IFRA webinar on p-BMHCA

March 29, 2019

Presenters:

Amaia Irizar - IFRACristina Arregui – IFRA

Kristin Radke – BASFPaul Schuster – BASF

Andreas Natsch – Givaudan

John Piper - Emerald

1. p-BMHCA – History and background

2. Review of key Regulatory Processes

a. REACH/CoRAP, GHS and EU CLP

b. Self-classification and EU CLH process: legal obligations (SDS and Annex

VI of CLP)

c. IFRA Labelling Manual

d. CMR 1 classification as it relates to Cosmetics Regulation (Annex II)

3. p-BMHCA – BASF, Givaudan, Emerald

a. Scientific background – MoA

b. Potential impact for structurally related muguets & CMRs

4. Summary – current timeline and processes

5. Questions & answers - IFRA

Agenda

1st TSCA8(e) notification on testicular effects in rats towards US EPA in 1990

Study was shared with RIFM and included in database

Since 10th April 1995 statement on BASF SDS chapter 11: “..In studies on rats damage onthe testes was discovered..”

Under assumption that the effects seen are rat specific and no effects were seen inmonkeys and mouse, no C&L was proposed, but further testing needed

RIFM performed studies in 1992, 1993 dermal absorption & toxicokinetic (rat and human)

RIFMs first Risk Assessment done in 1995: “safe under current use conditions”

Aug 2007: via information letters, customers and industry associations & RIFM wereinformed about test results of a 1-Gen reproduction toxicity study (range finder) in rats

German BAuA was informed about the test results and further studies in non-rodentspecies were provided

Q3 2008: TSCA(8e) notification of additional rabbit and dog studies by BASF

Self-classification as CMR2 (CMR3 old), R62 announced & Submission of an Annex XVdossier to German BAuA

History and Background (I)

3

EU REACH regulation entered into force meanwhile….

Substance evaluation (CoRAP) under REACH (→ hazard assessment)

– Evaluating member State: Sweden

– 2014 + 2018: study requests, including reproduction toxicity

– Awaiting final decision

SCCS process (→ approval of safety in EU cosmetics)

– Since 2013: discussions, mainly around genotoxicity

– Mar 2019: Follow-up response on sample quality (contaminants, stabilizer)

– → opinion put "on hold" until data is received

CLH process (→ Harmonization of C&L in Europe)

– 2013 + 2017: dossier submissions

– RAC voting Nov 2018 → Rep. 1B (H360F) and Rep. 2 (H361d)

History and Background (II)

4

CoRAP

CLH

SCCS

Under EU CLP1, a substance must be self-classifiedwhen it presents hazardous properties and has noharmonised classification in Annex VI to CLP.

This classification is communicated down the supplychain through the Safety Data Sheet (SDS) and therecipient must follow it unless the recipient hasscientific evidence to disagree.

Once a new/revised SDS is received the recipient hasto update the classification “without undue delay”in the EU and within 90 days in the US for instance.

EU CLP Self-classification

5

1 Regulation (EC) No 1272/2008 on the classification, labelling and packaging of substances andmixtures (CLP Regulation)

Mandatory classifications in the EU

It is a lengthy process which normally takes around 4years, not counting the 18 months of transitional periodprior application.

It can be started by a Member State or industry.

Mixtures containing substances with a harmonisedclassification do not trigger a harmonised classification ofthe mixture.

EU CLP Harmonised classification

6

Substance

Registry of

Intentions ATP ATP date Application date

Styrene Jun-10 6 Jun-14 Jan-16

HICC Jan-12 9 Jul-16 Mar-18

Linalool Jan-12 10 May-17 Dec-18

Isoeugenol Nov-13 13 Oct-18 May-20

Acetaldehyde Jan-14 13 Oct-18 May-20

EU CLP Harmonised classification

7

IFRA members via the GHS TF agree on self-classificationsthrough the LM.

List of fragrance substances (~1700) and Natural Complexsubstances classifications:

– UN GHS fragrance substances

– US OSHA Classifications

– UN Transport Classifications

The LM does not necessarily adopt the EU CLP harmonisedclassifications in Annex VI and the GHS classification for p-BMHCA in the LM will continue to be CMR2.

Self-classifications communicated by suppliers through SDSsand legally binding EU CLHs overrule the LM classificationsonly in the EU.

IFRA-IOFI GHS Labelling Manual (LM)

8

COM has issued new detailed practical guidelines showingthe feasibility of regulating all newly harmonisedclassified CMR substances through an annual Omnibus.

COM considers that the 15-months timeline for banning aharmonised CMR for use in cosmetics should be calculatedfrom the date of entry into force of the harmonised CMRclassification (publication of the ATP), rather than from thedate of its application (18 months later).

This means that the ban for cosmetics will become effective 3months before the harmonised classification becomesmandatory applicable.

COM presented an amended draft Omnibus Regulation and itsAnnex (both attached) to incorporate the CLP - ATP 10, whichenters into application by 1 December 2018.

EU Harmonised CMR classification and Cosmetics

Regulation

The ECHA RAC opinion to classify p-BMHCA as CMR 1B is likely to have severeimpact on the future use of the substance in cosmetic products in Europe asin the case of CMR 1A and 1B classification the EU Cosmetics Regulationimposes a ban unless the following conditions for a material are met:

– (a) they comply with the food safety requirements as defined in Regulation(EC) No 178/2002;

– (b) there are no suitable alternative substances available, as documentedin an analysis of alternatives;

– (c) the application is made for a particular use of the product categorywith a known exposure; and

– (d) they have been evaluated and found safe by the SCCS for use incosmetic products.

SCCS requests more information following the last SCCS plenary held on 26February before publishing an opinion under the current mandate.

SCCS and DG Grow ask for clarification on composition of samples used fortesting before finalizing their opinion.

Information sent to IFRA for subsequent submission to SCCS.

State of play

SCCS Submission I –

March 2013

SCCS Submission II –

March 2017

Suppl. I to Sub. II –

Dec 2018

Feb 2015: Response

addressing questions

on MoS and genotoxicity

March 2017: Additional

genotoxicity data

New OECD 428 data

Results OECD 443 under REACH

CoRAP

Updated max use levels

Feb 2018: Response commitment new

Ames and MNT studies

Defense of robustness of safety

Commitment to ensure safety re

max levels

Disagreement with comments

Dec 2018: Negative in vitro

Ames and Micronucleus Test Results

March 2019: Preparation of

response to request for clarification

Final Opinion ?ON HOLD

Dec 2017

Preliminary Opinion SCCS/1591/17

March 2016

Revised Opinion SCCS/1540/14

BM

HC

A T

F

2012: CLH Intentions as

CMR2 Reprotox

SCCS Opinion on p-BMHCA: overview of events

The response to the request for clarification has been submitted by IFRA andit is anticipated that the final opinion will be issued in the coming months.

p-BMHCA – Mode of Action

Coenzyme A depletion

Key findings supporting the current MoA:

➢ Metabolization of p-BMHCA to TBBA is an

identified key event

➢ p-BMHCA has an impact on lipid and fatty acid levels

→ Complex lipid synthesis is disrupted

➢ Transient binding of TBBA to the intracellular component Coenzyme A (CoA) for further

metabolization and excretion is physiological BUT: TBBA-CoA accumulates in rat cells

Hypothesis: p-BMHCA/TBBA decreases levels of complex lipids (→ pivotal

for successful sperm formation) due to accumulating TBBA-CoA.

CoA

CoA

CoA

CoA

CoA

CoA

CoA

p-BMHCA TBBA

Lipid synthesis

CoA CoA

CoA

p-BMHCA – Testicular/Sperm toxicity

Human relevance

➢ Testes/Sperm toxicity only observed in responder species (rats and dogs) -> Species specificity

➢ TBBA is formed at lower levels in humans (comparable to non-responder species)

➢ Sustained TBBA-CoA accumulation in rat BUT not in human liver cells

RAT HUMAN

CoA

CoA

CoA

CoA

Lipid synthesis

CoA

CoA

CoACoA

CoA CoA

CoA

CoA

CoA

CoA

CoA

Lipid synthesis

CoA

CoA

CoA

?

p-BMHCA TBBA p-BMHCA TBBA

p-BMHCA

Further experimental activities

➢ Current experimental status:

• Mode of action (sustained TBBA-CoA) has been investigated in vitro inhuman/rat liver cells + rat testes tissues

➢ Goals for next experimental steps:

• Confirmation of rat testes results in independent experiment

• Inclusion of new endpoint (testes lipid analysis) for further confirmation of themode of action

• Assessment of human relevance by using comparative in vitro study withhuman testes

Test system Assay type Laboratory Time Endpints

Bio-Alter®Rat testis

Ex vivo cultures; Seminiferous tubules; Sprague Dawley rats (22-days-old)

KallistemGivaudan

Q2/3 2019

- Cytotoxicity- Blood testis barrier function- Quantification of Spermatocytes/Sperm - Quantification of TBBA-CoA-conjugates

BASF SEQ3/4 2019

- Array analysis of complex lipids

p-BMHCA

Further experimental activities II

Test system Assay type Laboratory Time Endpoints

Bio-Alter®Human testis

Ex vivo cultures; Seminiferous tubules;

KallistemGivaudan

2019 - Cytotoxicity- Blood testis barrier function- Quantification of Spermatocytes/Sperm - Quantification of TBBA-CoA-conjugates

Potential assessment of complex lipids in a follow-up test, if indicated

Suitability currently investigated

Regulatory decisions on one substance can have direct impact on either:

– Functionally and structurally-related substances due to e.g. postulatedsimilar Mode of Action

• E.g. Silvial, Bourgeonal, Cyclamenaldehyde, m-BMHCA, Jasmorange,…

– Other fragrance CMRs due to regulatory pressure on fragrancematerials as such by especially European Authorities

• E.g. some Salicylates, Helional, Citrylal, trans-2-hexenal, Indoflor,….

Consumer perception can become skewed, and F&F is forced to changeformulations not just for one substance, but many.

This has a tremendous effect on innovation – new materials with bettertoxicological profile and/or products which at the end do not smell thesame anymore.

16

Potential Impact on other muguets & CMRs

Regulatory processes on BMHCA

Expected timelines as of today (Mar 2019)

➢ IFRA Labelling Manual: The LM will reflect the UN GHS classification CMR 2 ~ end of 2022

➢ Harmonized R 1B: legally binding only after end of ATP transition period ~ end of 2022

➢ Update of Cosmetic Regulation: triggered by ATP and ~15 months thereafter ~ end of 2022

➢ Stop of EU cosmetic uses ~ end of 2022

2018 2019 2020 2021 2022 2023

Opinion put on hold to discusscomposition of test batches

RAC VotingR 1B

Transition periodto allow phase-out

Annex II of Cos Reg(= ban or restriction)

CoRAPREACH

ProcessRegulation

Final decision

CLHCLP

SCCSCosmetic Regulation Genotoxicity

studies

Year

2nd draft decisionFurther studies requested

Banfrom EU cosmetics

legally binding

15th ATPPublication of

R 1B in Regulation

trigger

18

Thank you

Backup slides

Classification thresholds of mixtures

GHS vs. OSHA HCS Standard

OSHA levels lower than under GHS!

Companies have identified CMRs (self - classification) because of REACH testing and transmitted through SDSs

New CMRs – The issue

21

Ingredients with an EU harmonised classification as CMR are banned for use in cosmetic products in the EU.

To defend the use of a given ingredient in cosmetics, consortia are formed with the involvement of interested clients.

EU Member States may propose harmonised CMR classifications at EU level

SDSs