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Scheduling delegate's final decisions, March 2016
Scheduling medicines and poisons
Part A - Final decisions on matters referred to an expert advisory committee
1. Scheduling proposals referred to the November 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#15)
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
- To include a new Schedule 5 entry for isethionate (2-hydroxyethanesulfonic acid).
In August 2014, the Applicant, as part of an application to the Australian Pesticides and Veterinary Medicines Authority (APVMA), requested that the delegate consider not including isethionate in a schedule entry. The OCS evaluated the information provided by the applicant and advised the applicant (in the draft human health risk assessment report of August 2015) that a Schedule 5 entry is appropriate for isethionate.
The applicant responded to the August 2015 OCS draft human health risk assessment report indicating that they have no objections to OCS's scheduling proposal.
Specific issues/questions raised by the delegate
The delegate asked the committee the following questions:
- The name 'isethionate' seems inappropriate for listing. The CAS No. 57267-78-4 specifically refers to the ammonium salt of 2-hydroxyethanesulfonic acid. Should an entry in the Schedules refer to that ammonium salt under that name, or should the entry specify 2-hydroxyethansulfonic acid, therefore picking up all salts?
- The product under consideration is a mixture of the ammonium, monoethanolamine, diethanolamine, triethanolamine and tetraethanolamine salts (887g/l in all). The toxicity tests were all done with this mixture. There are current SUSMP entries for mono-, di- and tri-ethanolamines in Schedules 6 (>20%) and 5 (5-20%), with only preparations <5% exempt. All these entries exempt salts and derivatives, so there may not be an issue that the proposed product would be captured by the current ethanolamine entries. Does the ACCS confirm that the proposed listing in S5 for this product will not conflict with current ethanolamine entries?
- Are there any non-AgVet products or uses of 2-hydroxyethansulfonic acid (isethionate) or its salts that might be inadvertently captured by the proposed entry?
Figure 7. Chemical structure of isethionate (sodium salt)
The acute toxicity end-points for isethionate are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||Rat||Low (LD50 >2000 mg/kg bw)||Schedule 5|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||Low (LD50 >2000 g/kg bw)||Schedule 5|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||Low (LC50 >6295 mg/m3)||Schedule 5|
|Eye irritation||Rabbit||Slight||Schedule 5|
|Skin sensitisation||Guinea pig||Non-sensitiser||-|
In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, Wistar Hannover rats (12/sex/dose) were orally administered the test substance via gavage at 0, 250, 500 or 1000 mg/kg bw isethionate. Male rats received the test substance for 28 days and female rats received the test substance for 54 days (including pre-mating, mating and through gestation and lactation). A satellite group of animals (5/sex) were administered 0 and 1000 mg/kg bw/d of the substance to assess reversibility of findings. Deionised water was used as a vehicle.
There were no mortalities, treatment related clinical findings including neurobehavioral changes in any of the treatment groups. Slight changes in body weight and body weight gain were observed. However, these changes in bodyweight and bodyweight gain were small in magnitude and there was no time or dose response relationship, and were not considered to be treatment related. There was no adverse, treatment related effect on food consumption in any of the treatment groups.
Changes in haematology parameters included decreased mean red blood cell count, haemoglobin, haematocrit and platelets in the mid and highest doses, attaining statistical significance in high dose males (red blood cell count, haemoglobin and haematocrit). Moreover, animals exposed to 500 and 1000 mg/kg bw/d showed changes in clinical chemistry parameters, however there was no clear, consistent, and statistically significant, dose related adverse effects observed at any dose and therefore were not considered to be treatment related.
Both male and female rats exposed to 500 mg/kg bw/d showed increased kidney weights. Increased adrenal weights were seen in males exposed to 500 and 1000 mg/kg bw/d. Low incidence microscopic findings were observed in high dose males including pelvis dilatation and mild congestion in the kidney, mild bilateral tubular degeneration of the testis and mild bilateral tubular degeneration of the epididymis.
Low incidence microscopic findings were observed in high dose females including mild diffuse vacuolisation and isolated hepatocellular hyperthrophy of the liver, slight unilateral pelvis dilatation and slight congestion in the kidney, slight unilateral kidney pelvis dilatation and slight bilateral pelvis dilatation of the kidney.
However, a comprehensive histopathological examination of tissues was not conducted as only the high dose and control animals were examined microscopically. Therefore, the toxicological significance of these findings is unknown in the absence of microscopic examination in the mid-dose groups.
The genotoxic potential of the compound was tested in an Ames test using four strains of S. typhimurium and a strain of E. coli which gave negative results with and without metabolic activation.
The applicant did not provide carcinogenicity studies.
Reproduction and developmental toxicity
A separate reproduction or developmental toxicity study has not been provided by the applicant. The repeat dose toxicity study (discussed under Repeat-Dose Toxicity) provided by the applicant contained a reproductive/developmental toxicity screening test for isethionate.
In the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, rats (12/sex/dose) were orally administered the test substance via gavage at 0, 250, 500 and 1000 mg/kg bw/d. Male rats received the test substance for 28 days and female rats were received the test substance for 54 days (including pre-mating, mating and through gestation and lactation). A satellite group of animals (5/sex) were administered 0 and 1000 mg/kg bw/d of the substance to assess reversibility of findings.
Changes in a number of reproductive effects, including increased pre-implantation loss (17.9% increase), decreased fertility index (22.3% decrease) and increased gestation index (12.5% increase) were seen in the high dose treatment group compared with controls. These were not statistically significant and there was no clear dose response relationship to the findings.
Evaluation of pups and litter showed that on day zero, one pup out of 69 and on day four, one pup out of 68 from the control group died. One pup out of 90 treated with 250 mg/kg bw/d and six pups out of 75 treated with 500 mg/kg bw/d of the test substance were found dead on day four, however there were no dead pups in the high dose group. Therefore, in the absence of a dose response relationship and the low magnitude of pup deaths, the finding was not considered to be treatment related. The mean body weight of pups on days zero and four postnatal was similar in all groups.
Observation in humans
No information was provided.
No information was provided.
No information was provided.
Isethionate is not specifically listed in the SUSMP.
Isethionate has not been considered for scheduling previously.
Pre-meeting public submissions
Two public submissions were received. The first submission questions the wording of the entry: isethionate (2-hydroxyethanesulfonic acid) noting that according to Part 1, Section 2 of the Poisons Standard, all salts and derivatives are included in entries, unless specified. Isethionate and its salts are used in some cosmetic products and scheduling will impact those existing products. The US Cosmetic Ingredient Review (CIR) deemed isethionate as a safe cosmetic ingredient, when formulated to be non-irritating. The submission seeks for isethionate to remain unscheduled or at least to have a lengthy implementation date applied.
The second submission states isethionate salts are used as alternatives to lauryl sulfates in cosmetics. It refers to the US CIR on isethionate salts that concluded these to be safe for use in cosmetics when formulated to be non-irritating. The submission suggests surfactants do not require scheduling as the risks are known to consumers and due to no international restrictions being in place. They note, however, that a precedent has been set, with ammonium cocoyl isethionate appearing in Schedule 6. Therefore they ask if scheduling is decided upon that a low cut-off (currently used at up to 25%) in rinse-off cosmetics be put in place.
The public submission is available at Public submissions on scheduling matters.
ACCS advice to the delegate
The committee recommended that 2-hydroxyethansulfonic acid and its salts does not require a schedule listing but that the Delegate consider listing the substance in Appendix B for reasons of Part 2, Areas of Use.
The reasons for the recommendations comprised the following:
- The committee noted that the data for the substance was lacking, and what data there is points to a marginal toxicological profile. The Committee agreed that there is no real requirement to schedule and an entry in Schedule 5 would not have any real regulatory impact.
The committee also proposed a new reason in Appendix B, Part 2, Area of Use be created with wording to the effect of adjuvants in agricultural products.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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 delegate considered the following in regards to this proposal:
- Scheduling proposal;
- Public submissions received;
- ACCS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors10;
- Other relevant information.
Delegate's interim decision
The specific application for scheduling under consideration relates to the use of mixed salts of 'isethionate' as an adjuvant in agricultural herbicide tank mixes. The delegate notes, and accepts, ACCS advice that this substance does not require listing in the Schedules because of its low toxicity and use pattern. Listing in Appendix B for this specific agricultural use avoids any scheduling impacts associated with the use of isethionate salts in cosmetics and other domestic products, as flagged in the industry submissions.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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.
Appendix B - New Entry
ISETHIONATE, as mixed ammonium and ethanolamine salts of 2-hydroxyethanesulfonic acid
Part 1 - Reasons for Entry
a) low toxicity; and
b) use pattern restricts hazard
Part 2 - Area of Use
1.11 Adjuvant in agricultural products
Public submissions on the interim decision
Two submissions were received.
The first submission supported the Delegate's interim decision to list Isethionate in Appendix B with clear wording on area of use as an adjuvant in agricultural products, to ensure there will be no impact on the scheduling of cosmetics and therapeutic goods.
The second submission noted Isethionates are used in cosmetic preparations, and one of the salts, ammonium cocoyl isethionate, is specifically scheduled. They agree isethionates when used as surfactants belong in Appendix B, however they do not agree that entry should be restricted to agricultural uses. They further note their concern about continuing to regulate surfactants that are commonly used in cosmetics and consumer products globally, such as ammonium cocoyl isethionates, using current concentration restrictions and mandatory statements are not in line with international practice. They cite a recent government statement of support for the "Accepting Trusted International Standards" policy and believe the current regulation of surfactants through the Poisons Standard should be reconsidered.
Edited versions of public submissions are available at Public submissions on scheduling matters.
Delegate's final decision
The delegate notes the submissions received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.
The delegate notes the ongoing concerns expressed about previous actions to schedule surfactant ingredients in cosmetics and consumer products, but declines to review such decisions at this time. The proposed wording limiting the Appendix B entry to use of this specific mixture of isethionate salts as an adjuvant in agricultural products does not require any label changes or other controls associated with use of isethionates (except the currently scheduled ammonium cocoyl isethionate) in any cosmetic or consumer products.
Appendix B (Part 3) - New Entry
ISETHIONATE, as mixed ammonium and monoethanolamine salts of 2-hydroxyethanesulfonic acid
Part 1 - reasons for entry
a) Low toxicity and
b) use pattern restricts hazard
Part 2 - Area of Use
1.11 Adjuvant in agricultural products.
The proposed implementation date is 1 June 2016.