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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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3.6 Butyl benzyl phthalate

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new entry for butyl benzyl phthalate (BBP) in Schedule 10 of the Poisons Standard for cosmetic use, with no exemption cut-off.

Scheduling application

  • This was a general application. The applicant's proposed amendments to the Poisons Standard are:

Schedule 10 – New Entry

BUTYL BENZYL PHTHALATE for cosmetic use.

The applicant's reasons for the request are:

  • BBP is classified as reproductive and developmental toxicant in accordance with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).
  • Toxic effects related to repeated exposure to BBP include systemic toxicity (increased liver and/or kidney weight), fertility (mediated by testicular toxicity) and developmental toxicity (antiandrogenic effects, reduced birth weight, embryolethality and teratogenicity). BBP is considered to have a toxicity profile equivalent to dibutyl phthalate (DBP) – a phthalate of similar molecular weight and sharing one monoester metabolite, monobutyl phthalate. Reproductive toxicity induced by BBP might have serious long-term effects on the development and reproduction of future generations if the exposure occurs within a critical window of human development.
  • The available data indicates that BBP, along with DBP and diethylhexyl phthalate (DEHP), are antiandrogens with a mode of action that involves alterations of steroidogenesis and gene expression critical for the male reproductive development. Although there are uncertainties regarding the exact mechanism by which BBP affects fertility, foetal hormonal levels, and growth and development in rodents, this is considered a plausible mode of action for phthalates that is relevant to humans if the exposure to antiandrogenic phthalates, including BBP, is high and within a critical window of human development.
  • While there is no current indication of BBP being used in cosmetics in Australia, BBP may be considered as a possible substitute for other phthalates that are currently listed in Schedule 10 (e.g. DBP, DEHP), based on its properties, functions and uses. This may result in an increased exposure to BBP.
  • As a result, imposing a similar regulatory measure on phthalates and classifying them as toxic to reproduction is warranted. This is due to the uncertainties of market availability, potential for substitution, the severe and irreversible (fertility-based and teratogenic) health effects and exposure levels in different population groups.

Current scheduling status and relevant scheduling history

Butyl benzyl phthalate is not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.

Related compounds dibutyl phthalate, diethylhexyl phthalate (considered in March 2011), diethylphthalate, diisobutyl phthalate, dimethylphthalate and di(methyloxyethyl) phthalate are listed in Schedule 10 of the Poisons Standard for cosmetic use or for use in leave-on skin products.

Australian regulatory information

No restrictions on the introduction (manufacture and/or import) or use of BBP were identified in Australia. BBP has the potential to be substituted for already regulated phthalates (e.g. DBP, DEHP). Given this, there is potential for widespread use of BBP in a variety of consumer products, including cosmetics.

BBP is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017, and is not an excipient or active in any products on the ARTG, although it does have the Australian Approved Name butyl benzyl phthalate.

There are no reports of adverse events related to BBP on the Database of Adverse Events Notifications (DAEN).

International regulations

EU

BBP is currently listed in the European Commission Cosmetic Ingredients and Substances (CosIng) Annex II (List of substances prohibited in cosmetic products) and Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) Annex XIV (List of substances subject to authorisation).

Canada

BBP is controlled in Canada according to the Canada Consumer Products Safety Act: Phthalates Regulations (SOR/2016-188). These regulations restrict the usage of phthalates, including BBP, in soft vinyl children's toys and child care articles to not more than 1000 mg/kg of di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) or benzyl butyl phthalate (BBP) when tested in accordance with a method that conforms to good laboratory practices.

USA

According to the electronic Code of Federal Regulations (e-CFR), Title 16, Chapter II, Subchapter B, Part 1199 – Children's toys and child care articles: Phthalate-containing inaccessible component parts, the sale of any "children's toy or child care article" containing more than 0.1 percent of three specified phthalates (di-(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and benzyl butyl phthalate (BBP)) are prohibited.

Substance summary

Table 3.6.1: Chemical information for butyl benzyl phthalate
Property Butyl benzyl phthalate
Chemical structure chemical structure of Butyl benzyl phthalate
Molecular formula C19H20O4
Molecular weight 312.4 g/mol
CAS name 1,2-Benzenedicarboxylic acid, butyl phenylmethyl ester
CAS number 85-68-7
IUPAC and/or common and/or other names Butyl benzyl phthalate (INCI); Benzyl butyl benzene-1,2-dicarboxylate (IUPAC)

The following information was extracted from the PEC report for BBP and the NICNAS Human Health Tier II Assessment for C4-6 side chain transitional phthalates, publicly available on the NICNAS website.

Table 3.6.2: Acute toxicity end-points for butyl benzyl phthalate
Toxicity Species Butyl benzyl phthalate SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 mg/kg bw Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 mg/kg bw Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) No data are available No data are available N/A
Skin irritation Rabbit Slight Schedule 5
Eye irritation Rabbit Slight Schedule 5
Skin sensitisation (GPMT) Guinea pig Negative Nil

Acute toxicity

BBP has low acute oral and dermal toxicity in animals (LD50 >2000 mg/kg bw).

Irritation

BBP may cause slight eye and skin irritation.

Sensitisation

BBP may be a slight skin sensitiser in humans.

Repeat-dose toxicity

BBP is not considered to cause severe systemic effects other than reproductive and developmental effects following repeated oral exposure. Limited data are available on repeated dermal and inhalational exposure.

Mutagenicity and genotoxicity

BBP was negative in in vitro and in vivo mutagenicity and genotoxicity tests.

Carcinogenicity

The International Agency for Research on Cancer (IARC, 1999) considered that on the weight of evidence the available data do not provide adequate evidence of carcinogenicity for BBP in humans.

Reproductive and developmental toxicity

In the PEC assessment for BBP (NICNAS, 2015) there is sufficient evidence in appropriate animal studies to conclude that BBP causes testicular toxicity and/or toxic effects to fertility. These effects are more prominent after perinatal exposure (i.e. F1 generation). Testicular toxicity induced by BBP is manifested reproducibly as statistically significant reductions in testes weights, testicular and accessory sex organ atrophy, as well as dose-dependent decreases in spermatozoa concentrations. Although deleterious effects of BBP on the testes and/or fertility were sometimes observed at the higher or the same dose levels as other toxic effects, they are highly specific and not considered secondary consequences of systemic maternal toxicity.

There are also sufficient reports of BBP-induced developmental toxicity, including prenatal, neonatal and postnatal endpoints. They commonly included resorption, post-implantation loss or embryo-foetal death, foetal malformation, teratogenicity, decreased foetal weight and birth weight. For reproductive development, females seem less susceptible than males to the adverse effects of BBP. In males, there are reports of reduced foetal testosterone levels, altered neonatal anogenital distance and retained infant areolae and delayed puberty. Following puberty there were decreases in testosterone, impaired sexual differentiation, malformed reproductive organs (including hypospadias and cryptorchidism), and altered reproductive functions (including increased testicular pathology, sperm abnormality, and reduced fertility in F1 generation).

These are clear results in appropriate animal studies. The effects have been observed in the absence of marked maternal toxicity (mainly reduced body weight gain accompanied by a decreased food consumption), or around the same dose levels as other toxic effects (mainly increased kidney and/or liver weight). The findings are not considered secondary non-specific consequences of the maternal toxic effects. On this basis, BBP is currently classified as a Reproductive Toxicant Category 1B with the hazard statements 'May damage the unborn child. Suspected of damaging fertility'.

Observation in humans

The human data on the reproductive and developmental effects of BBP are limited. However, the available data indicate that BBP is considered to have a toxicity profile equivalent to DBP and DEHP with a mode of action that involves alterations of steroidogenesis and gene expression critical for the male reproductive development. Reproductive toxicity induced by BBP may have serious long-term effects on the development and reproduction of future generations if the exposure occurs within a critical window of human development.

Public exposure

While there is no current indication of BBP use in cosmetics in Australia, BBP may be considered as a possible substitute for other phthalates that are currently listed in Schedule 10 (e.g. DBP, DEHP), based on its properties, functions and uses.

Pre-meeting submissions

Two (2) public submissions were received and both supported the proposal.

Main points in support:

  • A Schedule 10 entry for cosmetic use is consistent with the EU Cosmetics Regulation for butyl benzyl phthalate and with other phthalates that are considered hazardous.
  • There is no known use of butyl benzyl phthalate in cosmetics in Australia.

The public submissions will be made available on the TGA website.

Summary of ACCS advice to the delegate

The committee recommended that a new Schedule 10 entry for butyl benzyl phthalate be created as follows:

Schedule 10 – New Entry

BUTYL BENZYL PHTHALATE.

The committee also recommended an implementation date of 1 February 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice were:

  • There is a potential for butyl benzyl phthalate to be used in cosmetic products. Currently, there is no evidence of butyl benzyl phthalate being used in cosmetics in Australia. However, the banning or strict limits of other similar phthalates increases the risk of substitution with butyl benzyl phthalate. Applying similar scheduling controls on butyl benzyl phthalate can manage this risk.
  • Risk of reproductive and developmental toxicity makes butyl benzyl phthalate unsuitable for use in cosmetics.
  • Inclusion of butyl benzyl phthalate in Schedule 10 for use in cosmetics provides consistency with the EU cosmetic regulations.

Delegate's considerations

The delegate considered the following regarding this proposal:

  • Scheduling proposal
  • ACCS advice
  • Public Submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information

Delegate's interim decision

The delegate's interim decision is to create a new Schedule 10 entry for butyl benzyl phthalate. The proposed Schedule entry is as follows:

Schedule 10 – New Entry

BUTYL BENZYL PHTHALATE.

The proposed implementation date is 1 February 2018. This is the earliest possible implementation date and no known products in Australia will be affected.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the interim decision are:

  • There is a potential for butyl benzyl phthalate to be used in cosmetic products. Currently, there is no evidence of butyl benzyl phthalate being used in cosmetics in Australia. However, the banning or strict limits of other similar phthalates increases the risk of substitution with butyl benzyl phthalate. Applying similar scheduling controls on butyl benzyl phthalate can manage this risk.
  • Risk of reproductive and developmental toxicity makes butyl benzyl phthalate unsuitable for use in cosmetics.
  • Inclusion of butyl benzyl phthalate in Schedule 10 for use in cosmetics provides consistency with the EU cosmetic regulations.

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