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Scheduling delegate's final decisions: ACCS, November 2015
Scheduling medicines and poisons
Part A - Final decisions on matters referred to an expert advisory committee
2. Scheduling proposals referred to the August 2015 ACCS meeting
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
- the delegate received a request to consider amending the current Schedule 5 entry for hydramethylnon to include a concentration cut-off exemption at 0.365% w/w.
In March 2014, the applicant, as part of an application to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to extend the usage of a currently registered product (professional use), requested that the delegate consider amending the current Schedule 5 entry for hydramethylnon to allow for the inclusion of a product containing 0.365% w/w hydramethylnon.
The OCS performed a risk assessment for the professional use of the product in August 2013. The extension of use to include the domestic user was considered as part of the risk assessment provided to APVMA on 4 December 2014. The OCS considers that the uncertainty regarding reproductive toxicity is sufficient to retain the schedule 6 entry, particularly for professional users.
In considering the available information, the OCS considers that the professional use pattern for the product is consistent with a Schedule 6 entry. This recommendation is based on the potential for long term use of hydramethylnon, which may result in delayed onset of irreversible effects to male fertility at low doses. Recommendations for appropriate label statements have been made for the application of the product via aerial and hand –held spreaders, however, the risk to workers arising from hand dispersal of bait could not be sufficiently mitigated through the use of PPE. Whilst the acute toxicity profile is consistent with a Schedule 5 entry and the risk for the domestic user of the product is considered acceptable (i.e. MOE > 100), the uncertainty regarding the potential for harm arising from an accidental poisoning scenario is considered sufficient to retain the Schedule 6 entry for the domestic market.
The reasons for the request were:
- The product has low acute toxicity via oral and dermal exposure and does not cause skin irritation or sensitization which is consistent with Schedule 5.
Delegate's reasons for referring this to the committee
This is a re-scheduling proposal for a substance previously considered by the NDPSC and currently listed in Schedules 5 and 6. Since there is disagreement between the recommendations of the OCS evaluation report, and the applicant's response, the delegate requested advice from the ACCS.
The delegate asked the committee the following questions:
- The key issue considered by the NDPSC in 1996 was whether a brief exposure to a granular bait containing hydramethlynon represented a risk of testicular toxicity to a child ingesting a small amount of the bait. The DPSC in 1990 had apparently been satisfied that it was unlikely a child could access a sufficient dose of hydramethylnon when contained in a plastic labyrinth bait station, and it allowed a down-scheduling for such a product to Schedule 5. Pyriproxyfen, the other active ingredient of the granular ant bait under consideration in this proposal has low toxicity, and was included in Appendix B at the August 1994 NDPSC meeting.
- Testicular atrophy and resultant infertility appear to be the main reasons behind listing hydramethylnon in Schedule 6, because other aspects of its toxicity are more consistent with listing in Schedule 5. The OCS evaluation report on a current product submission (granular ant bait in a shaker pack for domestic use and a different pack for professional use) notes that no specific toxicity study has been provided to address the testicular toxicity concerns raised by the NDPSC. The sponsor has argued that the likely exposure pattern for a child ingesting enough of the granular product is negligible, and that in a single dose experiment in rats, impaired fertility was not seen after a dose of 800 mg/kg (OCS noted that this was assessed 3 weeks after the exposure). Which argument does the ACCS support in relation to the testicular toxicity potential?
- Does the OCS evaluation report provide any information on the Mode of Action (MoA) for the testicular toxicity, and if not, how critical is this lack of information?
- Do the differences in the proposed use patterns (frequency of application and method of application) justify having a product with identical actives and toxicological profile in Schedule 6 for professional use, and in Schedule 5 for domestic use? If so, does the wording of the Schedule 5 sub-clause adequately differentiate the domestic product shaker pack from the professional product?
- Is the wording of the proposed specification of the 'shaker pack for domestic use containing 500g or less of the granular material' consistent with wording used in the SUSMP and consistent with enforcement by State/Territory law?
Figure 1: Molecular structure of hydramethylnon (CAS: 67485-29-4): tetrahydro-5,5-dimethyl-2(1H)-pyrimidinone(3-(4-(trifluoromethyl)phenyl)-1-(2-(4-(trifluoromethyl)phenyl)ethenyl)-2-propenylidene)hydrazone
The acute toxicity end-points for this chemical are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||Rat||Low (LD50=1131 mg/kg bw)||Schedule 6|
|Acute dermal toxicity LD50 (mg/kg bw)||Rabbit||Low (LD50>15 g/kg bw)||Schedule 5|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||Low (LC50>600 mg/m3 no deaths)||Schedule 6|
|Skin sensitisation (Local lymph node assay)||Guinea pig||Non-sensitiser|
The acute toxicity of the product forming the basis for the down scheduling consideration at 0.365 % w/w hydramethylnon (plus 0.250 % w/w pyriproxyfen) is included in the table below.
|Toxicity end point||Hydramethylnon||Pyriproxyfen||Synergy Ant Bait|
|Oral (mg/kg bw)||Low (LD50=1131 mg/kg bd/w)||Low (LD50>5000 mg/kg bd/w)||Low (LD50>2000 mg/kg bd/w no deaths)|
|Dermal (mg/kg bw)||Low (LD50>15 g/kg bd/w)||Low (LD50>2000 mg/kg bd/w)||Low (LD50>2000 mg/kg bd/w no deaths)|
|Inhalational (mg/m3)||Low (LC50>600 mg/m3 no deaths)||Low (LC50>1300 mg/m3)||Low *|
|Skin irritation||Slight||Nil||Non irritant|
|Skin sensitisation||Nil||Nil||Non sensitiser|
*product toxicity was estimated from available information on product ingredients
Repeat dose toxicity
In a 3-week dermal toxicity study, New Zealand White rabbits (10/sex/dose) were administered 0, 10, 50, or 250 mg/kg bw hydramethylnon on abraded or unabraded skin for 6 hours/day, 5 days/week for 3 weeks. The vehicle was not stated. Clinical signs of systemic toxicity were not observed in any group during the treatment. Food consumption and body weight gains were reduced in the high dose groups only. High dose females presented with significantly reduced platelet counts at termination. High dose group animals also showed reduced relative liver and brain weights, but these changes were probably related to the lower body weights. The dermal irritation was of similar severity in all groups when compared to controls, indicating an irritant vehicle rather than a test material-related effect. The NOEL for systemic toxicity following dermal application was 50 mg/kg bw/d, based on reduced appetite, reduced body weight and reduced platelet counts observed at the next highest dose.
In a 28-day feeding study, CD rats, (3/sex/dose) received 0, 50, 100, 200, 400 or 800 ppm hydramethylnon in their diet. The 800 ppm group was killed moribund at the end of the second week. Anorexia and significant reduction of food consumption occurred in the three highest dose groups. Depressed weight gain and decreased relative weight of a number of organs was observed at the 400 and 800 ppm level. Gross pathology was unremarkable; histopathological examination revealed focal tubular degeneration of testes in the group of 200, 400 and 800 ppm. The NOEL was 100 ppm (approximately 5 mg/kg bw/d) based on anorexia, decreased food consumption, reduced weight gain and testicular atrophy seen at 200 ppm and above.
In another 28-day feeding study, CD rats (6/sex/dose) were given 0, 25, 50, 75, or 100 ppm hydramethylnon in diet. No mortalities or clinical signs of toxicity were noted. A slight decrease in food consumption was noted in the 100 ppm group, accompanied by depressed weight gain in females during the first half of the study. Haematological values remained within the normal range in all groups. The NOEL was 75 ppm (approximately 3.75 mg/kg bw/d) based on the reduced weight gain and food consumption in the 100 ppm group.
In a 91-day feeding study, CD rats (20/sex/dose) were given 0, 25, 50, 100 or 200 ppm hydramethylnon. No mortality occurred during the treatment period. Decreased food intakes were observed in high dose males during all treatment weeks except weeks 9, 10 and 13. Decreased food intake was also noted in females during the first 3 weeks. A significant decrease in body weights of high dose rats of both sexes occurred throughout the study. Clinical chemistry, haematological parameters and urinalysis were unaffected by treatment. No organ weight changes were noted with the exception of decreased absolute and relative testicular weights in high dose animals, accompanied by testicular atrophy at ≥100 ppm. The NOEL was 50 ppm (approximately 2.5 mg/kg bw/d) based on testicular lesions at 100 ppm and above.
In a 91-day oral study, beagle dogs (4/sex/dose) received 0, 3, 6 or 12 mg/kg bw/d hydramethylnon in gelatin capsules. Middle and high dose dogs began to refuse food from second week of the experiment; all high dose dogs were sacrificed moribund by day 53 and only one male and one female dog at 6 mg/kg bw/d survived through to study termination. The mean body weight gains were depressed in the middle and high dose groups probably as a result of appetite loss. These dogs exhibited intermittent episodes of tremors and short episodes of convulsions, with occasional vomiting. Liver weights of low dose males as well as the liver/body weight ratio were increased, however, no abnormal hepatic histopathology was found in low dose animals. Gross pathology indicated cachexia in all middle and high dose dogs accompanied by wasting of muscle and subcutaneous fat and also accompanied by testicular atrophy in the middle and high dose dogs. No NOEL was established in this study.
In a 26-week sub-chronic toxicity study, beagle dogs (4/sex/group) were administered 0, 0.33, 1.0, or 3.0 mg/kg bw hydramethylnon by oral capsule. No deaths were observed. Clinical signs of toxicity consisted of a dose-related increased incidence of soft and mucoid stools and diarrhoea in all treated groups. Treatment-related changes in organ weights included a dose-related increase in the liver weights, liver/body weight ratios and liver/brain weight ratios in the middle and high-dose males and females (except the liver/brain ratio in the high dose females). Gross necropsy finding indicated only a yellow-coloured body fat in 4/8 high dose dogs. The NOEL in this study was 1 mg/kg bw/d based on the toxicity at 3.0 mg/kg bw/d consisting of reduced body weights and anorexia in one animal.
In an 18-month chronic toxicity study, CD mice (50/sex/dose) were given 0, 25, 50, 100 or 200 ppm hydramethylnon in the diet. A dose-related increase in mortality over the course of the study was seen, with clear indications of treatment-related mortality evident by week 26 of the study. Mean body weights were reduced in the two highest dose groups. Food consumption was decreased in the highest dose group only after 12 weeks. Histological examination indicated major lesions in the testes of males at 50, 100 or 200 ppm. The dose-related lesions consisted of hypospermia, interstitial cell hyperplasia of Leidig cells and germinal cell degeneration. Other lesions included an increased incidence of pigment-laden macrophages in alveolar spaces of the lung at 200 ppm group and an increased incidence and severity of pigment accumulation in the cytoplasm of cortical renal tubules among 200 ppm females. An increased incidence of renal amyloidosis was observed in males administered 100 and 200 ppm hydramethylnon and females administered 50, 100 and 200 ppm hydramethylnon. The amyloidosis was bilateral, with a glomerular distribution in mild cases and glomerular and tubular involvement in the more severe lesions. No increase in tumours was detected in the study. The NOEL in this study was 25 ppm (3.75 mg/kg bw/d) based on the testicular atrophy and renal amyloidosis observed at 50 ppm and above.
In a 2-year chronic toxicity study, CD rats (50/sex/dose) received 0, 25, 50, 100 or 200 ppm hydramethylnon in the diet. No clinical signs were observed during the study. Food consumption was decreased in the high dose group (both sexes) and mean body weights were reduced in high dose animals (both sexes) and middle-dose females. Clinical pathology was unaffected by treatment. A statistically significant decrease was observed in absolute and relative testes weight (% brain) in the two highest male dose groups, and a decrease in the relative weight (% body) for the highest dose group. These testes weight changes correlated with small and soft testes at gross necropsy examination, and a significant increase in the incidence of bilateral testicular atrophy characterised by almost complete loss of germinal cell and, arteritis tissue in histopathological examination. Increased absolute and relative heart weights in the two highest dose groups was also observed (without histopathological correlates), and an increased absolute and relative kidney weight in ≥50 ppm males and ≥100 ppm females. Glomerulonephrosis was increased in the highest dose group. Hydramethylnon was not oncogenic at any dose tested after evaluation. The NOEL for this study was 50 ppm (2.5 mg/kg bw/d) based on the toxic effects consisting of reduced food consumption and body weight gain and increased incidence of testicular atrophy and exacerbated glomerulonephritis at 100 ppm and above.
Hydramethylnon was negative in the Ames test. Hydramethylnon caused infertility in male rats, due to aspermia, in a dominant lethal test when administered at doses of 30 or 90 mg/kg bw/d for 5 days. At 30 mg/kg bw/d infertility was reversed in all animals at 12 weeks after dosing, while partial reversal of infertility was noted at 90 mg/kg bw/d after 17 weeks in 5/10 animals, with remaining 90 mg/kg bw/d males noted as infertile. Treatment with the compound had no effect on implantation parameters in females. Hydramethylnon did not induce chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of metabolic activation.
There was no evidence of treatment related carcinogenicity in long term repeat dose studies with rats and mice.
Reproduction and developmental toxicity
In a 3-generation reproduction study, CD rats were given hydramethylnon for 3 successive generations at 0, 25, 50, 100 or 200 ppm. No treatment-related deaths occurred in the adult generations. Mean body weight gains of males at 100 or 200 ppm and females at 50, 100 or 200 ppm were significantly reduced in the growth period. While offspring generations (F1 onwards) were not retained at ≥100 ppm due to lack of offspring, the subsequent F1 and F2 generations at 25 and 50 ppm showed normal weight gain and food consumption during the growth phase. The reproductive performance at the two highest dose levels in the F0 generation was markedly reduced. At 100 ppm, mating indices were higher than controls during both mating periods, however, none of the females delivered an F1a litter and only 6 females delivered an F1b litter. Litters of these females contained fewer pups and some oedematous pups. At 200 ppm, mating indices were generally lower than controls for both mating intervals and none of the females delivered litters. The reduced fertility in the F0 group at 100 or 200 ppm was accompanied by increased incidence of small testes in these groups from week 19, tubular degenerative changes and aspermia, with 200 ppm males also presenting with mineralisation of a few degenerated tubules. The NOEL was 50 ppm (2.5 mg/kg bw/d) based on reduced fertility at ≥100 ppm.
In a 2-generation reproduction study, CD rats received hydramethylnon at 0, 25, 50 and 75 ppm in the diet. Reduced body weight gains during the 10 week premating period and a transient reduction in food consumption in the first 3-4 weeks of dosing were recorded in F0 males at 50 ppm and in both sexes at 75 ppm, attaining statistical significance for body weight gain in males only. Maternal weight gains during gestation were significantly reduced in the 75 ppm group in both generations. A decrease in male mating index was seen in F1 males at 75 ppm. Decreases in male fertility index, female pregnancy rate and gestation index were observed in both generations at 75 ppm. A greater number of F1 males in the 50 and 75 ppm groups did not mate in the 10 day cohabitation period. Smaller litter sizes at birth were observed in the 75 ppm groups of both generations with statistical significance attained for F1 litters (from F0 dams). Other litter parameters were comparable in all groups. There were no dose-related microscopic changes in females. In males, multifocal degeneration of the seminiferous tubules in the testes was observed in F1 animals at 75 ppm, which also had increased cell debris in the epididymes. Complete testicular unilateral or bilateral germinal epithelial degeneration/atrophy with only Sertoli cells remaining was seen in 3/30 F0 and 1/30 F1 males at 75 ppm and in 1/29 F0 rats at 50 ppm (none in F1 MD group). The NOEL for general toxicity and reproduction was 25 ppm (2.1 mg/kg/day) in the diet based on reduced food consumption and decreased mating index at 50 ppm.
Hydramethylnon technical administered as a single oral dose of 0 or 800 mg/kg bw to male rats (10/group) had no significant effect on their reproductive performance when tested 3 weeks after dosing by mating with untreated females, and had no secondary effects on the reproductive performance of untreated female rats bred to these rats.
Two separate 8-week feeding and recovery studies were performed in mature and maturing rats to determine whether pathologic changes of the testes seen in previous studies were due to reduced food intake or to hydramethylnon, and to determine whether these changes were reversible when hydramethylnon was removed from the diet. Hydramethylnon was administered to rats (12/group) in the diet at 0, 200 or 400 ppm for four weeks, with animals retained for a recovery period dosed on untreated diet for an additional four weeks. Additional pair-feeding negative control groups (matching food intake with 200 and 400 ppm groups) were also used in this study. Comparison of results indicated that maturing rats were more sensitive to testicular atrophy induced by hydramethylnon than mature rats. Testicular atrophy was directly related to hydramethylnon administration and not mediated via reduced weight gain as demonstrated in comparison with pair-fed negative control groups. The testicular pathology was not reversible and appeared to increase in severity with time after dosing ceased, indicating a time lag between dosing and reproductive toxicity. Hepatic cell degeneration caused by hydramethylnon observed in this study at the 400 ppm dose level was reversible.
A teratology study in rabbits was performed, with animals administered 0, 5, 10 or 20 mg/kg bw/d hydramethylnon on days 6 to 18 of gestation by oral gavage. Two dams from the high dose group died in the post-treatment period. Six dams aborted on days 25 to 29 (three in 10 and 20 mg/kg bw/d respectively). Dose-related decrease in mean maternal body weight was noted at 10 and 20 mg/kg bw/d groups, and a reduction in mean maternal body weight gain at 5 mg/kg bw/d. No treatment-related foetal effects were observed. Overall, no NOEL was established for maternotoxicity. A foetal NOEL of 20 mg/kg bw/d (highest dose tested) was established, as hydramethylnon was not teratogenic or foetotoxic at doses ≤20 mg/kg bw/d.
A teratology study in rats was conducted, with animals administered hydramethylnon at 0, 3, 10 or 30 mg/kg bw/d by gastric intubation on gestation days 6-15. Pregnancy rates were similar in all groups. Two females in the high dose group died on gestation days 7 and 16. Mean body weight gains of dams were reduced in the middle and high dose group during the post-dosing interval. Additional maternotoxicity in the high dose group only included red nasal mucous, alopaecia, soft stool and anogenital staining. A small thymus was observed in some high-dose females. An increase in the incidence of rudimentary structures and incompletely ossified supraoccipital bones was noticed in high dose group. The NOEL for maternotoxicity was 10 mg/kg bw/d based on the death and additional maternotoxicity. The compound was not teratogenic or foetotoxic in rats at ≤30 mg/kg bw/d in this study, and a foetal NOEL was established at 30 mg/kg bw/d.
Observation in humans
No information was provided.
Refer to OCS human health risk assessment report.
No information was provided.
Hydramethylnon is currently listed in Schedules 5 and 6.
Hydramethylnon is listed in Schedule 6 of the Poisons Standard except when included in Schedule 5. The Schedule 5 entry for hydramethylnon is for solid baits containing 2 per cent or less of hydramethylnon in welded plastic labyrinths.
Pyriproxyfen is currently listed in Appendix B.
The following is a record in chronological order of considerations by various committees relating to hydramethylnon.
At the July 1987 meeting of the Drugs and Poisons Scheduling Committee (DPSC), hydramethylnon was considered and placed into Schedule 6 based on irreversible testicular effects observed in several animal species and study duration. A product containing 1.65 % hydramethylnon and enclosed in a welded plastic labyrinth was also considered at this meeting and was determined by the committee as suitable for inclusion in Schedule 5.
The DPSC meeting of February 1988 considered information from the applicant regarding the testicular atrophy seen in immature rats. The company's reply to the committee noted testicular effects in various short-term studies and a reproduction study: however, not all of these studies had been supplied by the sponsor for evaluation. The aforementioned studies were subsequently supplied by the sponsor and evaluated by the NHMRC Toxicology Unit before discussion of hydramethylnon at the May 1989 meeting of the DPSC. It was noted at that meeting that the studies "showed that rats had been immature in the beginning of the study and that the testicular effects were seen in the worst case situation. A simple or brief exposure of immature rats to hydramethylnon at high doses briefly but reversibly impaired fertility in male rats."
In August 1990, the DPSC considered a review of toxicological data in support of two new formulations. Both formulations were available in a welded plastic labyrinth. The committee supported clearance for both of these products.
At the NDPSC meeting in November 1996, the committee considered a request (unsupported by new data) for reconsideration of the Schedule 6 entry for hydramethylnon, in order to accommodate the low acute toxicity profile of a granular ant bait product containing 7.3 g/kg hydramethylnon.
The committee considered previous scheduling discussions for the compound and the toxicity profile for hydramethylnon. The following extract (in Italics) is from the 1996 NDPSC minutes:
In previous considerations the Committee considered that with the granular formulation these serious testicular effects occurred at levels which could pose a danger to a small male child in a domestic setting. However, it was noted that repeated exposure was required in the animal studies to cause the sustained testicular effect and a question was raised whether a child was likely to be similarly exposed. In relation to this question it was observed that this end-point would not normally be looked for in a standard acute study but which quite clearly was evident in the shortest of the repeat-dose studies. Hence the critical information lacking was at what point is the onset of the effect and whether or not it can be produced by a single or several acute exposures. Limited information available at the May 1989 NDPSC meeting indicated that a single or brief exposure of rats to hydramethylnon at high doses briefly but reversibly impaired the fertility of male rats.
In view of this lack of specific information on testicular atrophy from single high doses which children may access and allowing for species difference, the Committee considered that Schedule 6 remained appropriate.
It was the Committee's view that the Schedule 6 classification would not preclude the registration of this product for domestic use under the terms of the NHMRC criteria guidelines for registering such products, because of the need for the specific "POISON" label warning to the consumer.
Pyriproxyfen, the other active ingredient of the granular ant bait under consideration in this proposal has low toxicity, and was included in Appendix B at the August 1994 NDPSC meeting. The following is a summary of considerations by the committee relating to pyripoxyfen.
The Committee considered toxicological data relating to a submission requesting an exemption from scheduling for pyriproxyfen, a synthetic juvenile hormone analogue which is an insect growth regulator with insecticidal activity against houseflies, fleas, cockroaches and mosquitoes. Pyriproxyfen was intended to be used with an appropriate pesticide (e.g. deltamethrin) to control fleas and cockroaches in domestic, industrial and public health situations.
The Committee noted that pyriproxyfen has low toxicity, is not a skin sensitiser.
The Committee considered that the overall acute toxicity of pyriproxyfen was low, and apart from some liver toxicity at high doses, there was little toxicological concern in repeat-dose studies. The compound was not carcinogenic, mutagenic or teratogenic.
Based on the above toxicity profile, an exemption from scheduling was considered appropriate.
Pre-meeting public submissions
No public submission was received.
Summary of ACCS advice to the delegate
The committee recommended the current scheduling remains appropriate.
Delegate's interim decision
The current Scheduling for hydramethylnon remains appropriate.
An implementation date is unnecessary since no schedule change is proposed.
The reasons for the interim decision comprised the following:
Hydramethylnon is an insecticide used primarily in ant baits. It is included in both Schedule 5 and 6, the Schedule 6 listing based primarily on concerns of possible testicular toxicity in children. The current submission seeks an amendment to the current Schedule 5 entry, which currently allows for an ant-bait enclosed in a plastic labrynth. The requested amendment to the Schedule 5 entry would allow a granular product (combined with pyriproxyfen) to be used as both a professionally applied product (in Schedule 6) and the same material in a 'shaker pack' for domestic use in Schedule 5.
The delegate notes the advice of the ACCS and agrees that there is a need for the granular product to be retained in Schedule 6 for both domestic and professional use. The ACCS noted that only the professional product currently warns against use in areas where children may be present. Retaining the proposed domestic product in Schedule 6 would ensure that a POISON label warning would be more effective than WARNING in order to alert user to the need for care in using the product, particularly around children.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- ACCS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors7;
- Other relevant information.
Public submissions on the interim decision
No public submissions were received.
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.