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Scheduling delegate's final decisions, March 2016
Scheduling medicines and poisons
Part B - Final decisions on matters not referred to an expert advisory committee
3. Agricultural and Veterinary Chemicals
In December 2015 the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) for the approval of cloquintocet acid as a new active constituent, recommended that the delegate consider creating a new entry for cloquintocet acid in Schedule 5 of the SUSMP. No cut-off exemptions for cloquintocet acid were proposed by OCS and no registration application has been received for a product containing cloquintocet acid.
The applicant has submitted a data package seeking approval of the new active constituent cloquintocet acid. The applicant has asked that cloquintocet acid be considered for exemption from scheduling and listing in Appendix B to the SUSMP.
Figure 1. Structure of cloquintocet acid
Cloquintocet acid is a crop safener and is not classified in a chemical class. The role of a crop safener is to prevent the phytotoxic action of the accompanying herbicide with which it is mixed. Cloquintocet acid is currently not listed in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP).
Cloquintocet acid is the primary in vivo mammalian metabolite of cloquintocet-mexyl and hydrolysis of the mexyl occurs rapidly in vivo so that systemic exposure is primarily to cloquintocet acid. The toxicological assessment of cloquintocet acid was limited to the conduct of key studies to confirm toxicological equivalence to cloquintocet-mexyl and allow bridging to the toxicological database already available for cloquintocet-mexyl for human health assessment.
The acute toxicity end-points for this chemical are listed in the below table.
|Toxicity||Species||Cloquintocet Acid||SPF* Classification|
|Acute oral toxicity LD50 (mg/kg bw)||Rat||
LD50 >2000 mg/kg bw no deaths or treatment related clinical signs
Low oral toxicity
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||
LD50 >5000 mg/kg bw no deaths or treatment related clinical signs
Low dermal toxicity
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||
4-hr LC50 > 6110 mg/m3 no deaths
Low inhalational toxicity
|Skin irritation||Rabbit||Non irritating||N/A|
Conjunctival redness (scores 1-2) resolved by 72h
Slight eye irritant
|Skin sensitisation (LLNA)||Mice||Non sensitising (concentrations ≤50% active ingredient)||N/A|
* Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
- Low acute oral toxicity in rats (LD50 >2000 mg/kg bw, no deaths). Low acute dermal toxicity in rats (LD50 >5000 mg/kg bw; no-deaths). Low acute inhalational toxicity in rats (4-hr LC50 >6110 mg/m3, no deaths).
Not irritating to the skin of rabbits. Slightly irritating to the eye of rabbits.
Not a skin sensitiser in mice up to 50% w/v (LLNA test).
No guideline short-term toxicity studies were submitted. Short-term (7-14 day) studies in rats were carried out either as probe studies or to establish palatability in the test diet and these studies were not suitable for establishing NOELs for cloquintocet acid. The repeat dose studies indicated there were palatability issues with test diets containing high concentrations of cloquintocet acid, often resulting in transient effects on body weights and food consumption.
In a guideline-compliant subchronic (13 week) study in rats, cloquintocet acid was administered at dietary concentrations of up to 2100ppm (116/127 mg/kg bw/d in males/females). Effects on body weight, body weight gain and food consumption were attributed to the palatability of the test diet. Cloquintocet acid did not induce deaths, changes in clinical signs, ophthalmoscopy or treatment-related findings in functional tests, prothrombin time, serum thyroid hormone parameters or gross pathological or histopathological alterations. Slight but statistically significantly increased platelet counts in females administered cloquintocet acid at 2100 ppm were not considered toxicologically relevant. A number of other findings at the high dose were dismissed due to lack of dose response relationship or lack of correlation with other relevant toxicological findings. A slight but statistically significant decrease in absolute and relative spleen weights at 2100 ppm cloquintocet acid with no corresponding gross or histopathological changes was not considered to be toxicologically significant. The no-observed-effect level (NOEL) for the Crl:WI(Han) rat was the highest dose tested, a targeted concentration of 2100 ppm X204558 (equivalent to time-weighted average concentrations of 116 or 127 mg/kg bw/day in males and females, respectively).
Mutagenicity and genotoxicity
Genotoxicity assays for gene mutation in vitro in bacterial cells (reverse mutation using five strains of S. typhimurium) and mammalian cells (forward mutation in CHO K1 cells) and a cytogenetic assay in vitro using human peripheral lymphocytes, were negative, with and without metabolic activation for cloquintocet acid (X204558). Based on the uniform negative findings, cloquintocet acid (X204558) is not mutagenic or genotoxic.
No carcinogenicity studies with cloquintocet acid were provided.
Reproduction and developmental toxicity
In a screening oral one-generation (reduced) reproductive toxicity study (Ellis-Hutchings, 2014b), groups of 10 male and 10 female Crl:CD(SD) rats were administered cloquintocet acid at 0, 105, 700 or 2100 ppm, equivalent to 0, 7.38, 48.2 or 123 mg/kg/day for males and 0, 6.98-11.1, 48.9-75.5 or 125-227 mg/kg/day for females given 0, 105, 700, or 2100 ppm during the pre-breeding gestation and lactation phases of the study, respectively. There were no treatment related and toxicologically significant effects in parental animals. Body weight and/or body weight gain and food consumption were initially lower (greatest on days 1-2) and attributed to the decreased palatability of the test diets) in males and females in the mid (700 ppm) and high dose (2100 ppm) groups. There were no treatment-related effects on clinical signs, litter size (survival) or pup body weights. At the pup necropsy at LD 4 there were no macroscopic changes or findings of gross external morphological alterations attributed to treatment following exposure to cloquintocet acid. The reproductive and offspring NOEL were both identified at the highest dose of cloquintocet acid tested (2100 ppm or 123/125-127 mg/kg bw/day, M/F) based on the lack of treatment-related and toxicologically significant effects in adult males, dams and pups. A parental (systemic) NOEL was also identified at 2100 ppm (equivalent to time-weighted average concentrations of 123 or 125-227 mg/kg bw/day in males and females, respectively) based on the lack of toxicologically significant effects in adults (both sexes) and dams up to and including the high dose of 2100 ppm cloquintocet acid.
Noting the screening nature of the study, under the conditions of the study, OCS considers that cloquintocet acid is unlikely to be a reproductive or developmental toxicant in rats, and is likely to share comparable reproductive and developmental toxicity potential with cloquintocet-mexyl.
No dedicated neurotoxicity studies were submitted. However, cloquintocet acid did not show signs of neurotoxicity in rats in submitted acute toxicity studies or in a FOB in a subchronic (dietary) 90 day toxicity study.
Observation in humans
No information provided.
No information provided. No product proposed at this time.
No information provided.
CLOQUINTOCET ACID is not specifically scheduled.
CLOQUINTOCET MEXYL included in Schedule 5 of the SUSMP.
CLOQUINTOCET ACID has not been previously considered for scheduling; therefore, scheduling history is not available.
Delegate's interim decision
Schedule 5 - Amended Entry
CLOQUINTOCET MEXYL - delete the word MEXYL
The reasons for the interim decision comprised the following:
The delegate's interim decision is to amend the current Schedule 5 entry for Cloquintocet mexyl, removing reference to the mexyl ester so that cloquintocet and all its salts and esters are captured by the entry. The delegate notes that cloquintocet acid lacks the weak sensitisation potential of the mexyl ester, but that otherwise, the toxicological profile of the acid and mexyl ester are comparable, and consistent with SPF criteria for listing in Schedule 5, based on eye irritancy.
The OCS evaluation report notes that cloquintocet acid has a low toxicity profile, with slight eye irritancy the only toxicity endpoint that is consistent with SPF criteria for listing in Schedule 5. The OCS report also notes that cloquintocet acid is a metabolite of cloquintocet mexyl, a substance already included in Schedule 5 on the basis of slight eye irritancy and weak sensitisation potential. The delegate proposes to accept the OCS recommendation to also list cloquintocet acid in Schedule 5, but to do so by amending the current entry for cloquintocet mexyl, noting that this ester would still be considered a Schedule 5 substance because of the Part 1 para 2(c) definition that an entry in the schedules includes all salts, esters, ethers or derivatives of listed substances. The delegate does not see a need to have two entries in Schedule 5 for cloquintocet and its mexyl ester. Accordingly, the scheduling proposal is to amend the current entry as shown.
The delegate considered the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- OCS evaluation report;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors1;
- Other relevant information.
Submissions on the interim decision
The applicant had no objections to the Delegate's interim decision.
Delegate's final decision
The delegate has confirmed 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.
CLOQUINTOCET MEXYL - delete the word MEXYL
Implementation date: 1 June 2016.