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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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2.8 Chloroacetamide

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new entry for chloroacetamide in Schedule 6 of the Poisons Standard, with no exemption cut-off.

Scheduling application

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

Schedule 6 – New Entry

CHLOROACETAMIDE.

The applicant's reasons for the request are:

  • Chloroacetamide is a sensitiser with human data demonstrating that allergic reactions can be elicited at concentrations lower than 0.3% (use conditions in cosmetics products);
  • Allergy prevalence rates up to 3% have been reported in Australia. These allergy prevalence rates are higher than those reported in a number of European countries;
  • Chloroacetamide may be harmful to male fertility following repeated exposure. The SCCS (2011) calculated a margin of safety (MoS) of 20 (a MoS of at least 100 indicates that a cosmetic ingredient is considered safe for use);
  • Chloroacetamide is reported to be used in cosmetic products in Australia;
  • Chloroacetamide is prohibited or restricted for cosmetic use overseas. The European Commission is currently considering prohibiting chloroacetamide;
  • The EU SCCS and US CIR have concluded that chloroacetamide is unsafe for use as a cosmetic ingredient (when used under current use conditions of 0.3%); and
  • The NICNAS IMAP report for acetamide, 2-chloro- is publicly available on the NICNAS website.

Current scheduling status and relevant scheduling history

Chloroacetamide is not currently scheduled and has not been previously considered for scheduling. Therefore, a scheduling history is not available.

N,N-diallyl-2,2-dichloroacetamide

A related molecule, N,N-diallyl-2,2-dichloroacetamide is in Schedule 5 of the Poisons Standard as follows:

Schedule 5

N,N-DIALLYLDICHLOROACETAMIDE except in preparations containing 10 per cent or less of N,N-diallyldichloroacetamide.

N,N-diallyldichloroacetamide (Eradicane) was first considered for scheduling in August 1978 by the Poisons Schedule (Standing) Committee (PSC). The compound is known as a 'crop protection agent' in that it allows higher concentrations of EPTC than normal to be used without damage, in controlled in weeds in maize crops. The applicant sought exemption from scheduling. However, due to the limited toxicity data consideration of the application was deferred pending receipt of full 90-day studies. The secretariat was asked to clarify the impurities in the product formulation.

In August 1979 the PSC considered reports of 13-week studies in rats and dogs and agreed that based on the data presented, a Schedule 5 entry would be appropriate.

In November 1979 the PSC agreed to a proposal to exempt from scheduling, preparations containing 10% or less of N,N-diallyldichloroacetamide (LD50 1710 mg/kg).

Australian regulatory information

Chloroacetamide is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017 as follows:

Table 2.8.1: Permissible ingredients and requirements applying to chloroacetamide when contained in a medicine
Column 1 Column 2
Ingredient Name
Column 3
Purpose of the ingredient in the medicine
Column 4
Specific requirements(s) applying to the ingredient in Column 2
1300 CHLOROACETAMIDE E Only for use in topical medicines for dermal application.

According to the TGA Ingredient Database, chloroacetamide is available for use as an:

  • Active ingredient in biologicals and prescription medicines; and
  • Excipient in biologicals, devices, export only, listed medicines, over the counter and prescription medicines.

Chloroacetamide is not currently used in any proprietary ingredient formulations.

Chloroacetamide is not in any products currently registered with the Australian Pesticides and Veterinary Medicines Authority (APVMA).

International regulations

European Union (EU)

Currently, chloroacetamide is authorised as a preservative in cosmetics products in entry 41 of Annex V to Regulation (EC) No 1223/2009, at a concentration up to 0.3% w/w in ready for use preparations. However, in 2015, there was a consultation process on a proposal to remove entry 41 from Annex V, and to add chloroacetamide to the list of substances prohibited in cosmetic products of Annex II to Regulation (EC) No 1223/2009 (European Commission, 2015). A decision had not been finalised at the time of the preparation of this assessment report.

The Scientific Committee on Consumer Safety (SCCS) opinion conclusion states 'On the basis of the data available, the SCCS comes to the conclusion that 2-chloroacetamide is not safe for consumers when used under the current use conditions of 0.3% in cosmetic products. Human data demonstrate that allergic reactions can be elicited at concentrations lower than 0.3% (use conditions in cosmetics products).

USA

In 1991, the United States CIR concluded that chloroacetamide is unsafe for use as a cosmetic ingredient (CIR, 1991). The CIR conclusion states 'Based on the data included in this report and the reconfirmation that Chloroacetamide is a potential human sensitiser at use concentrations, it is concluded that Chloroacetamide is unsafe for use as a cosmetic ingredient'.

New Zealand

Chloroacetamide is listed in the New Zealand Cosmetic Products Group Standard – Schedule 7: Preservatives cosmetic products may contain with restrictions.

ASEAN

Chloroacetamide is listed on the Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex VI – Part 1 – List of preservatives allowed for use in cosmetic products:

  • Maximum authorised concentration 0.3%;
  • Conditions of use and warnings which must be printed on the label 'Contains chloroacetamide'.

Canada

Chloroacetamide is included on the Health Canada List of prohibited ingredients (The Cosmetic Ingredient 'Hotlist'). Chloroacetamide is also subject to Significant New Activity (SNAc) provisions in Canada (Government of Canada).

Substance summary

Chloroacetamide is used as a herbicide and a preservative in cosmetics, domestic and therapeutic products.

Table 2.8.2: Chemical information for chloroacetamide
Property Chloroacetamide
Chemical structure chemical structure of chloroactemaide
Molecular formula C2H4ClNO
Molecular weight 93.5 g/mol
CAS name Acetamide, 2-chloro-
CAS number 79-07-2
IUPAC and/or common and/or other names 2-Chloroacetamide (IUPAC);
Chloroacetamide (INCI).

The following information was extracted from the Human Health Tier II Assessment report for Acetamide, 2-chloro-, publicly available from the NICNAS website.

Table 2.8.3: Acute toxicity end-points for chloroacetamide
Toxicity Species Chloroacetamide SPF (2015) Classification
Acute oral toxicity, LD50 (mg/kg bw) Rat
Mouse
Rabbit
70 – 370
150 – 155
122
Schedule 6
Acute dermal toxicity, LD50 (mg/kg bw) Rat >2000 Schedule 5
Acute inhalational toxicity, LC50 (mg/m3/4h) No data available N/A N/A
Skin irritation Rabbit Slight Schedule 5
Eye irritation Rabbit Moderate Schedule 5
Skin sensitisation (GMPT/patch test) Guinea pig
Human
Positive
Positive
-

Acute toxicity

Chloroacetamide is classified as 'Toxic if swallowed'. The available data support this classification (see above and IMAP report for more information).

Irritation

Chloroacetamide is reported to slightly irritate skin in animal studies. The effects were not sufficient to warrant hazard classification for skin sensitisation. Chloroacetamide is moderately irritating to eyes in animal studies warranting hazard classification.

Sensitisation

Chloroacetamide is classified as hazardous for sensitisation. The positive results reported in guinea pig maximisation tests (GPMT) and observations of sensitisation in humans support this classification.

In a study conducted according to OECD TG 406, Dunkin-Hartley guinea pigs were given chloroacetamide at induction doses of between 0.003 - 0.3% applied intra-dermally, followed by topical induction by applications of either between 0.3 - 30% or 0.5 - 50%. The challenge and rechallenge concentrations of 30 and 5%, respectively, of chloroacetamide in an aqueous polyethylene glycol (PEG) vehicle were topically applied to the clipped and shaved skin of the animals. Challenge concentrations of 30% caused irritation responses; thus, results at 5% were considered more robust. Positive reactions were seen for all induction doses for both challenge and re-challenge groups.

Numerous reports are available, which demonstrate that chloroacetamide can elicit contact allergies in humans.

In a 10 year retrospective study (2001–2010) of Australian patch testing data, 139 positive reactions (3%) were reported out of 4576 patients tested at 0.2% chloroacetamide in petrolatum. In another Australian study, examining patch test data for chloroacetamide tested at a concentration of 0.2% in petrolatum from 1993–2006, the rate of chloroacetamide allergy was reported as 2.1%. These allergy prevalence rates are higher than those reported in a number of European countries.

A significant number of international studies have identified chloroacetamide as a cause of contact allergy in both patch test volunteers and patients with suspected contact dermatitis.

Repeat-dose toxicity

Effects on the male reproductive system were the most sensitive effects observed in repeated dose toxicity studies (See Reproductive and Developmental Toxicity below).

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, chloroacetamide is not considered to be genotoxic routes.

Carcinogenicity

No data were available.

Reproduction and developmental toxicity

Severe testicular effects were observed in repeat dose studies. These appear to be associated with effects on male fertility. While limited data are available, there is no evidence that chloroacetamide causes specific developmental toxicity in the absence of maternal toxicity.

In a 90-day oral toxicity study conducted according to OECD TG 408 (see IMAP report for details), relevant histopathological changes in males at the highest dose (50 mg/kg bw/day) were depression and/or cessation of spermatogenesis and moderate proliferation of Leydig cells and other interstitial cells in the testes. Epididymal size was reduced, with marked absence of mature and immature sperms with only loose connective tissue present. These effects were reversible within the recovery period.

In other 90-day studies similar dose-dependent reproductive effects at the same doses (12.5 and 50 mg/kg bw/day) were reported. These include decreased testes weights in males and impaired spermatogenesis. Overall a NOAEL of 10 mg/kg bw/day was established for the testes effects.

In a dominant lethal test described previously (see IMAP report for details), the number of resorptions, the mutagenicity index and the number of viable foetuses remained unchanged throughout the entire study. A reduction in the fertility index, number of implantations and foetuses were observed during the first 3 weeks of exposure. However, after week 4, effects were no longer observed. These effects indicate toxic effects on male fertility during the first 3 weeks.

In a combined developmental and reproductive toxicity study, doses were selected based on preliminary study findings of reduction in maternal organ weight as well as maternal and offspring body weight changes at the highest dose of 60 mg/kg bw/day.

Pregnant Wistar rats were dosed in 2 series:

  • 0, 3, 12 or 48 mg/kg bw/day, daily during gestation day (GD) 7 through GD 17 to determine offspring effects; and
  • 0 or 24 mg/kg bw/day, daily during GD 14 to postnatal day (PD) 2 to determine effects on the reproductive systems of offspring.

In the first series, effects reported at the highest dose in offspring include: increased number of unossified sternebrae and forelimb phalanges as well as reduced body weight of viable foetuses. These effects were reported in the presence of maternal toxicity including; reduced body weight gain and organ weight (thyroid and gravid uteri).

In the second series, maternally toxic effects included reduced body weight gain and food consumption during late gestation. Offspring generation effects were limited to lower body weight in the highest dose group. No differences in the reproductive organs of offspring were noted. A NOAEL of 3 mg/kg bw/day was determined based on body weight reduction of dams (based on body weight reductions) and pups (based on ossified sternebrae and the number of ossified forelimb phalanges).

In further developmental toxicity studies in rats, with administrations by the subcutaneous or intraperitoneal routes, doses ranged between 20–2000 mg/kg bw/day. All studies included a single dose or two doses on consecutive days. Doses above 50 mg/kg bw/day were embryotoxic, with pup mortality being reported at 50%. No malformations were reported.

Observation in humans

Numerous reports are available, which demonstrate that chloroacetamide can elicit contact allergies in humans (see sensitisation above).

Public exposure

Chloroacetamide is used as a preservative up to concentrations of < 1%.

Allergy prevalence rates for chloroacetamide are higher in Australia than those reported in a number of European countries.

Chloroacetamide has been identified as being used in cosmetic products in Australia. In Australia chloroacetamide is reported to be used in a popular brand of sorbolene lotion that is marketed for use in sensitive skin. Medical practitioners in Australia commonly recommend sorbolene products to patients with eczema.

Chloroacetamide has reported potential domestic use as a preservative in detergents, paints, glues and emulsions. It is used in concentrations of less than 1% and most often 0.2 – 0.5%. Available North American databases do not give evidence for use of chloroacetamide in consumer products, indicating chloroacetamide is not likely to be widely available for domestic use.

Chloroacetamide has reported use overseas as a preservative in cosmetic and domestic products up to 1%.

Pre-meeting public submissions

Two (2) public submissions were received and both were in support.

Main points in support:

  • No exemption cut-off for cosmetic use in line with the US CIR and the EU SCCS opinion.
  • An appropriate exemption cut-off should be considered for domestic products, given the lower level of direct exposure, and hence a lower risk of sensitisation associated with the use of these products.

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

Summary of ACCS-ACMS advice to the delegate

The committee recommended that new Schedule 6 and Appendices E and F entries be created for chloroacetamide as follows:

Schedule 6 – New Entry

CHLOROACETAMIDE

  1. in preparations for cosmetic use; or
  2. in preparations for topical therapeutic use; or
  3. in other preparations containing more than 0.3 per cent of chloroacetamide.

Appendix E, Part 1 – New Entry

CHLOROACETAMIDE

Standard Statement: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)).

Appendix F, Part 1– New Entry

CHLOROACETAMIDE

Warning Statement: 28 (Repeated exposure may cause sensitisation).

Safety Direction: 4 (Avoid contact with the skin).

The committee also recommended an implementation date of 1 June 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; and (c) the toxicity of a substance.

The reasons for the advice were:

  • There is a significant risk of skin sensitisation when chloroacetamide is applied to the skin. This offset the benefits of chloroacetamide as a preservative. Chloroacetamide is toxic if swallowed.
  • Internationally, chloroacetamide is used as an herbicide and a preservative in cosmetics, domestic and therapeutic products.
  • In Australia, chloroacetamide has been identified as being used in cosmetic products. Herbicide use has not been identified on PubCRIS (APVMA database). Chloroacetamide has reported potential domestic use as a preservative in detergents, paints, glues and emulsions.

Delegate's considerations

The delegate considered the following regarding this proposal:

  • Scheduling proposal
  • ACCS-ACMS 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 new Schedule 6 with Appendices E and F entries for chloroacetamide in the Poisons Standard. The proposed Schedule entry is as follows:

Schedule 6 – New Entry

CHLOROACETAMIDE

  1. in preparations for cosmetic use; or
  2. in preparations for topical therapeutic use; or
  3. in other preparations containing more than 0.3 per cent of chloroacetamide.

Appendix E, Part 1 – New Entry

CHLOROACETAMIDE

Standard Statement: A (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)).

Appendix F, Part 1– New Entry

CHLOROACETAMIDE

Warning Statement: 28 (Repeated exposure may cause sensitisation).

Safety Direction: 4 (Avoid contact with the skin).

The proposed implementation date is 1 June 2018. A later implementation date allows for industry alignment.

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; and (c) the toxicity of a substance.

The reasons for the interim decision are:

  • There is a significant risk of skin sensitisation when chloroacetamide is applied to the skin. This offset the benefits of chloroacetamide as a preservative. Chloroacetamide is toxic if swallowed.
  • Internationally, chloroacetamide is used as an herbicide and a preservative in cosmetics, domestic and therapeutic products.
  • In Australia, chloroacetamide has been identified as being used in cosmetic products. Herbicide use has not been identified on PubCRIS (APVMA database). Chloroacetamide has reported potential domestic use as a preservative in detergents, paints, glues and emulsions.

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