient safety data
Japan (MHLW)	Not approved in cosmetics	Ongoing	Not listed as permitted UV filter
Denmark (EPA)	Proposed SVHC under ECHA	2021	Endocrine disruption (thyroid and estrogen)

In particular, the European Commission adopted Regulation (EU) 2024/996, which removed 4-MBC from Annex VI (permitted UV filters) and added it to Annex II (prohibited substances), effective 1 May 2025 for placing on the market and 1 May 2026 for sell-through (European Commission, 2024). This regulatory decision followed the final opinion of the SCCS, which concluded that no safe concentration of 4-MBC could be established due to endocrine activity, systemic absorption, and genotoxic concerns (SCCS, 2022).

The UK Scientific Advisory Group on Chemical Safety (SAG-CS) independently arrived at the same conclusion in 2025. Opinion 18 confirmed that 4-MBC meets the WHO definition of an endocrine disruptor, has insufficient reproductive and genotoxicity data, and cannot support a Margin of Safety under any use scenario (SAG-CS, 2025).

In contrast, Australia has not published any toxicological safety review of 4-MBC since the TGA’s 2005 internal file note, which acknowledged insufficient data to establish a NOAEL or assess dermal/oral absorption. At that time, the TGA's Senior Toxicologist advised against immediate regulatory action and recommended awaiting the outcome of the EU’s evaluation (TGA, 2005). That evaluation is now final, and it has resulted in international regulatory bans.

This growing international divergence highlights the urgent need for the TGA to harmonise its position with other major regulators. This submission seeks that alignment under the IN1 category, without proposing a new product or use, and based solely on finalised decisions from Comparable Overseas Bodies (COBs).

4. SCCS Review Summary

In its Final Opinion (SCCS/1640/21) on 4-Methylbenzylidene Camphor (4-MBC), the Scientific Committee on Consumer Safety (SCCS) concluded unequivocally that “no safe concentration of 4-MBC could be established for cosmetic use” (SCCS, 2022). This conclusion, adopted on 27 October 2021, formed the basis for the European Union’s decision to ban 4-MBC under Regulation (EU) 2024/996.

The SCCS identified multiple toxicological concerns that precluded approval of 4-MBC for continued use in cosmetics or sunscreens:

• Endocrine Disrupting Activity: 4-MBC demonstrated both estrogen receptor agonist and androgen receptor antagonist properties. These effects were confirmed through in vitro receptor-binding assays and in vivo endocrine studies. The SCCS acknowledged consistent hormonal disruption, particularly regarding thyroid hormone modulation, as well as effects on the hypothalamic-pituitary-gonadal axis (SCCS, 2022).

• Genotoxicity Concerns: While in vitro mutagenicity studies were mostly negative, the SCCS found that genotoxic potential could not be excluded, especially due to a lack of data on relevant metabolites and incomplete long-term data. The Committee stated that “the information provided is insufficient to fully evaluate potential genotoxicity,” and that a safe concentration could not be derived precisely because genotoxic risk remained unresolved (SCCS, 2022).

• Systemic Exposure: Human and animal studies confirmed that 4-MBC is absorbed dermally and leads to measurable systemic exposure. The SCCS cited a Systemic Exposure Dose (SED) that exceeded thresholds of toxicological concern even at low concentrations. The Committee stated it was not possible to derive a Margin of Safety (MoS), given the high bioavailability and low confidence in defining a NOAEL or acceptable exposure level (SCCS, 2022).

• Lack of Definitive Safety Data: The SCCS concluded that the data submitted were inadequate to support the establishment of a safe use level. In the absence of robust reproductive toxicity, chronic toxicity, or long-term carcinogenicity data, the Committee emphasised that “no concentration of 4-MBC can be deemed safe” for use in cosmetic products, including therapeutic sunscreens (SCCS, 2022).

This comprehensive assessment forms the scientific foundation for 4-MBC’s removal from Annex VI and addition to Annex II of the EU Cosmetics Regulation, effectively banning its use across the EU.

SCCS Opinion Contributors and Review Rigor

The SCCS's Final Opinion on 4-Methylbenzylidene Camphor (SCCS/1640/21) was the product of a rigorous scientific review process, conducted by a panel of highly qualified experts in toxicology, chemistry, and related fields. The SCCS operates under strict Rules of Procedure that ensure scientific excellence, independence, and transparency. All members and external experts are required to act independently and declare any conflicts of interest. The comprehensive review was performed by a dedicated SCCS Working Group, which then presented its findings to the full Committee for adoption.

Key SCCS members and external experts contributing to this and other opinions, demonstrating the high level of expertise involved, include:

• ✓ Dr. J. Ezendam (Rapporteur): Immunotoxicologist, RIVM, Netherlands

• ✓ Dr. E. Gaffet: CNRS Research Director, France; expertise in nanomaterials (~750 publications, H-index = 51)

• ✓ Prof. C.L. Galli: Full Professor of Toxicology, University of Milan, Italy; expertise in risk assessment, mechanistic toxicology (200+ publications)

• ✓ Dr. B. Granum: Expert in environmental medicine, immunotoxicology, allergy, skin sensitisation, Norway

• ✓ Prof. E. Panteri (Rapporteur): Professor, Faculty of Pharmacy, NKUA, Greece; expertise in Pharmaceutical Analysis, Bioanalysis, risk assessment (100+ publications, H-index 24/26)

• ✓ Prof. V. Rogiers (SCCS Vice-Chair): Professor Emeritus, VUB, Belgium; expertise in in Vitro Toxicology, Dermato-Cosmetology, Alternative Methods

• ✓ Dr. Ch. Rousselle: Head of Department of Risk Assessment, ANSES, France

• ✓ Prof. T. Vanhaecke: Full Professor of Toxicology, VUB, Belgium; expertise in 3R alternative methods, in vitro toxicology (>150 publications)

• ✓ Dr. N. von Goetz (External Expert): Lecturer, ETH Zurich, Switzerland; expertise in Human Exposure Analysis, Environmental Modelling (Expert in multiple SCCS/EFSA working groups).

This expert panel systematically analyzed all available data on 4-MBC, covering chemical properties, exposure, toxicokinetics, and a wide range of toxicological endpoints, including irritation, sensitisation, systemic toxicity, reproductive effects, genotoxicity, carcinogenicity, phototoxicity, human data, and special investigations into endocrine activity. Their integrated final conclusion was reached after thorough discussion and formal voting (SCCS, 2022).

5. Australian Exposure Context

According to Cancer Council Australia, recommended sunscreen use involves applying at least 35 mL (approximately 7 teaspoons) for a full-body application and reapplying every two hours when outdoors, particularly after swimming, sweating, or towel drying. Australia has one of the highest sunscreen usage rates globally, driven by intense ambient UV radiation, high outdoor exposure, and national skin cancer prevention initiatives. The Therapeutic Goods Administration (TGA) applies a default whole-body sunscreen use assumption of 140 mL per day, equivalent to 140,000 mg/day for most lotion-based formulations (TGA, 2025).

Despite 4-Methylbenzylidene Camphor (4-MBC) being permitted for dermal use at concentrations up to 4%, the TGA has not published a formal toxicological risk assessment or Margin of Safety (MoS) calculation for this ingredient. However, applying the TGA’s own standard exposure model (TGA, 2025), it is possible to retrospectively estimate systemic exposure using current EU hazard data.

TGA Margin of Safety Model (2025 Framework)

SED = (A × C × DAp) / BWA = Application amount (mg/day)C = Concentration of ingredient (%)DAp = Dermal absorption fractionBW = Body weight (kg)MoS = NOAEL / SED

Inputs for 4-MBC:

A (Amount Applied): 140,000 mg/day (140 mL/day assumed at 1 g/mL)C (Concentration): 4% (0.04)DAp (Dermal Absorption): 10% (TGA default for organic UV filters)BW (Body Weight): 60 kgNOAEL: 25 mg/kg bw/day (SCCS, 2022)

Calculation:

SED = (140,000 × 0.04 × 0.10) / 60 = 9.33 mg/kg bw/dayMoS = 25 / 9.33 ≈ 2.68

This result is far below the required safety threshold of 100, confirming that under the TGA’s own conservative assumptions, 4-MBC poses an unacceptable systemic exposure risk in typical Australian use scenarios.

By comparison, the SCCS calculated a similar or lower MoS using European defaults (17.6 g/day ), and still deemed the risk unacceptable. The UK SAG-CS (2025) reached the same conclusion, stating that 4-MBC cannot meet the required safety margin under any plausible exposure model.

Notably, the TGA has never published a MoS or systemic exposure estimate for 4-MBC, and internal communications from 2005 confirm that no reliable NOAEL or dermal absorption data were available at the time (TGA, 2005). These data gaps remain unresolved. In light of the TGA’s 2025 system-wide update to sunscreen risk assessments, continued inclusion of 4-MBC in the Determination appears incompatible with established safety thresholds.

6. Engagement with TGA's Internal Review and Public Trust Concerns

The TGA has undertaken an internal review of sunscreen active ingredients, acknowledging “safety signals reported overseas” and prioritising ingredients “based on the availability of nonclinical safety data to TGA” (Documents 12, 19 AR). As part of this audit of its safety data holdings, the TGA convened an Expert Stakeholder Roundtable on 18 December 2024 to discuss its toxicology review of sunscreen ingredients (Document 15 AR).

This roundtable included representatives from the Commonwealth Department of Health and Aged Care, NICNAS (now AICIS), ARPANSA, Cancer Council Australia, and multiple TGA divisions including Scientific Evaluation, Post-Market Surveillance, and Regulatory Science (Document 15 AR). The group reviewed the TGA’s draft risk assessment of seven active sunscreen ingredients, noting that there was “a theoretical risk with two of the seven chemicals,” but ultimately concluded that “there was no clear evidence to bring about a change in practice at this time” (Document 15 AR).

There was a strong internal emphasis on maintaining public messaging that “the benefits of sunscreen continue to far outweigh any risks” (Documents 17, 19 AR) and on avoiding language that could lead consumers to “shun sunscreen” (Document 15 AR). Messaging strategy discussions also reveal a shift toward minimising public visibility: plans were made to “only release the literature reviews,” “tweak the web page content,” and not push information through social media or email newsletters at this stage (Documents 13, 16, 18 AR). This cautious approach was framed as protecting sunscreen compliance but may unintentionally erode public confidence in regulatory transparency.

While the TGA’s intent to promote sunscreen use is understandable in Australia’s high-UV context, the consistent de-emphasis of emerging safety concerns—particularly those involving endocrine activity and systemic exposure—creates a risk of perceived regulatory inertia. International assessments (e.g. SCCS, FDA) have flagged 4-MBC as unsafe, and internal TGA documents themselves identify “theoretical risks”, yet no formal regulatory response has followed.

The public’s right to understand why Margin of Safety (MoS) calculations were excluded from the final published report was cited in a recent Freedom of Information (FOI) request (Document 20 AR). That request sought clarity on how internal concerns had been translated—if at all—into policy or regulatory action.

It is essential to reiterate that under Section 26BE(2) of the Therapeutic Goods Act 1989, the Secretary must consider “the safety and quality of the ingredient concerned” in making any variation to the Determination. While stakeholder roundtables are valuable for consultation, they do not have statutory authority and cannot override the TGA’s legal obligation to safeguard public health—particularly for sensitive populations such as pregnant women and children.

7. TGA Assessment Status

To date, the Therapeutic Goods Administration (TGA) has not published a full toxicological evaluation or public safety report on 4-Methylbenzylidene Camphor (4-MBC). The most recent substantive position is a 2005 internal file note, obtained under FOI (Document 11 AR), in which the agency’s Senior Toxicologist acknowledged that:

• A NOAEL could not be established;

• Dermal and oral absorption data were lacking;

• And no action should be taken until the European Scientific Committee on Cosmetic Products (SCCP) reached a conclusion:

“Based on these, there is no cause for urgent action and hence it is recommended that we wait for the outcome of the SCCP’s evaluation of 4-MBC.” – TGA Senior Toxicologist, 11 November 2005 (Document 11 AR)

Since that time, the SCCP’s successor body (SCCS) has conducted a full re-evaluation and concluded that no safe concentration of 4-MBC can be established (SCCS, 2022). The UK’s SAG-CS has independently confirmed this finding (SAG-CS, 2025), yet no updated assessment or position statement has been issued by the TGA.

Additionally:

• No MoS calculation has been published by the TGA under Australian exposure assumptions;

• No post-market surveillance data or adverse event reviews on 4-MBC have been released;

• The TGA has not updated its public-facing database entry for 4-MBC since 2022.

Internal stakeholder summaries from 2024–2025 confirm that 4-MBC was included in the TGA’s multi-ingredient toxicology review, but no separate scientific dossier or regulatory action was pursued. Instead, internal communications reveal an emphasis on retaining the ingredient administratively, pending further data (Documents 4 AR, 10 AR).

As a result, 4-MBC remains listed in the Therapeutic Goods (Permissible Ingredients) Determination at concentrations up to 4%, despite the absence of any formal risk characterisation and in direct contradiction to finalised overseas regulatory decisions.

This IN1 application seeks to close that gap by formally relying on:

• SCCS Final Opinion (SCCS/1640/21)

• UK SAG-CS Opinion 18 (2025)

Both of which fulfil the requirements of Comparable Overseas Body (COB) evaluations under the TGA’s IN1 pathway.

8. Impurities

4-Methylbenzylidene Camphor (4-MBC) is an aromatic ketone and benzylidene derivative—structural classes that raise inherent concerns about photodegradation and reactive intermediate formation, particularly under sunlight or prolonged storage. These concerns were highlighted in the SCCS Final Opinion (SCCS/1640/21), which cited unresolved genotoxic potential relating to metabolites and degradation products of 4-MBC, rather than its technical grade alone.

To assess whether marketed materials comply with recognised quality standards, three independently sourced batches from reputable manufacturers were analysed. All batches conform to either USP-NF monograph specifications or equivalent enterprise standards for identity, purity, and impurity thresholds.

Summary of CoA Results from Three Suppliers:

Manufacturer	Batch No.	Assay (%)	Loss on Drying (%)	Total Impurities (%)	Camphor (%)	Each Impurity (%)
Suzhou Greenway Biotech Co.	20250516	98.7	0.08	0.1	ND	0.04
Bisor Corporation	BMBC230112	99.6	0.29	0.11	0.0012	0.08
Hangzhou Simero Biotechnology	4MBC-2025052402	99.6	0.09	0.1	ND	0.05

Sources:

• Suzhou Greenway Biotech Co., Ltd. CoA, 16 May 2025

• Bisor Corporation CoA, 12 January 2023

• Hangzhou Simero Biotechnology Co., Ltd. CoA, 25 May 2025

All three batches demonstrated:

• Assay values within 98.0–102.0%,

• Total impurities below 0.5%,

• Camphor content within specified limits (≤0.01%) or not detected,

• No single impurity exceeding 0.1%,

• UV and IR spectral identity confirmed,

• Moisture content well below 0.2%, consistent with pharmacopeial limits.

These results confirm the availability of commercial- and pilot-scale material that meets pharmaceutical-grade purity requirements.

However, it is essential to distinguish manufacturing compliance from toxicological certainty. The SCCS and SAG-CS concerns relate not to the impurity content in these batches, but rather to endogenous and photometabolite toxicity, which remain uncharacterised. These unresolved risks were central to the COBs’ conclusion that no safe concentration could be derived for 4-MBC—even when the parent compound meets all analytical standards.

In conclusion, the data presented here support the technical purity and identity of currently available 4-MBC, but do not address the broader toxicological uncertainties that underpin this IN1 request for full removal from the Permissible Ingredients Determination.

9. Toxicokinetics

4-Methylbenzylidene Camphor (4-MBC) is a lipophilic, systemically bioavailable UVB filter that exhibits significant percutaneous absorption and tissue distribution following dermal application. Multiple in vivo and ex vivo studies have confirmed that 4-MBC penetrates the stratum corneum and is absorbed into the bloodstream, where it has been detected in human plasma and urine after sunscreen use (SCCS, 2022).

The Scientific Committee on Consumer Safety (SCCS) acknowledged the following toxicokinetic properties in its final opinion (SCCS/1640/21):

• Absorption: Human dermal absorption estimates range from 3% to over 10% depending on formulation. The SCCS applied a conservative default of 10% dermal absorption, consistent with EU and TGA risk modelling.

• Systemic Exposure: At just 4% concentration, systemic exposure doses (SED) in humans were estimated to exceed 9.3 mg/kg bw/day using Australian exposure defaults (140 mL/day and 60 kg body weight).

• Distribution and Accumulation: 4-MBC is highly lipophilic (log P ~5.5) and exhibits bioaccumulation in adipose tissue and persistence in blood plasma, particularly with repeated exposure. Biomonitoring studies have detected 4-MBC in plasma even days after last application, confirming systemic retention.

• Metabolism and Elimination: Animal data indicate hepatic biotransformation of 4-MBC into hydroxylated and conjugated metabolites, some of which may retain or enhance endocrine-disrupting activity. The metabolic profile in humans remains insufficiently characterised.

• No Defined NOAEL for Systemic Toxicity: Despite repeated-dose toxicity studies in animals, the SCCS concluded that no reliable NOAEL could be established, in part due to inconsistent dosing studies and lack of data on relevant metabolites.

The UK’s Scientific Advisory Group on Chemical Safety (SAG-CS) also flagged systemic exposure as a key concern, citing insufficient toxicokinetic modelling and the absence of a validated Point of Departure (PoD) for human risk assessment.

Using the TGA’s own risk framework, as applied in its 2025 sunscreen safety review, a retrospective Margin of Safety (MoS) calculation for 4-MBC based on 140 mL/day application and 10% dermal absorption yields:

• SED = (140,000 mg/day × 0.04 × 0.10) / 60 kg = 9.33 mg/kg bw/day

• MoS = 25 / 9.33 ≈ 2.68

This MoS falls significantly short of the required threshold of 100, confirming that systemic exposure under typical Australian use conditions presents an unacceptable risk.

Despite this, the TGA has not published any toxicokinetic evaluation, nor has it issued a revised opinion on 4-MBC’s systemic bioavailability since its 2005 internal file note (Document 11 AR), which itself acknowledged the absence of reliable dermal and oral absorption data.

10. Toxicodynamics

4-Methylbenzylidene Camphor (4-MBC) exhibits well-documented endocrine-disrupting effects through direct interaction with hormonal receptors. Rather than acting through therapeutic mechanisms, it produces undesired toxicodynamic effects via interference with the estrogenic, androgenic, and thyroid systems at low systemic concentrations.

Documented Mechanisms of Action

According to the Scientific Committee on Consumer Safety (SCCS) and the UK Scientific Advisory Group on Chemical Safety (SAG-CS), 4-MBC acts through:

• Estrogen receptor (ER) agonism, mimicking endogenous estrogens;

• Androgen receptor (AR) antagonism, blocking male hormone pathways;

• Thyroid modulation, suppressing circulating thyroid hormone levels (T4) in vivo.

These mechanistic effects have been observed at low exposure levels and confirmed in both in vitro and in vivo models (SCCS, 2022; SAG-CS, 2025). Both bodies concluded that 4-MBC meets the WHO criteria for an endocrine disruptor, and that no safe exposure threshold can be established.

Vulnerable Populations

The hormonal disruption associated with 4-MBC presents heightened risk for:

• Pregnant women (placental transfer potential),

• Lactating mothers (4-MBC detected in breast milk),

• Infants and children (developing endocrine systems).

Given 4-MBC’s high lipophilicity (log P ~5.5) and potential for bioaccumulation, it is likely to concentrate in fat, breast, and reproductive tissues over time.

MoS Comparison – TGA vs Li et al (2023). Absorption Models

To quantify the exposure risk, two systemic exposure scenarios were modelled using:

1. The TGA’s default dermal absorption value of 10%, and

2. The Li et al. (2023) human ex vivo study estimate of 2.35%.

Key Assumptions (both models):

✓ Daily sunscreen use = 140 g/day✓ 4-MBC concentration = 4%✓ Body weight = 60 kg✓ NOAEL = 25 mg/kg bw/day (SCCS, 2022)

Table: Margin of Safety (MoS) Under Two Exposure Models

Parameter	TGA Default (10%)	Li et al. (2.35%)
Dermal Absorption (DAp)	10% (0.10)	2.35% (0.0235)
SED (mg/kg bw/day)	9.33	2.19
MoS (25 / SED)	2.68	11.4
Regulatory Threshold (MoS)	100	100
Conclusion	❌ Not Safe	❌ Not Safe

Even under the more conservative Li et al. absorption model, the Margin of Safety remains an order of magnitude below the required threshold. This confirms that systemic exposure to 4-MBC under current Australian conditions cannot be considered safe, regardless of which absorption model is applied.

Why MoS Is Scientifically Invalid for 4-MBC

Even if MoS values were above 100, they would still be toxicologically irrelevant, because:

• Endocrine disruptors may act without a threshold, especially via receptor-mediated pathways.

• Lipophilic accumulation over time is not captured in point-in-time SED models.

• Species differences in hormone sensitivity undermine NOAEL-based extrapolations.

Both SCCS and SAG-CS concluded that no safe concentration of 4-MBC can be established for sunscreen use based on these toxicodynamic considerations. Additional mechanistic evidence from independent peer-reviewed studies further reinforces these conclusions. Schreurs et al. (2005) demonstrated that 4-MBC activates estrogen receptors in vitro using a luciferase-based reporter gene assay, with potency comparable to known xenoestrogens. In an in vivo uterotrophic assay, Tinwell et al. (2002) confirmed that 4-MBC induced a dose-dependent increase in uterine weight in immature rats—an established endpoint for estrogenic activity. Similarly, Seidlova-Wuttke et al. (2006) reported significant modulation of lipid metabolism and pituitary hormone levels in ovariectomised rats treated with 4-MBC, suggesting systemic hormonal disruption beyond receptor binding. Collectively, these findings substantiate the SCCS and SAG-CS determination that 4-MBC exerts toxicodynamic effects through multiple endocrine pathways and does so at exposure levels relevant to human sunscreen use.

11. Adverse Reactions

Although 4-Methylbenzylidene Camphor (4-MBC) has been used in sunscreen formulations for over two decades, its adverse effect profile remains under-characterised due to a lack of robust post-market surveillance and limited human epidemiological data. Importantly, the absence of reported adverse events does not imply safety, especially for compounds with endocrine-disrupting potential and bioaccumulative properties.

Reported Clinical Observations and Human Data Gaps

In its final opinion, the SCCS (2022) noted that only a single short-term clinical study—conducted under Good Clinical Practice (GCP) conditions—was available for review. That study showed no immediate thyroid function disruption, but was deemed insufficient to exclude systemic endocrine or reproductive effects, particularly with chronic exposure. No long-term human studies investigating fertility, developmental toxicity, or hormonal biomarkers were provided (SCCS, 2022).

Similarly, the UK SAG-CS (2025) concluded that the human safety profile of 4-MBC remains inadequately studied, and identified the absence of epidemiological follow-up and lack of long-term exposure assessment as critical limitations.

Biomonitoring Evidence of Systemic Presence

Although no formal adverse event signals have been reported in Australia, biomonitoring studies have detected 4-MBC in:

✓ Human plasma after repeated dermal application,✓ Breast milk, indicating maternal transfer to infants,✓ Urine, confirming systemic absorption and elimination.

These findings demonstrate that 4-MBC is systemically bioavailable, and that repeated use leads to internal exposure, particularly in sunscreen users with high-frequency application patterns (e.g. athletes, outdoor workers, children).

Vulnerability of Specific Populations

Given the mechanism of endocrine disruption, the following populations are considered at elevated risk from systemic exposure to 4-MBC:

✓ Pregnant women – potential for placental transfer and fetal thyroid disruption✓ Lactating mothers – transfer via breast milk; effects on neonatal development✓ Infants and children – incomplete endocrine system development; higher surface-area-to-body-weight ratio✓ Males of reproductive age – anti-androgenic effects with potential impact on fertility

TGA’s Post-Market Position

Despite the ingredient’s inclusion in therapeutic sunscreen products since the early 2000s, the TGA has not published any post-market pharmacovigilance summary, nor has it issued an alert or discussion paper on 4-MBC safety. The most recent TGA assessment document (2005 internal file note) acknowledged the absence of key toxicological data and deferred its position pending EU evaluation—which is now final (TGA, 2005; Document 11 AR).

Given the long-standing gap in real-world safety monitoring, and the increasing evidence of systemic exposure and toxicodynamic concern, it is no longer scientifically justifiable to maintain the current permissive status for 4-MBC.

12. TGA Gap Table

Parameter	U.S. FDA	European Union (EU)	Australia (TGA)
Regulatory Body / Framework	Food and Drug Administration (OTC Drug Monograph)	Scientific Committee on Consumer Safety (SCCS) / Cosmetics Regulation (EC) No 1223/2009 (Annex II)	Therapeutic Goods Administration (Permissible Ingredients Determination)
4-MBC CAS No.	36861-47-9	36861-47-9	36861-47-9
GRASE / Permitted Status	Not GRASE – Insufficient data to classify as safe and effective	Prohibited – Listed in Annex II (substances banned in cosmetics)	Permitted up to 4% for dermal use
Maximum Permitted Concentration	N/A (Not permitted)	0% – No permitted concentration (outright prohibition)	4% (currently permitted) / Proposed: 0% (requested removal)
Primary Exposure Assumption	No exposure assumptions formalised (data insufficient for GRASE)	16–18 g/day – EU default full-body sunscreen application estimate	144 g/day – Cancer Council Australia recommendation (full-body + reapplication)
Formal Toxicological Assessment Published	No definitive GRASE ruling; data gaps remain	Yes – SCCS/1640/21: "No safe concentration can be established"	No formal published toxicological assessment or systemic safety review
Key Safety Concerns Leading to Restrictions	Endocrine disruption concerns, insufficient data	Endocrine activity (ER agonist, AR antagonist), thyroid disruption, genotoxicity, high systemic exposure, no MoS	High exposure, lack of TGA review, SCCS safety signal, potential public health risk
Margin of Safety (MoS) Status	Not established – data insufficient	MoS not calculable due to endocrine activity (SCCS/1640/21)	Not calculated; internal review deferred to SCCP outcome (2005)

Comparable Overseas Body (COB) Evaluation

This submission relies on the safety evaluations conducted by the European Union Scientific Committee on Consumer Safety (SCCS/1640/21, finalised March 2021) and the UK Scientific Advisory Group on Chemical Safety (SAG-CS, Opinion 18, May 2025) as COB reports under the IN1 application category. These bodies meet the TGA's criteria for Comparable Overseas Bodies as outlined in the Guidance on the Use of COB Reports (TGA, 2023).

The SCCS evaluation addresses the majority of safety requirements outlined in Table 4 of the Mandatory Requirements for an Effective Application to Vary the Permissible Ingredients Determination, including:

• Characterisation of the active substance and its impurities

• Dermal and systemic exposure modeling

• Acute toxicity, repeat-dose toxicity, and genotoxicity studies

• Pharmacokinetics and endocrine disruption assessments

The SCCS concluded that no safe concentration of 4-MBC could be derived due to unresolved concerns around endocrine activity and the inability to calculate an acceptable margin of safety. This was based on both systemic exposures estimates and mechanistic data (e.g. ER and AR receptor activity, thyroid effects).

The UK SAG-CS report independently confirmed that no safe level could be established, citing similar systemic toxicology concerns and explicitly referencing the SCCS opinion. The SAG-CS further validated this conclusion using UK/EU-specific regulatory definitions of endocrine disruption based on WHO/IPCS criteria and in vivo endpoints.

These COB evaluations are considered comprehensive and robust. However, to address potential jurisdictional differences in exposure assumptions, this dossier also provides:

• A recalculated MoS based on Australian exposure assumptions (ASEM model: 144 g/day )

• An updated NOAEL of 25 mg/kg bw/day and revised systemic dose estimate using 2.35% dermal absorption

• Additional literature (2021–2025) covering human plasma data, bioaccumulation, and breast tissue detection

No gaps were identified between the COB evaluations and the core safety elements required under Table 4. The supplemental data provided strengthens, rather than contradicts, the conclusions reached by SCCS and SAG-CS. No new data were found that would weaken the case for removal of 4-MBC from the Permissible Ingredients list. This submission also demonstrates that under both the TGA’s default dermal absorption assumption (10%) and a human-relevant estimate from Li et al. (2023) (2.35%), the MoS remains below regulatory thresholds (2.68 and 11.4, respectively), validating the SCCS’s position that no safe level can be established.

Literature Search Strategy and Data Inclusion Justification

A structured literature search was conducted to identify studies relevant to the toxicology, pharmacokinetics, systemic exposure, and regulatory status of 4-Methylbenzylidene Camphor (4-MBC) published since the most recent COB evaluations (SCCS/1640/21 in 2021 and SAG-CS Opinion 18 in 2025). The purpose of the search was to determine whether any new data either strengthens or contradicts the conclusions of those bodies and to ensure alignment with current TGA expectations under Table 4 of the Mandatory Requirements.

Databases searched:

• PubMed

• ScienceDirect

• Google Scholar

• OECD eChemPortal

• EU SCCS Opinions Database

Date range: January 2021 – July 2025

Search terms (Boolean):

• (“4-Methylbenzylidene Camphor” OR “4-MBC”) AND (“toxicity” OR “endocrine” OR “genotoxicity” OR “carcinogenicity” OR “ADME” OR “margin of safety” OR “MoS” OR “NOAEL” OR “MCF-7” OR “plasma” OR “dermal absorption”)

Inclusion criteria:

• Peer-reviewed studies involving human, animal, or in vitro data on 4-MBC

• Biomonitoring studies in humans (urine, blood, breast tissue)

• Mechanistic studies relevant to endocrine pathways (e.g. ER/AR activity, NF-κB)

• Regulatory decisions from OECD-aligned jurisdictions published 2021–2025

Exclusion criteria:

• Studies unrelated to 4-MBC or using irrelevant analogues

• Non-English papers without validated translations

• Duplicate summaries of SCCS/SAG-CS reports

• Secondary reviews without new data

Summary of new data identified:

The search identified 7 relevant new publications, all of which have been integrated into this submission:

No.	Reference	Topic	Section Used
1	Murawski et al. (2021)	Human biomonitoring (GerES V)	Section 11
2	Schmidtkunz et al. (2023)	4-MBC in young adults	Section 11
3	Li et al. (2023)	Plasma absorption kinetics and PBK modeling	Section 9
4	Schreurs et al. (2005)	ER activation in in vitro reporter gene assays	Section 10
5	Seidlova-Wuttke et al. (2006)	Endocrine effects on fat, lipids, and pituitary hormones	Section 10
6	Tinwell et al. (2002)	Uterotrophic activity (in vivo endocrine evidence)	Section 10
7	SAG-CS (2025)	Genotoxicity + endocrine classification	Section 4
8	EU Regulation (2024/996)	Annex II reclassification (EU ban)	Section 3

These studies supplement and reinforce the conclusions of the SCCS and UK SAG-CS reports. No data contradicting their risk assessment or proposing a safe MoS for 4-MBC were found.

13. Conclusion and Submission Request

This IN1 application formally requests that 4-Methylbenzylidene Camphor (4-MBC; CAS No. 36861-47-9) be removed entirely (0%) from the Therapeutic Goods (Permissible Ingredients) Determination for use in therapeutic sunscreens in Australia.

The request is grounded in the following evidence:

✓ Final regulatory decisions by Comparable Overseas Bodies (COBs), including the European Union and United Kingdom, both of which concluded that no safe level of use could be established for 4-MBC due to its endocrine-disrupting properties (SCCS, 2022; SAG-CS, 2025).✓ The SCCS Final Opinion (SCCS/1640/21) documented mechanistic evidence of estrogen receptor agonism, androgen receptor antagonism, and thyroidal interference, and found that a Margin of Safety (MoS) could not be calculated, thereby disqualifying 4-MBC from safe cosmetic use.✓ Biomonitoring data from large human studies (e.g. Murawski et al., 2021) confirm that 4-MBC is detectable in the general population's urine and plasma, including in women of reproductive age, indicating chronic systemic exposure through dermal application.✓ More recent toxicokinetic modelling by Li et al. (2023) found 4-MBC present in blood plasma at bioactive levels and estimated human dermal absorption at 2.35%, reinforcing that systemic availability is not hypothetical.✓ A focused study by Schmidtkunz et al. (2023) reported elevated 4-MBC concentrations in young adults using commercial sunscreens, particularly in female participants—corroborating earlier concerns about gender-specific endocrine vulnerability.

Furthermore, this submission includes a retrospective MoS calculation using the TGA’s own default exposure model (140 g/day , 10% dermal absorption), which yields a MoS of 2.68—well below the accepted threshold of 100. A parallel calculation using Li et al.’s human absorption rate (2.35%) still results in a MoS of 11.4, underscoring that both regulatory and real-world scenarios indicate unsafe systemic exposure.

Despite this, the TGA has not conducted or published a toxicological assessment for 4-MBC. Its most recent internal evaluation (Document 11 AR) dates to 2005 and explicitly recommended waiting for the outcome of the SCCP review—an outcome that is now final, with 4-MBC banned in the EU under Regulation (EU) 2024/996.

Continued inclusion of 4-MBC in Australian therapeutic sunscreens is incompatible with:

✓ International regulatory consensus,✓ Available biomonitoring and exposure modelling data,✓ The TGA’s own exposure framework,✓ And its statutory obligations under Section 26BE(2) of the Therapeutic Goods Act 1989, which requires the Secretary to consider the “safety and quality of the ingredient concerned.”

Requested Action

We respectfully request that the TGA initiate the removal of 4-MBC (0%) from the Permissible Ingredients Determination, based on:

✓ Final COB safety assessments (SCCS/1640/21; SAG-CS Opinion 18),✓ Confirmed systemic exposure under typical Australian use conditions,✓ Updated toxicokinetic and biomonitoring data (Li et al., 2023; Murawski et al., 2021),✓ The absence of a TGA-published MoS or toxicological review since 2005.

This regulatory action is both scientifically justified and urgently necessary to align Australia’s sunscreen safety framework with that of other OECD jurisdictions and to preserve public trust in TGA’s oversight.

References

1. AICIS. (2024). Draft evaluation statement: Homosalate. Australian Industrial Chemicals Introduction Scheme.

2. Cancer Council Australia. (2024). Sunscreen use and sun protection guidelines. https://www.cancer.org.au

3. European Commission. (2024). Regulation (EU) 2024/996: Amending Annex II (List of substances prohibited in cosmetic products). Official Journal of the European Union.

4. Food and Drug Administration (FDA). (2019). Sunscreen Drug Products for Over-the-Counter Human Use: Proposed Rule. Federal Register, 84(38), 6204–6275.

5. SAG-CS. (2025). Opinion 18 on 4-Methylbenzylidene Camphor (4-MBC): Endocrine Disruption and Genotoxicity. UK Scientific Advisory Group on Chemical Safety.

6. Scientific Committee on Consumer Safety (SCCS). (2022). Final Opinion on 4-Methylbenzylidene Camphor (SCCS/1640/21). European Commission, Brussels.

7. Therapeutic Goods Administration (TGA). (2023). Mandatory requirements for an effective application to vary the Permissible Ingredients Determination. Australian Government Department of Health.

8. World Health Organization (WHO). (2002). Global assessment of the state-of-the-science of endocrine disruptors. International Programme on Chemical Safety.

9. Li, H., Bunglawala, F., Hewitt, N. J., Pendlington, R., Cubberley, R., Nicol, B., Spriggs, S., Baltazar, M., Cable, S., & Dent, M. (2023). ADME characterization and PBK model development of 3 highly protein-bound UV filters through topical application. Toxicological Sciences, 196(1), 1–15. https://doi.org/10.1093/toxsci/kfad081

10. Schmidtkunz, C., Küpper, K., Weber, T., Leng, G., & Kolossa-Gehring, M. (2023). A time trend of urinary 4-methylbenzylidene camphor metabolites in young adults from Germany. Environmental Research, 228, 115833. https://pubmed.ncbi.nlm.nih.gov/37028537/

11. Murawski, A., Schmied-Tobies, M. I. H., Rucic, E., Schmidtkunz, C., Küpper, K., Leng, G., Eckert, E., Kuhlmann, L., Göen, T., Daniels, A., Schwedler, G., & Kolossa-Gehring, M. (2021). Metabolites of 4-methylbenzylidene camphor (4-MBC), butylated hydroxytoluene (BHT), and tris(2-ethylhexyl) trimellitate (TOTM) in urine of children and adolescents in Germany – Human biomonitoring results of the German Environmental Survey GerES V (2014–2017). Environmental Research, 192, 110345. https://doi.org/10.1016/j.envres.2020.110345

12. Schreurs, R. H. M. M., Sonneveld, E., Jansen, J. H. J., Seinen, W., & van der Burg, B. (2005). Interaction of polycyclic musks and UV filters with the estrogen receptor (ER), androgen receptor (AR), and progesterone receptor (PR) in reporter gene bioassays. Toxicological Sciences, 83(2), 264–272. https://doi.org/10.1093/toxsci/kfi005

13. Seidlova-Wuttke, D., Christoffel, J., Rimoldi, G., Jarry, H., & Wuttke, W. (2006). Comparison of effects of estradiol with those of octylmethoxycinnamate and 4-methylbenzylidene camphor on fat tissue, lipids and pituitary hormones. Toxicology and Applied Pharmacology, 214(1), 1–7. https://pubmed.ncbi.nlm.nih.gov/16368123/

14. Tinwell, H., Lefevre, P. A., Moffat, G. J., Burns, A., Odum, J., Spurway, T. D., Orphanides, G., & Ashby, J. (2002). Confirmation of uterotrophic activity of 3-(4-methylbenzylidene)camphor in the immature rat. Environmental Health Perspectives, 110(6), 533–536. https://pubmed.ncbi.nlm.nih.gov/12003759/

15. United States Pharmacopeial Convention. (2022). Enzacamene Monograph. USP–NF. Official as of 01-Dec-2022. https://doi.org/10.31003/USPNF_M52010_04_01

Internal References

A. Therapeutic Goods Administration (TGA). (2024). Internal Briefing Note – Sunscreen Ingredients and Endocrine Disruption: Review Scope Proposal. Released under FOI Request 25-0009, Document 1 AR.B. Therapeutic Goods Administration (TGA). (2024, September). Toxicology Prioritisation Matrix – Seven Active Ingredients. Scientific Evaluation Branch. Released under FOI Request 25-0009, Document 2 AR.C. Therapeutic Goods Administration (TGA). (2024). Email Thread – AICIS and TGA Coordination on UV Filter Assessments. Released under FOI Request 25-0009, Document 3 AR.D. Therapeutic Goods Administration (TGA). (2024). Email Correspondence – Risk Communication Approach and Public Messaging Drafts. Released under FOI Request 25-0009, Document 4 AR.E. Therapeutic Goods Administration (TGA). (2024). Working Draft – Safety Review Communication Strategy: Seven UV Filters. Regulatory Science Branch. Released under FOI Request 25-0009, Document 5.F. Therapeutic Goods Administration (TGA). (2024). Email Summary – Scientific Input on Systemic Exposure and Dermal Absorption Rates. Released under FOI Request 25-0009, Document 6.G. Therapeutic Goods Administration (TGA). (2024). Preliminary Briefing – Ministerial Advice Strategy on Sunscreen Safety. Released under FOI Request 25-0009, Document 7 AR.H. Therapeutic Goods Administration (TGA). (2024). Email Chain – Revisions to Literature Review Outputs and Internal Dashboard References. Released under FOI Request 25-0009, Document 8 AR.I. Therapeutic Goods Administration (TGA). (2024, December). Presentation Slides – Sunscreen Ingredients Toxicology Review (Draft). Released under FOI Request 25-0009, Document 9 AR.J. Therapeutic Goods Administration (TGA). (2024, December). Draft Internal Risk Summary – UV Filters in Therapeutic Sunscreens. Scientific Evaluations Unit. Released under FOI Request 25-0009, Document 10.K. Therapeutic Goods Administration (TGA). (2005, November 11). File Note – 4-Methylbenzylidene Camphor. OTC Medicines Evaluation Section. Released under FOI Request 25-0009, Document 11 AR.L. Therapeutic Goods Administration (TGA). (2024, December 18). Meeting Minutes: Expert Stakeholder Roundtable – Sunscreen Ingredient Safety Review. TGA Toxicology Review Project. Released under FOI Request 25-0009, Document 12 AR.M. Therapeutic Goods Administration (TGA). (2024, December 15–20). Internal Emails – Public Communication Strategy for Sunscreen Safety Review. Scientific Evaluation and Regulatory Science Branches. Released under FOI Request 25-0009, Document 13 AR.N. Therapeutic Goods Administration (TGA). (2024, December). Draft Internal Brief – Literature Review Strategy for Seven Sunscreen Ingredients. Office of Scientific Evaluation. Released under FOI Request 25-0009, Document 14 ARO. FOI 25-0146 TGA - Notice of Decision.pdf: TGA, "Freedom of Information Request FOI 25-0146 Notice of Decision," April 16, 2025.