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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
In May 2015 the delegate received a request to consider creating a new entry for a new agricultural chemical, Bicyclopyrone, in Schedule 6 of the SUSMP with a cut-off to Schedule 5 at 20% or less.
The reasons for the request were:
- An applicant is seeking approval of the new active constituent bicyclopyrone, a member of the 4-hydroxyphenol pyruvate dioxygenase (HPPD)-inhibitor class of herbicides that belongs to the triketone chemical subclass. As a new chemical for AgVet use, it will require consideration by the Delegate/ACCS for SUSMP listing prior to final registration of products containing this active constituent.
- Currently proposed products attached to this application are for agricultural use.
Delegates reasons for referring this to the committee
While the toxicity profile of bicyclopyrone is reasonably straightforward, there is an issue relating to the interpretation of different findings in rabbit developmental toxicity studies. The OCS evaluation report recommends listing in Schedule 6, with provision for products containing 20% or less to be listed in Schedule 5. As this recommendation may be controversial, the delegate has decided to seek ACCS advice on the scheduling proposal.
The delegate asked the committee the following questions:
- The evaluation process for bicyclopyrone involved a co-operative assessment under the Global Joint Review (GJR) process, with input from the US EPA, Canadian PMRA and OCS. There have been some different interpretations of some of the studies between the three agencies, and the ACCS is asked to comment on the significance of these differences.
- While the acute toxicity profile for bicyclopyrone is consistent with SPF criteria for Schedule 5, or even unscheduled, the toxicological endpoint driving the OCS recommendation for listing in Schedule 6 is the finding of urogenital malformations, (seen from doses as low as 10 mg/kg/day) along with skeletal variations, septal variations of the heart and post-implantation loss from 50 mg/kg/day, and septal defects of the heart (i.e. diverticula or abnormal appearance of the septal wall) at 250 mg/kg/day in a study with Himalayan strain rabbits. These findings were not seen in another development toxicity study using a different strain of rabbits. The ACCS is requested to comment on these findings, and whether it agrees that they (along with any other toxicological findings) support Schedule 6 listing.
Figure 1: Structure of bicyclopyrone
The acute toxicity end-points for this chemical are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||Rat (HanRcc:WIST (SPF))||>5000 (no deaths)||Not Scheduled|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat (HanRcc:WIST (SPF))||>5000 (no deaths)||Not Scheduled|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat (HanRcc:WIST (SPF))||>5.2 (no deaths)||Not Scheduled|
|Skin irritation||Rabbit (NZW)||Non-irritant||Not Scheduled|
|Eye irritation||Rabbit (NZW)||Slight irritant||Schedule 5|
|Skin sensitisation (LLNA)||Mouse (CBA/Ca CruBR)||Not sensitising||Not Scheduled|
In the rat and dog the primary effect was an increase in plasma tyrosine levels in oral studies in which the levels were measured. Tyrosine levels not being measured in the mouse or rat studies. The available sub-chronic and chronic oral studies indicate that the rat is the most sensitive species to bicyclopyrone toxicity and the mouse the least sensitive, as demonstrated by NOAEL's in chronic studies of 0.72/0.88 mg/kg bw/d in males/females and 233/242 mg/kg bw/d in males/females respectively.
In rats, chronic oral administration of bicyclopyrone resulted in increased kidney weight, chronic progressive nephropathy (males only) and urine clinical chemistry changes as well as thyroid follicular hypertrophy (males only) and corneal opacity and corneal damage (neovascularisation) at 28.4/25.8 mg/kg bw/d in males/females, with decreased body weight and body weight gain seen at higher dose levels. Corneal opacity was also seen following chronic administration of bicyclopyrone in male and female dogs (at 25 mg/kg bw/d) while eye lesions (keratitis or degeneration of corneal epithelium) were seen in male rats (at 250 mg/kg bw/d) in in short-term dermal study.
The influence of bicyclone's MoA, 4-hydroxyphenyl pyruvate dioxygenase (HPPD) inhibition was investigated for the observed eye, thyroid and kidney effects in the rat, the most sensitive species.
Human cases of hereditary diseases that affect tyrosine metabolism indicates that corneal opacity is observed in human with plasma tyrosine concentration of approximately 3000 nmol/ml, and that this level of plasma tyrosine concentration is not expected to occur during occupational use of bicyclopyrone. In support of this, it is reported in the scientific literature that although humans can develop ocular lesions when tyrosine levels are highly elevated for prolonged periods of time, as seen in humans with the rare metabolic disease tyrosinaemia type II (OMIN 276600), the administration of HPPD inhibitors such as the pharmaceutical compound nitisinone given to children and young adults who have the metabolic disease tyrosinaemia type I (OMIN 276700), at doses which are intended to completely inhibit the HPPD enzyme rarely elevates tyrosine sufficiently to cause ocular lesions. Thus, it is clear that humans are significantly less sensitive than rats to elevated tyrosine levels due to HPPD inhibition and, thus, the observed corneal findings in rats (and dogs) following administration of bicyclopyrone are not considered relevant to humans.
It was demonstrated that bicyclopyrone was not an inhibitor of rat thyroid peroxidase activity in vitro. Furthermore, the effect of bicyclopyrone on liver and thyroid function was also determined in rats in vivo where it was demonstrated that dietary treatment of male rats with bicyclopyrone results in increased tyrosine, decreased T3 and T4 (thyroxine), increased thyroid follicular cell hypertrophy and increased liver weight associated with increased hepatocellular centrilobular hypertrophy and increased hepatic UDPGT activity. Thus, for the observed histopathological thyroid fidings there was evidence that bicyclopyrone affected thyroid hormone homeostasis. Further, due to known species differences in thyroid function, due to the plasma half-life of T4 being shorter in rodents (12 - 24 hours) than in humans (5 - 9 days), there is serum T4 binding with thyroxine-binding globulin in humans which is absent in rodents (meaning there is more unbound T4 in rodents susceptible to conjugation and biliary excretion), and constitutive TSH levels are significantly greater in rodents compared to humans (e.g. nearly 25 times greater in rats), rats are considered more susceptible to such thyroid hormone disturbances than humans. In support of this, it is reported in the scientific literature that in the rat free tyrosine can create conditions in the thyroid analogous to mild iodine deficiency, while the HPPD inhibitor nitisinone has been used for the treatment of type I tyrosinaemia since 1991, with some patients therefore taking the drug for >20 years, and during this time there have been no reports of effects on thyroid function. Thus, it is clear that humans are significantly less sensitive than rats to elevated tyrosine levels due to HPPD inhibition and associated thyroid hormone disturbances that can lead to histopathological changes in the thyroid. Thus, the observed thyroid findings in rats following administration of bicyclopyrone are not considered relevant to humans.
While the applicant proposed that the observed chronic progressive nephropathy associated with prolonged administration of bicyclopyrone to rats is due to elevated tyrosine following HPPD inhibition and are not relevant to man, the OCS does not consider that the limited data and evaluation presented establish that the observed chronic progressive nephropathy definitively occurred (solely) by HPPD inhibition and increased tyrosine levels. Consequently, OCS considers that this kidney finding in male rats is likely relevant to humans.
The observed systemic toxicity occurred at dose levels and exposure duration sufficiently far from the expected exposures associated with use patterns that they would not be consistent with SPF guidance on scheduling.
Bicyclopyrone was not mutagenic or clastogenic in vitro with and without metabolic activation, and in vivo was not clastogenic in rat bone marrow cells and did not induce DNA repair (indicative of DNA damage) in rat liver cells. Thus, the available data indicate bicyclopyrone is not an in vivo genotoxicant. Scheduling is not required for this human health endpoint.
In an 80 week carcinogenicity study in mice, a slight increase in the incidence of bronchiole-alveolar adenoma in the lung above the laboratory historical control range (36%, HC 24 - 30%), was seen near the limit dose of 1000 mg/kg bw/d (i.e. 940 mg/kg bw/d) in the absence of treatment related non-neoplastic change in the lung or bronchio-alveolar carcinoma. Additionally, this dose level exceeded the maximum tolerated dose (MTD) as shown by body weight gain being decreased for the duration of the study (↓13% to↓29%). Thus, this benign tumour finding in males does not provide robust and reliable evidence of a carcinogenic potential. No increased incidence of tumour findings was seen in female mice.
In the 104-week carcinogenicity phase of a dietary study in male rats, at 500, 2500 and 5000 ppm (equivalent to 0.28, 141 and 280 mg/kg bw/d ) a slight increase was seen in squamous cell papilloma of the cornea was seen in 2 males (4% animals) at each dose level along with squamous cell carcinoma of the cornea in 1, 1 and 3 males (2%, 2% and 6% of animals) respectively that was not statistically significant but was absent in control animals. These findings were seen in the presence of ocular opacity, keratitis and regenerative hyperplasia of the cornea, and as discussed above under 'Repeat dose toxicity', rats are significantly more sensitive to the effects of HDDP inhibitors than humans, and that the ocular keratitis and regenerative hyperplasia observed in rats is directly linked to the resulting highly elevated plasma tyrosine. Furthermore, the progression of ocular keratitis and regenerative hyperplasia in the rat cornea to corneal cell tumours at high levels of tyrosine, while not directly demonstrated, may further suggest a role of tyrosine and not bicyclopyrone in the development of these tumours. Consequently, overall, it is considered that the observed low incidences of corneal cell tumours in male rats only are unlikely to be relevant to humans. No increased incidence of tumour findings was seen in female rats.
Therefore, it is considered that no tumours relevant to humans were seen in male and female rats and mice, and therefore scheduling is not required for this human health endpoint.
Reproduction and developmental toxicity
Similar to findings in repeat dose studies, in a 2-generation dietary study in rats ocular effects including corneal opacity and vascular keratitis were seen in parental animals with decreased body weight and body weight gain also seen at higher dose levels. Ocular effects (corneal opacity, corneal roughness and vascular keratitis) and decreased bodyweight and bodyweight gain were also seen in offspring, in the presence of parental toxicity. In F1 parental males only, a significant increase in the number of abnormal sperm and a decrease in sperm velocities was seen at high dose levels in the presence of general toxicity (decreased body weight) in the absence of an effect on reproductivity. Consequently, bicyclopyrone is not considered a reproductive toxicant. Scheduling is not required for this human health endpoint.
Developmental toxicity studies on bicyclopyrone were performed in Wistar rats and in two species of rabbit, the New Zealand White and Himalayan, whose dose levels were determined from developmental dose-range finding studies.
In rats, skeletal variations (increased incidence of full or rudimentary supernumerary ribs, pelvic girdle malposition and long costal cartilage 11) were observed in the presence of maternal toxicity at doses of 100 mg/kg bw/d, the lowest dose tested. The skeletal variations while treatment related were considered a secondary non-specific consequence of the observed marked maternal toxicity (i.e. a corrected body weight gain decrease of 11% at GD 21, with decreases in body weight gain of 15 - 83% from GD 6 - 11). Thus, bicyclopyrone was not considered a developmental toxicant in rats.
In New Zealand White rabbits, evidence of foetotoxicity included an increased incidence of two skeletal variations (13th full rib, 27th pre-sacral vertebrae) in the absence of maternal toxicity at 10 mg/kg bw/d. While these increases in the 13th full rib (57.2% per litter) and 27th pre-sacral vertebrae (27.2% per litter) were outside of the upper laboratory historical control range (45.7% and 15.5% per litter respectively) and are treatment related OCS considers that the change in the incidence of these common variants (as demonstrated by the incidence seen in the historical control database) alone do not warrant classification as a hazard for developmental toxicity. Furthermore, it was noted that no additional skeletal findings, or visceral findings, were seen at increased dose levels in the presence of severe maternal toxicity (i.e. at a dose level producing mortality/moribundity in does). Thus, bicyclopyrone was not considered a developmental toxicant in NZW rabbits.
Two studies were available in Himalayan rabbits, one with dose levels of 0, 10, 50 and 250 mg/kg bw/d (study 1) and the other with dose levels of 0, 1, 10 and 250 mg/kg bw/d (study 2). Taking the findings together allowed a more informed view of potential spontaneous rates in foetuses and a more comprehensive dose response for maternal and foetal findings to be established.
In study 1, the maternal NOAEL was established at 50 mg/kg bw/d based on macroscopic findings in the stomach wall of females and a sustained absence in body weight gain (i.e. daily decreases of -1.51 to -8.12 g) from GD 7 - 13 at 250 mg/kg bw/day the highest dose tested. At 10 mg/kg bw/d the lowest dose tested, and in the absence of maternal toxicity, an increased incidence was seen in urogenital malformations (in 2% of foetuses, 14% of foetuses) that were absent in control animals from both studies along with skeletal variations. Also in the absence of maternal toxicity, at 50 mg/kg bw/d a treatment related and toxicologically significant increase was seen in septal variations of the heart (in 20% foetuses and 53% litters, with a highest incidence of 16% and 68% respectively seen in study 2) and in post-implantation loss (20.3% of implantation sites with a mean of per litter of 1.4, compared to upper historical control values of 15.9% and 1.2 respectively).
In study 2, the maternal NOAEL was established at 10 mg/kg bw/d based on two mortalities and signs clinical signs of toxicity along with signs of stomach irritation in two does at 250 mg/kg/d. At 10 mg/kg bw/d in the absence of maternal toxicity, and consistent with the findings in study 1 at the same dose level, urogenital malformation were seen (in 2% of foetuses and 5% of litters) along with skeletal variations.
Therefore, taking the findings from the two developmental studies in Himalayan rabbits together, it is considered that urogenital malformations were seen from 10 mg/kg/day along with skeletal variations, septal variations of the heart and post-implantaion loss from 50 mg/kg/day, and septal defects of the heart (i.e. deverticula or abnormal appearance of the septal wall) at 250 mg/kg/day in this study. Maternal toxicity was seen from 50 mg/kg bw/d, so the urogenital malformations and skeletal findings at 10 mg/kg bw/d were seen in the absence of maternal toxicity, while OCS considers that the observed septal variations and defects along with post-implantation loss seen in the presence of maternal toxicity were unlikely to be a secondary non-specific consequence of such (i.e. are considered evidence of a developmental toxicity potential). Thus, bicyclopyrone was considered to be a developmental toxicant in Himalayan rabbits and scheduling is required for this human health endpoint.
However, while skeletal findings were seen in Wistar rats and NZW rabbits (a secondary non-specific consequence of maternal toxicity in rats) bicyclopyrone was not considered to be a developmental toxicant in this species/strain. Thus, while the findings in one species do not warrant Schedule 7, although bicyclopyrone was only considered a developmental toxicant in one of two rabbit strains, Schedule 6 is considered more appropriate than Schedule 5 due to the nature of the observed foetal findings; visceral changes (urogenital malformations and septal variations in the heart) and post-implantation loss.
Other toxicology endpoints
Bicyclopyrone was not a neurotoxicant in male and female rats in an acute oral neurotoxicity study up to and including the limit dose (2000 mg/kg bw). In a subchronic dietary study, decreases in mean brain weight were seen in males only at 4 (8%), 35 (8%) and 336 (11%) mg/kg bw/d that were considered to be due to a high mean value in control males (2.38 g) when compared to the historical control range means (2.2 and 2.0 g from two studies), and it was noted that with the exception of 1 male in the 500 ppm dose group all brain weights in males at 50 and 500 ppm were within the historical control range (1.96 - 2.29 g). While at 5000 ppm, the brain weight in only 2 of the 5 males was lower than the minimum historical control value. Therefore, and noting an absence of an effect on functional parameters or histopathological changes to the brain, this finding in one sex is not considered to demonstrate an adverse effect and bicyclopyrone is not considered to be a neurotoxicant. Scheduling is not required for this human health endpoint.
Bicyclopyrone was not immunotoxic in female mice. Scheduling is not required for this human health endpoint.
Observation in humans
No information was provided.
At this time, the proposed agricultural use of bicyclopyrone is professional only, and so is not expected to result in general public (i.e. domestic) exposure. Spray drift considerations have not been considered.
Bicyclopyrone has been approved for use by Canada PMRA for agricultural use.
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Bicyclopyrone is not currently specifically scheduled.
Bicyclopyrone has not been previously considered for scheduling; no scheduling history is available.
Public pre-meeting submissions
Two public submissions were received. One submission agreed with the OCS assessment that in the studies assessed the skeletal variations, urogenital malformations and presence of significant maternal toxicity that occurred are not a dose-dependent effect of bicyclopyrone. The other provided comment on the OCS report to which the OCS replied by highlighting that the public submission did not take into account other abnormalities that occurred in the studies assessed.
The OCS considers the post-implantation loss and septal variations and defects of the heart at 250mg/kilo bw/d to be significant issues and are dose-dependent and therefore toxicologically significant. The OCS maintained their recommendation.
The public submissions are available at Public submissions on scheduling matters.
Summary of ACCS advice to the delegate
The Committee recommended a new Schedule 6 entry be created for bicyclopyrone except when in Schedule 5, for when preparations contain 20% or less of bicyclopyrone.
The committee recommended an implementation date of 1 February 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.
The reasons for the recommendations comprised the following:
- Foetoxicity or potential for developmental toxicity consistent with Schedule 6.
Delegate's interim decision
Schedule 6 - New Entry
BICYCLOPYRONE except when included in Schedule 5.
Schedule 5 - New Entry
BICYCLOPYRONE in preparations containing 20 per cent or less of bicyclopyrone.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.
The proposed implementation date is 1 February 2016. An early implementation date is proposed to facilitate clearance of the active ingredient by the APVMA and prior to registration of a product containing bicyclopyrone.
The reasons for the interim decision comprised the following:
The toxicological profile of bicyclopyrone is well characterised in the OCS evaluation report. While the low acute and chronic toxicity profile suggests that scheduling is not necessary, the developmental and fetotoxicity potential of bicyclopyrone suggest that it should be listed in Schedule 6, even though this toxicity is not consistent across relevant tests in different species and strains. The delegate notes that this is consistent with the advice provided by the ACCS. The delegate also accepts ACCS advice that the dose-related nature of the developmental toxicity allows for a product containing 20% or less of bicyclopyrone to be down-scheduled to Schedule 5, with adequate Margin of Exposure (MoE) estimates associated with its proposed uses. The delegate also notes ACCS comment that findings of unilateral kidney loss in some dams in the Himalayan rabbit study suggests a hereditary response, rather than a response related to bicyclopyrone. Since the OCS report drew attention to some developmental toxicity other than the urogenital effects, the delegate affirms that the Schedule 6 listing for bicyclopyrone remains appropriate.
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 factors4;
- Other relevant information.
Public submissions on the interim decision
One submission was received. The submission referred to the toxicity studies that were assessed in the OCS Health Report and wished to draw specific attention to the cardiac defects and post-implantation loss in Himalayan rabbits. The conclusions in the submission were that the toxicity issues related to the noted defects in Himalayan rabbits were restricted to the highest dose (250 mg/kg), whereas the observed defects in the lower doses were only incidental.
An edited version of the submission is 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 the information received does not overcome the reasons behind the interim decision. The delegate notes that the submission primarily addresses the cardiovascular defects and implantation losses noted in both studies in the Himalayan rabbit, and argues that the effects are only of significance at the highest dose, where there was evidence of maternal toxicity. However, there is some evidence that the dose-response may not be confined to only the highest dose, and the finding of such lesions in the heart that are possibly dose-related adds weight to the ACCS advice that Schedule 6 is a more appropriate listing, with an exemption to Schedule 5 at 20% based on estimates of the margin of exposure.
The delegate has confirmed that the reasons for the final decision are therefore in keeping with those for the interim decision.