Regulation (EU) No 528/2012 concerning the making available on the market and use of biocidal products
Evaluation of active substances
Assessment Report
Cholecalciferol
PT 14 (Rodenticides)
January 2018
Sweden
Cholecalciferol Product-type PT 14 December 2018
CONTENTS
1 STATEMENT OF SUBJECT MATTER AND PURPOSE ...... 3
1.1 Procedure followed ...... 3 1.2 Purpose of the assessment report ...... 5
2 OVERALL SUMMARY AND CONCLUSIONS ...... 6
2.1 Presentation of the Active Substance ...... 6 2.1.1 Identity, Physico-Chemical Properties & Methods of Analysis ...... 6 2.1.2 Intended Uses and Efficacy ...... 9 2.1.3 Classification and Labelling ...... 10 2.2 Summary of the Risk Assessment ...... 11 2.2.1 Human Health Risk Assessment ...... 11 2.2.2 Environmental Risk Assessment ...... 22 2.2.3 Assessment of endocrine disrupting properties ...... 36 2.3 Overall conclusions ...... 37 2.4 List of endpoints ...... 37
Appendix I: List of endpoints ...... 38
Chapter 1: Identity, Physical and Chemical Properties, Classification and Labelling . 38 Chapter 2: Methods of Analysis ...... 41 Chapter 3: Impact on Human Health ...... 42 Chapter 4: Fate and Behaviour in the Environment ...... 47 Chapter 5: Effects on Non-target Species ...... 50 Chapter 6: Other End Points ...... 51
Appendix II: List of Intended Uses (as proposed by the applicant with eCA remarks and conclusions in the last column)...... 52
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1 STATEMENT OF SUBJECT MATTER AND PURPOSE
1.1 Procedure followed This assessment report has been established as a result of the evaluation of the existing active substance cholecalciferol in product-type PT 14 (Rodenticides), submitted under Article 11 of the Biocidal Products Directive 98/8/EC, with a view to the possible approval of this substance. The evaluating Competent Authority accepted the received dossier on cholecalciferol as complete for the purpose of the evaluation on June 28th, 2013. The dossier has then been be assessed under Regulation (EC) no 528/2012 (BPR) in accordance with the transitional provisions in Article 90 of the BPR. In spite of the BPR requirements to submit data, which enable the assessment of the exclusion criteria, the dossier had data-gaps for carcinogenicity and reproduction toxicity. The applicant had submitted arguments for extensive waiving. The strategy to handle this situation was discussed at an early-working group meeting (WG III/2014) as well as at the 57th CA-meeting. Both committees concluded that it would not be justified to require more testing with this substance. Similarly, the information to assess the PBT-properties was not considered sufficient. Even here, extensive discussions took place. At an early-working group meeting (WG III 2014) it was concluded, that additional information on persistency in soil should be requested. A final version of the report of the requested study was received in October 2016. At WG I 2017 the results of this study were discussed, after consultation with the ECHA PBT EG. The soil degradation study (using tritiated substance) helped to establish that cholecalciferol is not persistent. At WG III 2014, it was also decided that more testing on bioaccumulation should be pending, to await the results of the degradation studies and due to methodological difficulties. As the substance is not regarded P, more testing on bioaccumulation is not considered necessary.
In conclusion, the eCA has accepted the available data package due to the following reasons:
1) The risk from human exposure is negligible: The substance is naturally occurring, it is endogenously produced and is essential for human health; hence, there is a physiological concentration range that is well tolerated by humans. EFSA has derived a tolerable upper intake level (UL) of 100 µg/day for adults and 50 and 25 µg/day in children and infants, respectively, levels below which only beneficial effects of vitamin D are expected. Toxicity is observed in animal studies at doses above these levels, but information available indicates that the potential risk for human health from the rodenticide use considered in this assessment is low. The estimated exposure of an operator placing rodenticide bait is <11 µg/day which is within current food and supplement ranges (EFSA, 2012). EFSA estimated in 2012 that the upper 95th percentile of intake in adults from food and supplements to be 24 µg/day. This means that even if the estimated operator exposure is added to the estimated supplement and food exposure, the exposure is well below the UL and is comparable to dose levels that can be produced from exposure to the sun. Secondary exposure of humans is considered rare when rodenticides are used in bait boxes (or covered and inaccessible). Therefore, exposure from this biocidal use is not expected to contribute significantly to the vitamin D exposure resulting from intake of food and supplements.
2) Due to difficulties in performance and interpretation of studies for bioaccumulation with cholecalciferol, the requirement of additional data for interpreting the B criterion is not considered useful. Cholecalciferol is ubiquitously occurring in plants, animals and fungi in the aquatic as well as the terrestrial environment as a result
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of endogenous synthesis. Additionally, the majority of the vertebrate taxa have systems for regulating the levels of cholecalciferol and the physiologically active metabolites, which would hamper the interpretation of bioaccumulation tests on cholecalciferol. However, this regulatory system only works at normal/endogenous doses and cholecalciferol functions as a toxicant/rodenticide at high doses.
3) There is a recognized need for effective rodenticides. There are few effective active substances approved for PT 14 use and those available mostly belong to the same class of substances, i.e. anti- vitamin K coagulants. Considering the existing problems with the hazardous properties, the meeting of the exclusion criteria and resistance of target organisms to some of these AVKs, it may be advantageous to use cholecalciferol that exerts its effects via a different mode of action.
4) Applicants need to be treated equal: The AVK rodenticides that were approved under the BPD were also subject to extensive waiving, including a subchronic toxicity study (90-days) in rodents, chronic toxicity studies in rodents, carcinogenicity studies in rodents, a teratogenicity study in the second species (normally in rats) and a two-generation reproduction (fertility) toxicity study (TNsG Chapter 1.4.1, 2003). However, the ecotox-data package has been waived for Cholecalciferol, which is not the case for AVK rodenticides. Even this was discussed at an early working group meeting (WG III 2014) and at WG I 2017, and was considered acceptable. The most important argument is that the applicant has not applied for uses that affect the aquatic environment.
5) Animal welfare: Article 90(2) BPR states “Every effort shall be made to avoid additional testing on vertebrates and to avoid causing delays to the review programme laid down in Regulation (EC) No 1451/2007 as a result of these transitional arrangements” The exclusion criteria in Article 5(1) of the Regulation trigger a need for a decision on whether or not the intrinsic properties of an active substance fulfil criteria for classification for CMR properties in category 1. The data currently available on cholecalciferol is not considered sufficient for an adequate assessment of classification with respect to C and R properties. Nevertheless, the estimated exposure during the intended use of cholecalciferol as a rodenticide is low and the contribution from this source to the overall exposure (endogenous and from food supplementation) is below the tolerable upper limit for humans that is proposed by EFSA. It is thus reasonable to assume that these exposure levels do not raise any concern for carcinogenicity, fertility or developmental effects; hence, further animal testing is not considered justified for the purpose of risk assessment. Therefore, in light of article 90(2) and the general urge of the BPR to minimise animal testing, the lack of data on classification should be handled by other means than to request further testing for the sole purpose of classification.
A proposal for classification and labelling according to Regulation (EC) No 1272/2008 (CLP Regulation) was submitted to ECHA in January 2016. The CLH dossier was discussed during the 39th RAC meeting in December 2016. With respect to hazard classes relevant for the exclusion criteria, RAC considered data available on germ cell mutagenicity sufficient to conclude criteria for classification not to be fulfilled. However, for hazard classes reproductive toxicity and carcinogenicity, no classification was proposed on the basis that the data available was not sufficient to conclude whether or not criteria for classification were fulfilled1. This is further discussed in relevant sections of 2.2.1.
1 RAC Opinion, ref CLH-O-0000001412-86-144/F Available at https://echa.europa.eu/documents/10162/fcc1958c-745f-ec68-eb38-
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On April 15th, 2016, the evaluating Competent Authority submitted to the Commission and the applicant a copy of the evaluation report, hereafter referred to as the competent authority report. The applicant was given the opportunity to provide written comments on the assessment report prior to its submission to the Agency.
At the first discussion by the BPC in June 2017 (BPC 21), the members of the BPC came to the conclusion that cholecalciferol is a candidate for substitution as no safe use could be demonstrated, due to the risk for primary and secondary poisoning. Consequently, a public consultation had to be initiated by ECHA after the BPC meeting. The results of the public consultation were considered in the updated opinion and the substance was discussed again in December 2017 at BPC 23.
At a late stage of the evaluation (November 2017) the ED-criteria were published in Regulation (EU) No 2017/2100, and it became clear that the criteria will become applicable before a decision can be taken for cholecalciferol. Therefore, the eCA identified cholecalciferol as fulfilling the criteria and thus falling under the exclusion criteria of Art. 5(1) of the BPR. This statement was made only few weeks before the second discussion in the BPC (BPC 23) took place and at a point in time where the guidance on ED criteria had not yet been published. However, the members of the BPC agreed with the eCA that Cholecalciferol meets the newly published criteria.
1.2 Purpose of the assessment report The aim of the assessment report is to support the opinion of the Biocidal Products Committee and a decision on the approval of Cholecalciferol for product-type PT 14, and, should it be approved, to facilitate the authorisation of individual biocidal products. In the evaluation of applications for product authorisation, the provisions of Regulation (EU) No 528/2012 shall be applied, in particular the provisions of Chapter IV, as well as the common principles laid down in Annex VI. For the implementation of the common principles of Annex VI, the content and conclusions of this assessment report, which is available from the Agency website, shall be taken into account. However, where conclusions of this assessment report are based on data protected under the provisions of Regulation (EU) No 528/2012, such conclusions may not be used to the benefit of another applicant, unless access to these data for that purpose has been granted to that applicant.
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2 OVERALL SUMMARY AND CONCLUSIONS
2.1 Presentation of the Active Substance Cholecalciferol (vitamin D3) is one of the two main forms of vitamin D. The other main form is ergocalciferol (vitamin D2) and they differ only by their side chains on the sterol structure. The active substance considered in this assessment is cholecalciferol (vitamin D3) only; however, the data used for the assessment of cholecalciferol includes studies on vitamin D2, vitamin D3 and its metabolites. Where the term “Vitamin D” is used without further definition, it refers to either or all of the above-mentioned forms. Vitamin D is an essential vitamin for vertebrates, controlling calcium and phosphorous homeostasis. Cholecalciferol is continuously produced in the skin from cholesterol with help from sunlight and is therefore naturally present in our bodies. Vitamin D is also supplied by intake of vitamin D-containing food such as fish, egg yolk and milk. The endogenous production of vitamin D in humans is low during the winter season within the EU area and therefore extra sources of vitamin D (e.g. fortified food and other types of vitamin D supplements) may be needed for some individuals to avoid problems such as rickets. Consequently, vitamin D is naturally present in the human body. Vitamin D is important for calcium homeostasis and skeletal bone ossification processes but it also has other important physiological functions such as being involved in renin production and insulin production (discussed in EFSA scientific opinion, 2012). Vitamin D is thus essential for humans but endogenous levels differ between individuals due to differences in age, exposure to sunlight and dietary intake. The human health hazard assessment considers effects resulting from exposure levels within as well as outside of the physiological range. Vitamin D is not only essential for humans, but is also used as a vitamin or for other functions in many other organisms. These include animals, such as mammals (comprising rodents) or fish (who are thought to accumulate high levels from their food web, especially planktonic microalgae), plants (from microalgae to higher vascular plants), and fungi. Animals and plants synthesise vitamin D3 from cholesterol and plant sterols, respectively. Fungi synthesise vitamin D2 from ergosterol. Commercially sold fodder for domestic animals is typically enriched in vitamin D3 for health purposes. Sterol compounds, such as cholesterol, are used as geochemical biomarkers in sedimentary records of lakes and oceans. Researchers use it for instance to distinguish whether the organic matter is from terrestrial or aquatic plants.
2.1.1 Identity, Physico-Chemical Properties & Methods of Analysis
2.1.1.1 Identity CAS-No. 67-97-0 EC No. 200-673-2 Other No. (CIPAC, CLP index #: 603-180-00-4 ELINCS) IUPAC Name (3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol CA Name (1S,3Z)-3-[(2E)-2-[(1R,3aS,7aR)-1-[(1R)-1,5- dimethylhexyl]octahydro-7a-methyl-4H-inden-4- ylidene]ethylidene]-4-methylenecyclohexanol Common name, Cholecalciferol (ISO common name) synonyms Vitamin D3 (synonym) Colecalciferol (synonym)
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Cholecalciferolum (synonym, Ph. Eur.2 7.0) Structural formula
Isomeric composition Cholecalciferol is defined as a pure enantiomer (see further the specification under impurities) Molecular formula C27H44O Molecular weight 384.64 (g/mol) Purity of a.s. min. 97% (includes also any pre-cholecalciferol present; see further information below) Cholecalciferol must comply with the Ph. Eur.* 7.0 (01/2008:0575 corrected 6.5) with respect to purity, impurity content and specific optical rotation Impurities As specified in Ph. Eur.* 7.0 (the identity of the impurities are also given in the Confidential document IIII-A2.8.1- 2.8.5):
Impurity A: max 0.1% Unspecified impurities (B to E): max 0.10% each Total impurities: max 1.0% Specific optical rotation (in aldehyde-free alcohol): +105.0° to + 112.0°
The representative sources for this application have provided information that supports the compliance with Ph. Eur.* 7.0 Further information A reversible isomerisation to pre-cholecalciferol (previtamin D3) takes place in solution, depending on temperature and time. The activity is due to both cholecalciferol and pre- cholecalciferol (reference Ph. Eur.* 7.0). This information is relevant for the analysis of cholecalciferol (which is done in solution) to show compliance with the Pharmacopoeia.
2 * European Pharmacopoeia (01/2008:0575 corrected 6.5)
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Pre-cholecalciferol Additives No additives Representative biocidal Harmonix Rodent Paste® and Selontra® (ready to use baits products containing nominally 0.075% pure cholecalciferol)
2.1.1.2 Physico-Chemical Properties All physico-chemical properties were determined for a batch of cholecalciferol with a purity of 99.6%. Cholecalciferol is a white solid powder with no odour. It melts at 83°C and 20 decomposes before boiling with an onset at 148°C. The relative density (D4 ) was determined as 1.02 and the water solubility was determined as less than 0.5 µg/L at 20°C in purified water (pH 6.5-7.1) based on the LOQ of the analytical method used (LC- MS/MS). Cholecalciferol does not dissociate under environmentally relevant pH range (pKa for the hydroxy group is estimated as 16.5). The vapour pressure is 4 x 10-5 Pa at 20 °C and 6 x 10-5 Pa at 25 °C (extrapolated values from experiments in the range 49-74°C) and 3 -1 the Henry’s law constant is calculated as 30.77 Pa.m .mol . The Log Pow is >5.0 in water in the neutral pH range which indicates that cholecalciferol may bioaccumulate. The solubility of cholecalciferol is greater than 250 g/L in all the tested organic solvents (n- heptane, xylene, 1, 2-dichloroethane, methanol, acetone and ethyl acetate). Cholecalciferol is not highly flammable and it does not self-ignite below 400°C. It is also not considered to be an explosive or oxidizing based on a structural assessment. There are no indications, based on experience in use, that cholecalciferol reacts with any common container material.
2.1.1.3 Analytical methods Acceptable analytical methods with respect to validation data were provided for all required matrices.
The content of cholecalciferol and related impurities in the technical material is determined in accordance with the European Pharmacopoeia (Ph. Eur.* 7.0) by normal phase HPLC- UV.
The content of cholecalciferol in the representative formulations are determined by normal phase HPLC-UV or reversed phase HPLC-UV. The entity determined by the methods is the sum of cholecalciferol and pre-cholecalciferol (see 2.1.1.1 above) which is then expressed as cholecalciferol.
For the residue analytical methods parent cholecalciferol is considered as the only relevant residue to monitor except in animal and human body fluids and tissues for which the metabolite 25(OH)D is also added to the residue definition.
Acceptable LC-MS/MS methods (validated for two ion transitions) have been provided for cholecalciferol in soil, water and body fluids and tissues. The LOQs of the methods as validated are 0.05 mg/kg, 0.05 µg/L and 0.05 mg/kg for soil, water and body fluids and
8 (54) Cholecalciferol Product-type PT 14 January 2018 tissues respectively. Even if there is not sufficient acceptable data available to fully derive an endpoint to which the analytical method for surface water must comply, the LOQ of 0.05 µg/L is considered sufficient as there are no indications of adverse effects at or below the water solubility (<0.5 µg/L).
The analytical method for body fluids and tissues was only validated for the parent compound as there are numerous diagnostic bioassay kits commercially available for the analysis of the metabolite 25(OH)D and these are used by accredited laboratories involved in human screening programs. The waiver for the metabolite is considered acceptable.
For the analysis of residues in air, an acceptable waiver was submitted based on expected negligible exposure (i.e. Vp of a.i. is 4 x 10-5 Pa at 20°C and it is not used in spraying applications).
In addition to these methods, a LC-MS/MS method (two ion-transitions) validated for food of plant origin was submitted to address the general requirement previously set for rodenticides to have a method that can be used in the case of suspected contamination of food. The validated LOQ is 0.05 mg/kg. It should be noted that the method is not validated for food of animal origin but for that purpose the method for body fluids and tissues can be used (validated for meat at 0.1 mg/kg). Given that no MRL is anticipated to be required from the use envisaged and as any cholecalciferol in food may originate from other sources (e.g. food additives) further data has not been requested.
2.1.2 Intended Uses and Efficacy The assessment of the biocidal activity of the active substance demonstrates that it has a sufficient level of efficacy against rats and mice and the evaluation of the summary data provided in support of the efficacy of the accompanying products, establishes that the products are efficacious in rats (brown rat) and mice.
The use of cholecalciferol as a rodenticide could cause suffering of vertebrate target organisms. Cholecalciferol produces a lethal hypervitaminosis and the onset of mortality in the rodent is delayed (occurs generally 3-10 days after baiting with cholecalciferol). Clinical signs of cholecalciferol toxicity prior to death include reduced eating, loss of bodyweight, hunched posture, piloerection, oligaemia, anergia and hypothermia. However, rodent control is needed to prevent disease transmission, contamination of food and feeding stuffs and structural damage. It has been recognised during the evaluation of the anti-vitamin K rodenticides (AVKs) that such substances do cause suffering in rodents. However, it was considered that it was not in conflict with the requirements of Article 5.1 of Directive 98/8/EC ‘to avoid unnecessary pain and suffering of vertebrates’, as long as effective, but comparably less painful alternative biocidal substances or biocidal products or even non-biocidal alternatives are unavailable. It is therefore suggested by the eCA that similar arguments also apply to cholecalciferol when considering the requirements of Article 19.1 of Regulation 528/2012.
The use evaluated is professional and non-professional control of mice and rats in and around buildings. The exposure calculations were made for paste bait in bait-boxes or covered and protected bait points of a similar level of protection, placed where no food or feed item contamination is expected. In addition, in order to facilitate the work of Member States in granting or reviewing authorisations, the intended uses of the substance, as identified during the evaluation process, are listed in Appendix II.
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2.2 Summary of the Risk Assessment
2.2.1 Human Health Risk Assessment
2.2.1.1 Hazard identification Several core studies have been waived on the basis that existing information is sufficient to address the data requirements of the legislation and conducting further studies would therefore be scientifically unjustified.
The data requirements waived include: 1. toxicokinetic studies 2. a 90 day study in a non-rodent (and subchronic studies via inhalation and the dermal route) 3. a two-generation fertility study 4. developmental toxicity studies 5. long-term/carcinogenicity studies The majority of information referred to by the applicant consists of publications of limited quality in terms of methodology and presentation of data. This data is yet considered sufficient for establishing an effects assessment upon which reference values for the risk assessment can be derived. Moreover, according to guidance for biocides, waiving of studies can be accepted if the exposure from the representative product(s) is expected to be low. The estimated user exposure resulting from the intended use of the representative product (in bait boxes) is within the range used for food supplementation. Even if the exposure estimated for the representative use is added to the estimated exposure from food and food supplements, the exposure level would still be comparable to endogenous levels produced following exposure to sun during summer. Therefore, from a risk perspective, these studies are not necessary. Waiving of the studies above and of any further tests investigating endocrine properties was discussed at a HH early working group meeting in June 2014 and at a CA meeting in September 2014. Both meetings supported the proposal to accept waiving of studies based on scientific grounds.
Absorption, distribution, metabolism and excretion: there is no robust study performed in accordance with the principles of GLP and OECD 417 guideline available. Nevertheless, since cholecalciferol is used for food supplementation there is an abundance of human data available in the open literature investigating effects following exposures in the supplement range. When ingested, cholecalciferol is rapidly absorbed from the small intestine and transported via chylomicrons and lymph to the liver where it is rapidly metabolised to 25- hydroxycholecalciferol. The metabolite is transported in the blood bound to vitamin D Binding Protein (DBP) and a portion of 25-hydroxycholecalciferol is further metabolised in the kidney to 1,25-dihydroxy vitamin D3, which is the hormonally active metabolite. Cholecalciferol is highly lipophilic and distributed to adipose tissue. The mode of action of cholecalciferol, for example the regulation of blood and tissue calcium levels, is mediated primarily via specific nuclear vitamin D receptors (VDR). These VDRs are expressed in various tissues including testes and skin (keratinocytes). The half-life of low doses of cholecalciferol in plasma is 4 to 5 days and the half-life of 1,25-dihydroxy vitamin D3 is approximately 14 hours. Metabolite 25-hydroxycholecalciferol declines with a half-life of 15 to 30 days. The metabolites described above are generally considered the major metabolites of cholecalciferol and are thus the most well studied. However, other metabolites can also exist. Vitamin D is excreted in the form of metabolites, primarily in faeces (bile) and to a lesser extent in urine. There is no information on the dermal absorption of cholecalciferol available but dermal absorption of the formulations tested was low (<1%).
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In summary, the information available for this endpoint is very limited. However, given the essentiality of vitamin D for humans, and that data suggest a widespread distribution of receptors and metabolizing enzymes in the body, the information is sufficient to conclude that the substance is absorbed and widely distributed in the human body. The reference values used for risk assessment are based on human data (see Doc IIA, sections 3.12-3- 14), thus information on oral absorption in humans is needed to convert these values into systemic values for use in the risk assessment of dermal and inhalation exposures. Since reference values are based on human data, information on the extent of oral absorption in rats is not needed thus conducting a guideline study to investigate the toxicokinetics in rats is not justified for the purpose of this review. Data available for “healthy” patients and patients with intestinal disorders indicate an absorption range from 0 to 99% (55-99% in the “healthy” group and 0-(28) 48% in the other). With such broad range, it is not possible to definitely conclude on the oral absorption in humans but 50% is considered a reasonable conservative estimate when converting oral exposure to systemic. If secondary exposure of children via hand to mouth transfer needs to be estimated, a default value of 100% must be used for the formulation.
Acute toxicity: acute toxicity studies indicate that cholecalciferol is acutely toxic, can cause death and gives rise to clinical signs potentially indicating neurotoxicity. The LD 50 values in rats were 35 mg/kg and 47 mg/kg in males and females respectively for the oral route, 61 and 185 mg/kg for the dermal route and 0.12 -0.38 mg/L via inhalation. Classification and labelling for acute toxicity is therefore warranted. The potentially neurological signs observed could result from hypercalcemia, acute neurotoxicity or represent a general toxic response. Since no biochemical analyses were made in the acute oral toxicity studies, it is not possible to determine whether or not the effects observed were secondary to hypercalcemia. The pathological examinations of animals that died during the observation period or were killed after the observation period showed hypercalcinosis of heart, spleen, kidney and blood vessels at a dose of 25 mg/kg bw and above. Since the effects were observed within the same dose range as mortality occurred, the clinical signs are considered to result from a generalised toxicity rather than a specific target organ toxicity. Therefore, they are taken into account in the classification for acute oral toxicity.
Irritation: Cholecalciferol is not irritating to skin or eyes.
Skin sensitisation: The results of a LLNA study indicate a dose-related increase of the stimulation index, the marker of a sensitizing potential in this type of test. Due to concomitant toxicity at the top dose, the result at this dose level (i.e a SI above the threshold for a positive response) needs to be discounted. The SI at the next highest dose border on qualifying as a positive result (2.6, which rounded to one figure, equals the threshold of ≥ 3 in OECD TG 429). For these situations, the guideline recommends that other relevant information, e.g. structural relationship with known sensitizers, information on excessive irritation and the nature of any dose-response are taken into consideration. No alert for sensitisation is raised in (Q) SAR analysis using the OECD Toolbox and there are no indications of massive irritation in the LLNA study or in the skin irritation study performed. The dose-related increase in SI seems to level off, as there is little difference between doses of 0.1 and 0.25%. Moreover, cholecalciferol is endogenously produced in the skin thus immunological reactions following skin contact are not expected. Some support for a sensitizing potential can be found in case reports describing reactions in healthy volunteers but it is noted that these volunteers were exposed to derivatives of cholecalciferol. Since the substance is endogenously produced in the skin, it seems reasonable to expect the same tolerance if the substance penetrates the skin. Therefore, cholecalciferol is not considered to be a skin sensitizer.
Repeated dose toxicity: From the data submitted to address this endpoint, i.e. human data summarised in the EFSA review and animal data for rats, hypercalcemia can be
12 (54) Cholecalciferol Product-type PT 14 January 2018 identified as the critical effect for the NOAEL. In the EFSA scientific opinion as well as in a review by the Institute of Medicines of the National Academies in USA (IoM), the NOAEL for hypercalcemia in humans was set at 250 µg/day (or 4.2 µg/kg bw/day for an adult of 60 kg). In rats, adverse effects of cholecalciferol, i.e. hypercalcemia co-occurring with renal and adrenal changes, were observed in the 28 day as well as in the 90-day study in rats. Mortality was observed at or above a dose level of 10 mg/kg bw/day in the 28-day study. Hypercalcemia occurred at doses at and above 0.06 mg/kg bw/day (90-day study). At this level, calcium was only modestly increased (4%) and this effect could thus be considered a NOAEL rather than a LOAEL for hypercalcemia. However, a concurrent low incidence of kidney findings (tubular degeneration/regeneration and tubule dilation) which were observed at a higher frequency at the next dose level indicate that the overall NOAEL is in the range 0.012-0.06 mg/kg bw/day. This NOAEL is approximately three times the NOAEL set for hypercalcemia in humans if adjusted for a human body weight of 60 kg. The effects are consistent between studies and indicate an impaired organ function at doses that are well within the guidance values for classification STOT-RE in the CLP regulation. The existing classification as STOT RE 1 is thus confirmed. There are no studies on repeated dose toxicity via dermal and inhalation routes. Since similar effects (i.e. calcifications of organs, decreased motor activity, motor coordination and muscle weakness) were observed in the acute toxicity studies following administration via the oral, dermal or inhalation route, it is reasonable to assume that similar effects would occur also via these routes. Therefore, classification STOT RE 1 is proposed for all routes. This proposal for classification and labelling was discussed during the 39th RAC meeting in December 2016. RAC confirmed classification STOT RE 1 (H372) with a SCL of 3% to category 1 and of 0.3% for category 2.
Genotoxicity: The genotoxic potential of cholecalciferol was investigated in three standard in vitro test systems (Ames test, mammalian cell gene mutation test, mammalian chromosome aberration test) as well as in an in vivo combined comet and micronucleus assay. The criteria for a positive response were fulfilled in one of the three Ames tests but no mutagenicity was observed in mammalian cells. In vivo, there was no increase of micronuclei observed but due to the absence of cytotoxicity in the bone marrow, the extent of exposure is unclear. In contrast, mutagenicity was observed in liver cells in the comet assay. Although this occurred at doses assumed to be close to lethal dose levels, there was no evident support from the histopathological examinations to consider effects as secondary to excessive toxicity. The data and the proposal for classification and labelling was discussed during the 39th RAC meeting in December 2016 and the meeting agreed not to propose classification for germ cell mutagenicity. “More specifically, RAC considers that cholecalciferol, taking the weight of the evidence into account, does not meet the criteria for mutagenicity as defined in the CLP regulation.” The condition “other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays” is not fulfilled with the weakly positive comet assay alone.
Long-term toxicity and carcinogenicity: There is no robust data available to assess if cholecalciferol has an intrinsic carcinogenic potential. In the justification made for non- submission of data (doc IIIA 6.7), the applicant argues that there is substantial data available to conclude that the substance lacks a carcinogenic potential and a “broad body of evidence supports an important role of Vitamin D3 on prevention of cancer incidence and mortality”. The data referred to in support of this claim is mainly based on clinical trials performed in humans. However, this data does not address if cholecalciferol could have an intrinsic carcinogenic potential at exposure levels outside of the physiological range. Consequently, the eCA does not agree that there is sufficient data available to adequately assess this endpoint. However, in view of the strategy proposed for this review (Doc IIA, section 1), the lack of data is acceptable from a risk assessment perspective considering that the expected
13 (54) Cholecalciferol Product-type PT 14 January 2018 exposure from the representative use is within the tolerable upper intake level set by EFSA.
The animal data available indicate that cholecalciferol causes proliferative changes in adrenals of rats, and phaeochromocytoma manifest in rats already after 26 weeks of exposure. The NOAEL was set at 0.125 mg/kg bw/day based on persistent increase in proliferative cells seen in conjunction with increased number of hot spots, hyperplastic nodules and pheochromocytoma at 0.25 mg/kg bw/day and above. This is consistent with the result from the 90-day study in which proliferative pathological changes of adrenals were observed at doses of ≥ 0.3 mg/kg bw/day. Since there are no studies available with durations covering the entire life span of the test species, it cannot be excluded that tumours with a latency of more than 26 weeks may develop. The mode of action of phaeochromocytoma formation cannot be established from the data available but taking into account the positive result obtained in the in vivo comet assay, a genotoxic mode of action cannot be excluded. The relevance of this finding to humans is unclear, but based on the limited human data available in the open literature (Summarised in the EFSA scientific opinion and in the systematic literature review made by NNR5) there is no association between cancer and exposure to cholecalciferol at doses comparable to those used for food supplementation. Any association at levels outside of this range in humans is unknown. Due to the poor data base, a robust proposal for classification and labelling could not be made but classification in at least category 2 was initially proposed in the CLH report since proliferative changes and phaeochromocytomas were observed already at 26 weeks. The proposal was discussed during the 39th RAC meeting in December 2016. RAC concluded “Overall, based on the short and poorly designed available chronic carcinogenicity studies where a single tumour in two dosed groups of male rats was observed, RAC concludes that the currently available data may be indicative of a carcinogenic potential, but the strength of evidence is not enough to classify vitamin D3 as a carcinogen in category 2. Overall, RAC considers that vitamin D3 should not be classified for carcinogenicity.” Consequently it was agreed that cholecalciferol should not be classified as carcinogenic.
Fertility and developmental toxicity: The data available to assess this endpoint is limited to a published study in rats and rabbits performed with metabolite calcitriol and to human data sparingly described in different reviews. The methodology used and the reporting of the animal study is not in accordance with recognized guidelines or the principles of GLP and the information is thus not considered to adequately address the data requirements. The applicant considers further animal testing for fertility and developmental toxicity scientifically unjustified since the influence of Vitamin D3 on human reproductive health/human development “is well-studied and intensively reported”. The applicant further states that biocidal use of cholecalciferol marginally contributes to the total vitamin D exposure and that vitamin D is essential for mammalian growth. The references claimed to substantiate these statements include two reviews (an evaluation of vitamin D safety made by EFSA in context of food fortification and vitamin D supplementation and a published systematic literature review of vitamin D made for the 5th edition of the Nordic Nutrition Recommendations (the NNR5 project)) and two published clinical trials describing exposure during pregnancy. None of these references contains any information on effects in humans following repeated exposure to doses above 100 µg/day during pregnancy. Consequently, there is no robust information available, neither for humans nor for animals, to assess the potential effects of cholecalciferol on fertility or developmental parameters in a relevant dose range. Nevertheless, further animal testing is not considered justified since the estimated exposure during the intended use of cholecalciferol as a rodenticide is low and the contribution from this source to the overall exposure (endogenous and from food supplementation) is below the tolerable upper intake limit for humans that is proposed by EFSA. Based on the information available, it is reasonable to assume that exposure levels
14 (54) Cholecalciferol Product-type PT 14 January 2018 comparable to the ranges used for vitamin D supplementation do not raise concern for fertility or developmental effects. Therefore, no further information is required from a risk assessment perspective. Classification was discussed during the 39th RAC meeting in December 2016. “RAC concludes that due to limitations of data on reproductive toxicity regarding all parameters required for an accurate assessment of effects on fertility, development and toxicity via lactation, RAC considers the available data for not sufficient to assess if the intrinsic properties of colecalciferol fulfil the criteria for classification. In addition, the human clinical trials reported do not add any concern at supplemental levels. Overall, RAC agrees with the DS3 that colecalciferol should not be classified as toxic to reproduction”.
Neurotoxicity: There are no studies available specifically addressing neurotoxicity but neurotoxicity endpoints were assessed in the 90-day rat study. Slight differences were observed in some of the neurological tests performed but most observations were restricted to high dose animals that also suffered from hypercalcemia and organ calcification. Moreover, the different types of effects observed were generally only present in one sex and examinations of neuronal organ weights and tissues were unremarkable. Therefore, although the toxicological significance of these observations is unclear, it is considered more likely that effects reflect general toxicity than toxicity specifically targeting the nervous system. Clinical signs of neurotoxicity were also observed in the acute toxicity studies, irrespective of administration route. However, since mortality was observed either at the same dose (inhalation, dermal toxicity studies) or at the next dose level (oral toxicity study), effects are considered to result from general toxicity. The effect of cholecalciferol on acetylcholine esterase or neuropathy target esterase (NTE) was not assessed in the studies submitted. Since the active substance is not an organophosphate or a carbamate, this information is not considered necessary. The clinical signs of neurotoxicity observed in acute toxicity studies and in the 90-day study in rats are considered to reflect general toxicity rather than toxicity specifically targeting the nervous system. Therefore, further testing for developmental neurotoxicity is not considered justified.
2.2.1.2 Effects assessment Cholecalciferol is an endogenous substance and is important for several physiological processes in humans such as calcium homeostasis. It is produced in skin from sun exposure and there is thus a physiological range that is well tolerated by the human body. Nevertheless, reference values need to be established to protect from adverse effects that may arise following exposure to dose levels outside of the physiological range. Normally, reference values such as the “acceptable exposure level (AEL)” for active substances used in biocidal products are based on NOAELs set in animal studies with study durations representing the intended exposure situation (i.e. short-term, medium-term and long-term exposure). In this assessment, the animal data is limited since many of the core studies have been waived with reference to human data available in the open literature. Nevertheless, hypercalcemia is considered the critical effect for the NOAELs set both based on this limited animal data and on human data. An AEL of 0.06-0.3 µg/kg bw/d can be derived based on the results from animal data. AELs are systemic values derived to serve as reference values in risk assessments for different exposure routes. The UL already established for cholecalciferol are external oral reference values but are used here as starting points for the derivation of systemic AELs. Converting the NOAEL set for adults (250 µg/day) into a systemic value by assuming an oral absorption of 50% results in a systemic value of 125 µg/day. This value is then divided by a safety factor of 2.5 and a body weight of 60 kg to derive an AEL of 0.00083 mg/kg bw/day (0.8 µg/kg). This AEL is comparable to the AEL
3 Dossier submitter
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Cholecalciferol Product-type PT 14 January 2018
2.2.1.3 Exposure assessment The types of representative products considered in this assessment are “ready to use” enrobed paste bait placed into bait-boxes by professionals or non-professionals. Users are not expected to wear gloves during application and the dermal absorption of the two representative products is approximately 0.2%. The exposure assessments were made according to guidance in HEEG opinions numbered 10, 12, 17 and/or based on a proprietary exposure study where data for paste bait (placing or spearing bait sachets) were used. The 75th percentile values in the underlying exposure datasets were used to assess exposure of professionals. The 90th percentile of the datasets was considered appropriate to assess exposure of non-professionals. According to the applicant, users are instructed to wear gloves; thus, oral exposure is not expected for professionals. Generally, non-professional users are not expected to use gloves. However provided that products are enrobed, the product labels advise washing of hands after handling and that products contain bitrex, exposure via the oral route is assumed to be negligible also for non-professionals. Considering that the product is a paste and that the vapour pressure of cholecalciferol is low, i.e. 6 x 10-5 at 25 ºC, inhalation exposure is assumed to be negligible. Consequently, dermal exposure is assumed to be the major route of exposure for users handling baits with cholecalciferol.
Incidental exposure to products applied in bait stations will be very limited. However, at least in theory, adults or children may be incidentally exposed if touching unprotected baits. Good practice and product labels will advise users how to prevent access to baits by children who may play in areas where baits have been placed. Small children accessing the bait could theoretically be exposed via finger to mouth transfer of residues or could even chew pieces of bait. In the exposure assessment made for this scenario, it was assumed that a child would consume up to approximately 5 grams in one bite and an infant could consume 10 mg following transient mouthing of bait treated with deterrent (TNsG on Human exposure to biocidal products, 2002 part 3 p 58 and 2007).
According to the applicant, the representative products can be described as follows:
1. Selontra®, containing 0.075% w/w (0.75 g/kg) cholecalciferol, is a ready-to-use rodenticide soft block bait, for the control of mice (Mus musculus/domesticus), brown rats (Rattus norvegicus) and black rats (Rattus rattus) including strains resistant to anticoagulants, for use by professionals and non-professionals in and around domestic, commercial and agricultural buildings. Selontra® is presented as 17g bait units individually enrobed. For rat control, bait points containing up to 8 units of bait are used at intervals of up to 10 metres apart. For mouse control, 2 units of bait are used per bait point, which are spaced 1 to 2 metres apart. All bait points are placed in dry locations and are protected to help prevent access by non-target animals. Bait points are inspected frequently and the bait point is replenished when bait take is observed. When no further take is observed it is considered that control has been achieved and bait points are removed from the site. 2. Harmonix Rodent Paste® containing 0.075% w/w (0.75 g/kg) cholecalciferol is presented as a paste and applied at covered bait points or in bait boxes for use by professionals and non-professionals in and around buildings. It is intended for the control of mice (Mus musculus/domesticus), brown rats (Rattus norvegicus) and black rats (Rattus rattus) including strains resistant to anticoagulants in and around domestic, commercial and agricultural buildings. Cholecalciferol is presented as 10 g enrobed bait units. For rats, it is intended that 100g to up to 200 g paste are used per bait point 3-10 m apart in heavy infestations and that 100g to up to 200 g paste are used per bait point 5-20 m apart in light infestations. For mice, it is intended that 10g to up to 20 g paste are used per bait point 2-10 m apart in heavy infestations and that 10g to up to 20 g paste are used per bait point 5-20 m apart in light infestations. The bait is placed in discrete locations within the infested area; it is not
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dispersed or broadcast within the environment. All bait points are placed in dry locations and are protected to help prevent access by non-target animals. Bait points are inspected frequently and the bait point is replenished when bait take is observed. When no further take is observed it is considered that control has been achieved and bait and bait points are removed from the site.
The scenario ”cleaning up dead rodents” was not assessed as the exposure was not anticipated to significantly impact on the overall conclusion on “safe use” taking into account that exposure levels would be below the low levels estimated for users placing/fixing/cleaning up baits. EFSA surveyed (in the scientific opinion on the tolerable upper intake level in 2012), the daily intake of vitamin D from food and supplements within EU. To assess the combined intake of vitamin D from food and food supplements and from rodenticide use, the upper 95th percentile of the daily intake reported in µg/day was converted to mg/kg bw/ day assuming a body weight of 60 kg for adults and 10 kg for toddlers.
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Cholecalciferol Product-type PT 14 January 2018 biodegradability test (OECD 301B guideline). An inherent biodegradability study was initially not submitted as a higher tier soil degradation study was provided. However, after an early- working group discussion at WG III 2014, a modified inherent test (OECD 302c) was undertaken. This gave unreliable results due to a too high detection limit, and no conclusion on biodegradability can be drawn from it. A study on biodegradation in seawater was also not provided which is justified as release of cholecalciferol to the marine environment is not expected.
One aerobic degradation study in soil was carried out using non-labelled material. The study was accepted on the basis that it was performed in accordance with the OECD guideline 307. However, the study was given a reliability score of 3 due to deficiencies. By using non- labelled material, it was not possible to detect and identify metabolites, measure bound residues or to calculate a mass balance. The results from the soil study suggested that cholecalciferol degrades with a half-life of 2.5–8.2 days (SFO), however this cannot be verified due to the lack of information as a result of using non-labelled material. The test therefore gives little information on the actual fate and behaviour in the soil compartment.
As a consequence, two new studies, which were aiming at the identification of metabolites and determining a half-life were submitted in February 2016 (cold substance in OECD 302 C, and tritium-labelled cholecalciferol in OECD 307). The applicant was able to detect (LC- MS/MS) 26 metabolites during the 45 days study. Two of the metabolites were identified as hydroxylated cholecalciferol, one formed quickly during the first day and then decreased from 14% AR until 3.5% AR on day 45. More polar metabolites were also seen. The non- extractable residues (NER) were identified by combusting the extracted pellet and measuring the tritiated water which formed upon combustion (~35 %AR by the end of the experiment). The NER were defined by the extraction method, which was four sequential 1-hour acetone extractions on an end-over shaker. The study with the tritiated cholecalciferol demonstrates that it is subject to degradation processes, and it was possible to estimate a half-life (SFO, 29.3 days at 20°C, corresponding to 62.4 days at 12°C).
Hydrolysis and photolysis studies have not been performed. The waiving of the hydrolysis study was accepted on the basis that cholecalciferol lacks functional groups that hydrolyse under environmental conditions. The photolysis waiver was provisionally accepted based on limited exposure to the aquatic compartment. For the purpose of the exposure assessment, these studies are not required. However, such studies are usually required to assess persistency in the PBT assessment in accordance with Annex XIII to Reg (EU) 1907/2006 (See section 2.2.2.3 of this document for more details).
Cholecalciferol has a vapour pressure of 6×10–5 Pa at 25°C and significant exposure of air is therefore unlikely. As the Henry´s law constant is quite high (30.77 Pa×m3/mol at 20°C) it can be assumed that the active substance has the potential to significantly partition from water to air. Given that the aquatic compartment is not considered relevant for the intended use of cholecalciferol, it is assumed that this exposure pathway will be negligible (ESD PT14, 2003).
The sorption properties of cholecalciferol were calculated in a study performed in accordance with OECD guideline 121, yielding an estimated Log Koc of >5.63 (Koc > 426580 l/kg OC at ~1 µg/l). With this high sorption, the current PEC-models, which are used for biocides, will regard cholecalciferol as non-mobile and therefore predict that it will not migrate to groundwater in significant quantities (low PEC). The soil degradation studies have facilitated identification of soil metabolites; consequently, it is now possible to derive information regarding what properties they may have (such as QSAR-derived degradation rate and mobility). Using EPI Suite v 4.1, the Koc of hydroxylated cholecalciferol is predicted to be just a factor 10 lower (less sorptive), and the biodegradability is very much the same as cholecalciferol. The potential exposure risk that these metabolites may pose to groundwater
23 (54) Cholecalciferol Product-type PT 14 January 2018 can therefore bee satisfactorily assessed. In currently used PEC models, they should be as immobile and degradable as cholecalciferol, and therefore not give a PECgw of concern.
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Cholecalciferol Product-type PT 14 January 2018
Assessment, Part C, Chapter R.11 (ECHA-12-G-24-EN, Nov 2012). • Comments from Member States on the first draft CAR, autumn 2016) • Recommendations from the PBT EG meeting, 14 November 2016. • Discussions at ENVWG I 2017. • Recommendations from PBT EG e-consultation, March 2017. • Votes from an Ad-hoc e-consultation after the ENVWG I 2017.
The applicant did not submit a PBT assessment. The eCA has performed the assessment on their behalf (see Document IIA).
In conclusion, we propose not to regard cholecalciferol as a PBT substance (see more in Doc II A).
The data available to assess the P-criterion consist of a ready biodegradability test, an inherent test (OECD 302 C) and two soil degradation studies (OECD 307). The applicant had waived the hydrolysis and photolysis studies. Cholecalciferol was considered not readily biodegradable based on the results from the ready-test. The inherent study is not reliable (due to too high LOD). The first soil degradation study was carried out with non- labelled material and as a result gives little useful information for assessing persistence regarding the actual fate and behaviour in the soil compartment. The second soil degradation study (2016) was carried out using tritium-labelled cholecalciferol. This study is reliable (see more detailed discussion in Doc II A, Chapter 4.3.1) and indicates “not P”. Additionally, the eCA screened for persistency according to QSAR screening criteria by estimating biodegradation using BIOWIN (version 4.10, sept 2010). Based on this screening, it was not possible to rule out persistency. However, since the single-soil test indicates a half-life of 29.3 days, and formation of 26 metabolites adding up to a total of 46% AR after 45 days (not including the NER), we find it is reasonable to conclude that cholecalciferol is not P.
In order to determine if the B-criterion is fulfilled, bioconcentration studies from waterborne exposure are traditionally required (although the latest OECD guideline allows for dietary exposure). However, due to difficulties in performance and interpretation of studies of this kind with cholecalciferol (as identified in the discussions in Doc IIA) the requirement of additional data on B for interpreting the PBT criteria may not be useful. For example, interpretation could be hampered due to the endogenous synthesis of cholecalciferol. Cholecalciferol is widely distributed in plants and animals in the aquatic and terrestrial environments and the majority of the vertebrate taxa have systems for regulating the levels of cholecalciferol and the physiologically active metabolites. In the absence of an aquatic bioconcentration test, a weight of evidence approach was adopted to assess the potential bioaccumulative properties of cholecalciferol, which found that there are indications that cholecalciferol may have bioaccumulative properties (see Document IIA for more details; earthworm BAF study and Graff et al fish feeding study). However, after consultations of the PBT EG and an ad-hoc consultation after WG I 2017, it was decided that the information supports the conclusion that cholecalciferol is not B.
Cholecalciferol meets the criteria for classification STOT RE 1 according to the CLP Regulation and therefore fulfils the toxicity criterion (T).
2.2.2.4 Exposure assessment Selontra®, containing 0.075% w/w (0.75 g/kg) cholecalciferol, is a ready-to-use rodenticide soft block bait, for the control of mice and rats for use by professionals and non-professionals in and around domestic, commercial and agricultural buildings. Selontra® is presented as 17 g bait units. For rat control, bait points containing up to 8 units of bait are used at
27 (54) Cholecalciferol Product-type PT 14 January 2018 intervals of up to 10 metres apart. The Selontra applicant had originally used the upper limit (10 m spacing) in the PEC calculations. This gives the lowest amount of bait stations, and hence the lowest PECs. The applicant later clarified (letter to eCA, 2015-11-20; internal file number B12-00135-352), that in an extreme worst-case 1 m spacing will be used also for rats. This gives a higher PEClocalsoil (0.646 mg/kg ww, and PEC/PNEC = 0.109). For mouse control, two units of bait are used per bait point, which are spaced 1 to 2 metres apart.
Harmonix Rodent Paste® containing 0.0750% w/w (750 ppm) cholecalciferol is presented as a paste and applied at covered bait points or in bait boxes for use by professionals and non- professionals for the control of mice and rats in and around domestic, commercial and agricultural buildings. Harmonix Rodent paste® is presented as 10 g bait units. For rats, it is intended that up to 200 g paste are used per bait point, 3–10 metres apart in heavy infestations and 100 g paste per bait point, 5–20 metres apart in light infestations. For mice, it is intended that up to 20 g paste is used per bait point, 2–10 metres apart in heavy infestations and 10 g per bait point, 5–20 metres apart in light infestations.
The cholecalciferol products, Selontra® and Harmonix Rodent Paste®, are intended to be used within enclosed bait stations or secured bait points in and around buildings only. All bait points are placed in dry locations and are protected to help prevent access by non- target animals. Bait points are inspected frequently and the bait point is replenished when bait take is observed. When no further take is observed, it is considered that control has been achieved and bait points are removed from the site. The bait is placed in discrete locations within the infested area; it is not dispersed or broadcast within the environment, nor used in burrows. According to ESD PT 14 (2003), the use of both products (Selontra® and Harmonix Rodent Paste®) precludes contamination of aquatic ecosystems, both freshwater and marine, and therefore PECsurfacewater, PECsediment, or PECSTP is not calculated.
We consider that the exposure of air is negligible in the scenario ‘in and around buildings’ according to ESD PT 14, and in addition, cholecalciferol has a low vapour pressure of 6.0×10-5 Pa at 25°C. The Henry´s law constant is quite high (30.77 Pa×m3/mol at 20°C) and therefore, it can be assumed that the active substance has potential to significantly partition from pure water to air. It is assumed that this exposure pathway will be negligible given that the aquatic compartment is not considered relevant for the intended use of this product. Consequently, exposure of air to Selontra® and Harmonix Rodent Paste® will be negligible.
Exposure to porewater via soil contamination is considered to be negligible for the active substance and therefore, no PEClocalsoil,porewater has been calculated. As indicated by its high KOC, cholecalciferol will strongly partition to soil particles. The ESD PT 14 states that a detailed groundwater scenario is not considered necessary due to the limited quantities of active substance, the limited frequency of use and the limited treated area. However, recently (TAB 1.3; Technical Agreements on Biocides), it was agreed that a groundwater assessment should always be performed, even for PT 14 when only hot spot applications are considered. However, this guidance does not apply yet. Our assessment for now is that groundwater contamination of the active substance is highly unlikely; furthermore, the risk of leaching of hydroxylated metabolites (two such were identified as major metabolites in the soil study) has been sufficiently investigated using QSAR, and their risk for groundwater can therefore also be ruled out (see Document II-A for more details).
Selontra® and Harmonix Rodent Paste® are intended to be used within enclosed bait stations or secured bait points in and around buildings. For this exposure scenario, the main exposure of the environment is expected to be soil (ESD PT14). The approach for calculating the local predicted environmental concentrations in soil (PECs) for both products were carried out for the intended uses in accordance with the worst-case scenarios outlined in the ESD PT14. Some modifications were applied to account for the worst-case intended uses.
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Cholecalciferol Product-type PT 14 January 2018 tiered approach was considered, in accordance with the guidance for AVK products given in ESD PT14 and the “Addendum relevant to Biocides to the TGD on Risk Assessment” (endorsed at the 23rd CA meeting November 2006). This guidance is for AVK products, but we used it also for cholecalciferol products.
In the first tier exposure assessment we assumed that the whole day’s food requirement of the non-target animal would be satisfied by consumption of rodenticide bait, and therefore the concentration in food would be the same as the concentration of active substance in the bait for any bird or mammal encountering rodenticide bait.
The second tier primary poisoning exposure assessment as described in the EUBEES ESD PT14 (2003) and the “Addendum relevant to Biocides to the TGD on Risk Assessment”, November 2006differentiates between acute and long-term primary poisoning. The acute exposure to non-target animals was calculated as an expected concentration (EC) of active substance in the non-target animal after a single day of exposure (single meal followed by 24 hours elimination). The long-term exposure was calculated as an expected internal concentration (ECn) of active substance in the non-target animal after 5 days (n = 5) of exposure to the rodenticide, also taking elimination from the body into account. The calculations with results are described in detail in Doc II BC.
However, the eCA considers ETE (estimated daily uptake or strictly: estimated theoretical exposure8) to be a more relevant parameter for the risk assessment than the estimated internal concentrations (EC and ECn), since the selected parameter is to be compared to a toxicity endpoint based on an oral intake dose, not an internal concentration. The calculations of ETE were performed by the eCA in two steps, where food intake rate of indicator species (FIR), the avoidance factor (AV), the fraction of animal’s diet obtained from the rodenticide treated area (PT) and the fraction of food type in the animal’s diet (PD) were varied. The diet concentration C varies for different scenarios (bait concentration for acute tier 1, concentration in poisoned rats in other scenarios etc.).
ETE = (FIR / bw) × C × AV × PT × PD
Calculations were performed for a few species of non-target mammals (dog, pig and young pig) as well as birds (tree sparrow, chaffinch, woodpigeon and pheasant), as exemplified in the ESD PT14. The most exposed mammalian and bird species were dog and tree sparrow, respectively, and ETE for these species are given in Table 2.2.2.4-3, and will be used in the risk assessment for acute and long-term primary poisoning.
8 ETE is defined in EFSA guidance Birds and Mammals.
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Cholecalciferol Product-type PT 14 January 2018 exogenous substance, does not trigger concerns for reproduction or populations, and at exposures arising from its use as a rodenticide will not cause adverse effects in humans. Further, due to existing widespread use as a food fortification and vitamin supplement, with uncontrolled release into the environment, exclusion of the very minor biocidal use would represent disproportionate regulation”.
Nevertheless, cholecalciferol is a pro-hormone metabolised into biologically active metabolites that together with parathyroid hormone are important for maintaining calcium and phosphorous homeostasis. Based on the results from toxicological studies, high dose administration (0.3 mg/kg bw/d) of cholecalciferol causes hypercalcemia and tissue mineralisation in rats and in other vertebrate non-target organisms. Consequently, cholecalciferol is considered to fulfil the criteria in section A and B of the Annex to Regulation (EU) No 2017/2100: It is nevertheless suggested by the eCA that approval should be considered, since:
• In spite of the endocrine properties, there is no risk to human health identified. The exposure from limited rodenticide use is estimated to be in the range of vitamin D supplementation. The combined exposure from rodenticide use, supplements and food is expected to be well within the tolerable daily upper intake level.
• There is a need for a compliment to and/or replacement for anti vitamin K (AVK) rodenticides. Cholecalciferol is considered to have a more favourable toxicological and ecotoxicological profile as compared to AVK rodenticides.
2.3 Overall conclusions The outcome of the assessment for cholecalciferol in product-type 14 is specified in the BPC opinion following discussions at the 21 and 23 meeting of the Biocidal Products Committee (BPC). The BPC opinion is available from the ECHA website.
2.4 List of endpoints The most important endpoints, as identified during the evaluation process, are listed in Appendix I.
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APPENDIX I: LIST OF ENDPOINTS
Chapter 1: Identity, Physical and Chemical Properties, Classification and Labelling
Active substance (ISO Common Name) Cholecalciferol Product-type 14
Identity Chemical name (IUPAC) (3β,5Z,7E)-9,10-secocholesta-5,7,10(19)- trien-3-ol Chemical name (CA) (1S,3Z)-3-[(2E)-2-[(1R,3aS,7aR)-1-[(1R)- 1,5-dimethylhexyl]octahydro-7a-methyl-4H- inden-4-ylidene]ethylidene]-4- methylenecyclohexanol CAS No 67-97-0 EC No 200-673-2 Other substance No. CLP index #: 603-180-00-4 Minimum purity of the active substance as In accordance with European Pharmacopoeia manufactured (g/kg or g/l) (Ph. Eur.* 7.0; 01/2008:0575 corrected 6.5): min. 970 g/kg (includes also any pre- cholecalciferol present; see further section 2.1.1) Identity of relevant impurities and None of the specified impurities are additives (substances of concern) in the considered relevant (see further the active substance as manufactured (g/kg) Confidential IIIA2.8-1-2.8-5)
Molecular formula C27H44O Molecular mass 384.64 g/mol Structural formula
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Physical and chemical properties Melting point (state purity) 83°C (99.6% purity) Boiling point (state purity) Decomposition before boiling with an onset at 148°C (99.6% purity) Temperature of decomposition Decomposition before boiling with an onset at 148°C (99.6% purity) Appearance (state purity) Solid white powder with no odour (99.6% purity)
20 Relative density (state purity) D 4 = 1.02 (99.6% purity) Surface tension Not required, as the water solubility of the active substance is < 1 mg/L Vapour pressure (in Pa, state Extrapolated (99.6% purity): temperature) 4 x 10-5 Pa at 20°C 6 x 10-5 Pa at 25°C Henry’s law constant (Pa m3 mol -1) 30.77 Pa m3/mol Solubility in water (g/l or mg/l, state 99.6% purity: temperature) <0.5 µg/L at 20°C in purified water (pH 6.5- 7.1) The threshold level is based on the LOQ of the analytical method used (LC-MS/MS).
No pH dependency is expected. Solubility in organic solvents (in g/l or 99.6% purity: mg/l, state temperature) n-Heptane: >250 g/L Xylene: >250 g/L 1,2-dichloroethane: >250 g/L Methanol: >250 g/L Acetone: >250 g/L Ethyl acetate: >250 g/L
Stability in organic solvents used in Not relevant, as the active substance is not biocidal products including relevant used in conjunction with organic solvents breakdown products
Partition coefficient (log POW) (state 99.6% purity: temperature) Log Pow >5 at neutral pH (6.7-7.0)
No pH dependency is expected.
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Hydrolytic stability (DT50) (state pH and See chapter 4 below temperature) Dissociation constant None within environmentally relevant pH. Computer assisted estimations indicate a pKa of 16.5 for the deprotonation of the hydroxyl- group. UV/VIS absorption (max.) (if absorption 99.6% purity: > 290 nm state ε at wavelength) Acidic conditions (1 N HCl + 50% acetonitrile, pH 1.1): 215 nm, ε = 16700 268 nm, ε = 18600 Neutral conditions (pur. Water +50% acetonitrile): 215 nm, ε = 16400 268 nm, ε = 18400 Alkaline conditions (1 N NaOH + 50% acetonitrile, pH 13.6): 268 nm, ε = 18400
Significant absorbance above 290 nm (tailing absorbance up to 310 nm). ε at 290 nm approx. 9200
Photostability (DT50) (aqueous, sunlight, See chapter 4 below state pH)
Quantum yield of direct See chapter 4 below phototransformation in water at Σ > 290 nm Flammability Not highly flammable (99.6% purity) No self-ignition below 400°C (99.6% purity) Explosive properties Not considered explosive based on structural assessment.
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Classification and agreed labelling with regard to physical/chemical data None with regard to toxicological data Acute Tox. 2 (all routes), STOT RE 1 with regard to fate and behaviour data with regard to ecotoxicological data
Chapter 2: Methods of Analysis
Analytical methods for the active substance Technical active substance (principle of According to European Pharmacopoeia (Ph. method) Eur. 7.0): Normal phase HPLC-UV Impurities in technical active substance Same method as for technical active substance (principle of method) (see entry above)
Analytical methods for residues Soil (principle of method and LOQ) Parent cholecalciferol: LC-MS/MS (two ion- transitions), LOQ 0.05 mg/kg Air (principle of method and LOQ) Not provided - not required (low vapour pressure of a.i. and not used in spraying applications) Water (principle of method and LOQ) Parent cholecalciferol: LC-MS/MS (two ion- transitions), LOQ 0.05 µg/L (surface water and drinking water) Body fluids and tissues (principle of Parent cholecalciferol: LC-MS/MS (two ion- method and LOQ) transitions), LOQ 0.05 mg/kg (blood) and 0.1 mg/kg (muscle) Metabolite 25(OH)D: acceptable waiver provided based on the commercial availability of numerous diagnostic kits for human screening. Food/feed of plant origin (principle of Parent cholecalciferol: LC-MS/MS (two ion- method and LOQ for methods for transitions), LOQ 0.05 mg/kg (wheat grain, monitoring purposes) apple, whole orange, soy bean) No ILV available - not required since MRLs are not required from the use envisaged Food/feed of animal origin (principle of Parent cholecalciferol: LC-MS/MS (two ion- method and LOQ for methods for transitions), LOQ 0.1 mg/kg (meat) monitoring purposes) No ILV available - not required since MRLs are not required from the use envisaged
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Chapter 3: Impact on Human Health
Absorption, distribution, metabolism and excretion in mammals Rate and extent of oral absorption: Human information on oral absorption indicates at least 50% oral absorption. Distributed in chylomicrons and lymph, then in plasma extensively bound to a specific binding protein (DBP). Rate and extent of dermal absorption for No dermal absorption studies provided on the the active substance: active substance Rate and extent of dermal absorption for Representative products: 0.2% the representative product(s)12:
Distribution: Widely distributed Potential for accumulation: Accumulation into adipose tissue Rate and extent of excretion: Major excretion route for cholecalciferol and its metabolites is faeces via the bile. A minor part is eliminated as metabolites in urine. Toxicologically significant metabolite(s) Metabolites of Cholecalciferol: 25-(OH) cholecalciferol (vitamin D status marker); then a portion is metabolised to 1,25-(OH)2 cholecalciferol, which is the principal active molecule. 24,25-(OH)2 cholecalciferol
Acute toxicity
Rat LD50 oral Male rats: 35 mg/kg Female rats 47 mg/kg Combined: 41 mg/kg
Rat LD50 dermal Male rats: 61 mg/kg Female rats: 185 mg/kg
3 Rat LC50 inhalation 130 – 380 mg/m (0.13-0.4 mg/L). 4h, nose- only
Skin irritation Not irritant
Eye irritation Not irritant
Skin sensitization (test method used and Not sensitising (LLNA) result)
12 Please consider Q5 on Derivation of dermal absorption values of section 4.1.1 of the Manual of Technical Agreements (MOTA), version 5. 42 (54) Cholecalciferol Product-type PT 14 January 2018
Repeated dose toxicity Species/ target / critical effect Regulates calcium homeostasis in mammals. Excess cholecalciferol results in hypercalcaemia and widespread tissue calcification. Key endpoint: blood calcium concentration. Lowest relevant oral NOAEL / LOAEL Humans (EFSA, 2012): NOAEL, 250 µg/person/day LOAEL not determined Rat 90 day study: NOAEL 0.012 µg/kg bw/day LOAEL 0.06 mg/kg bw/day Lowest relevant dermal NOAEL / LOAEL Dermal NOAEL: No data provided
Lowest relevant inhalation NOAEL / LOAEL Inhalation NOAEL: No data provided
Genotoxicity In vitro: positive in one of three Ames tests, negative in mammalian cell gene mutation test (mouse Lymphoma L5178 TK) and mammalian chromosome aberration test (Chinese hamster V79 cells). In vivo: negative in a Comet Assay study (the increase in DNA migration in the liver occurs at the MTD and without dose-dependence.) performed as a combined Comet Assay/ micronucleus assay No increase of micronuclei but unclear extent of exposure at target tissue.
Carcinogenicity Species/type of tumour Animal studies waived. 26 week rat study with limited parameters studied (non-guideline, supplementary data relevant for classification), adrenal phaeochromocytoma lowest dose with tumours 0.25 mg/kg bw/day A general NOAEL is not established (limited parameters studied) but NOAEL long term is considered covered by an AEL based on the human UL (100µg/day for adults) established by EFSA in 2012.
Reproductive toxicity Species/ Reproduction target / critical Animal studies waived. effect Lowest relevant reproductive NOAEL / Not established in test animals but NOAEL for LOAEL reproductive effects is considered covered by an AEL based on the UL (100µg/day for adults) established by EFSA in 2012.
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Species/Developmental target / critical Animal studies waived. effect 1, 25-dihydroxy vitamin D3 (calcitriol) study available in rats, rabbit (non-guideline, supplementary data only relevant for classification). Lowest relevant developmental NOAEL / 1, 25-dihydroxy vitamin D3 (calcitriol) study: LOAEL Maternal LOAEL (hypercalcemia): 0.3 µg/kg bw/day, developmental LOAEL (micropthalmia, cleft palate): 0.08 µg/kg bw/day Overall not established for cholecalciferol but NOAEL for development is considered covered by an AEL based on the UL (100µg/day for adults) established by EFSA in 2012.
Neurotoxicity / Delayed neurotoxicity Species/ target/critical effect Delayed neurotoxicity studies and developmental neurotoxicity waived. FOB included in 90 day study in rat: Decreased landing foot splay and grip strength (males). Decreased motor activity (females), at doses were blood calcium was increased and microscopic changes of kidneys occurred. Lowest neurotoxicity NOAEL / LOAEL. NOAEL: 0.012 mg/kg bw/day LOAEL: 0.06 mg/kg bw/day
Other toxicological studies No additional robust studies with study summaries were submitted by the applicant.
Medical data Medical surveillance data of cholecalciferol manufacturing workers showed no adverse effect in a study where the use of personal protection measures was considered. For clinical cases, the applicant refers to the EFSA 2012 review. The critical effect of excess intake of vitamin D leading to hypervitaminosis D or vitamin D toxicity is hypercalcaemia. Clinical symptoms associated with hypercalcaemia are fatigue, muscular weakness, anorexia, nausea, vomiting, constipation, tachycardic arrhythmia, and soft tissue calcification, failure to thrive, and weight loss. Hypercalciuria can be associated with hypercalcaemia and consequences of sustained hypercalcaemia are nephrolithiasis (kidney stones), nephrocalcinosis, and a decrease in kidney function. Case reports of fatal vitamin D toxicity are reported in the
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open literature where hypercalcemia and calcium deposition of soft tissues were observed, and impaired renal function and nitrogen retention occurred.
There are no known cases of cholecalciferol poisoning in humans from rodenticide use. If a poisoning event occurred, hypercalcaemia could arise. Therapeutic plans for hypercalcaemia treatment are available not limited to Vitamin D3 toxicosis. There are several methods for treatment: saline and furosemide, IV phosphates, calcitonin, corticosteroids, gallium nitrate, bisphosphonates. Vitamin D3 toxicosis may be slow in onset and recovery may also be slow, requiring regular monitoring over a period of several weeks but prognosis is good. Cholicalciferol fatal intoxication in one cat and one dog despite treatment for hypercalcemia after unknown amount cholecalciferol bait ingested. Vomiting and weakness in both species and additionally lethargy, anorexia and diarrhoea in the dog that also were actatic. The cat died of respiratory and cardiac arrest (severe pulmonary mineralization sequel of cholecalciferol intoxication). Clinical signs in cat <24h after ingestion. One dog with suspected intoxication vomited and had diarrhoea, relapsed after treatment for hypercalcemia but were clinically normal 18 months later. Information such as epidemiological data arising from medical uses of the active substance is available in section 6.12 of Doc IIIA.
Summary Value Study Safety factor ADI* (acceptable daily intake, external Please refer to EFSA, 2012 2.5 (adult) long-term reference dose) tolerable 5 (toddler) NOAEL: 250 upper intake µg/person/day limits set by EFSA 100/50 µg/person/day ARfD** (acute reference dose) Please refer to EFSA, 2012 2.5 (adult) tolerable NOAEL: 250 5 (toddler) upper intake µg/person/day limits set by EFSA 100/50 µg/person/day
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AEL- short-term, medium-term, long- 0.00083** EFSA, 2012 2.5 term (Operator Exposure, professionals mg/kg bw/day NOAEL: 250 and non-professionals) µg/person/day Reference value for dermal absorption No data No data No data concerning the active substance: Reference value for dermal absorption 0.2% In vitro OECD NA concerning the representative 428 product(s)4: *In case an ARfD/ADI is needed, the tolerable upper intake limits set by EFSA serve as reference values. **Corrected for an oral absorption of 50%
Acceptable exposure scenarios (including method of calculation) Production of active substance: NA Formulation of biocidal product NA Professional users Primary exposure, operator loading baitboxes with paste bait and cleaning-up and disposing remaining bait from baitboxes. Tier 1 without gloves. Rat treatment: a-selontra 8.3% of AEL (HEEG opinion 10, 17, 75th percentile) b-harmonix rodent paste® 11 % of AEL (HEEG opinion 10, proprietary data on surrogate product, 75th percentile) Mouse treatment: a-selontra 2.3% of AEL (HEEG opinion 10, 17, 75th percentile) b-harmonix rodent paste® 1.1 % of AEL (HEEG opinion 10, proprietary data on surrogate product, 75th percentile)
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Non-professional users Primary exposure, operator loading baitboxes with paste bait and cleaning-up and disposing remaining bait from baitboxes. Tier 1 without gloves. Rat treatment: a-selontra 11% of AEL (HEEG opinion 10, 17, 90th percentile) b-harmonix rodent paste® (placing or fixing bait respectively) 0.25% and 1.6% of AEL (HEEG opinion 10, proprietary data on surrogate product, 90th percentile) Mouse treatment: Rat treatment: a-selontra 0.36% of AEL (HEEG opinion 10, 17, 90th percentile) b-harmonix rodent paste® (placing or fixing bait respectively) 0.025% and 0.16% of AEL (HEEG opinion 10, proprietary data on surrogate product, 90th percentile)
Secondary exposure Toddler (1 yr) ingesting product containing aversive agent: 15% of AEL (TNsG on Human exposure to biocidal products, 2002, part 3 p. 58 and 2007) Indirect exposure as a result of use NA Aggregate/combined exposure Estimated upper 95th intake level via food and supplements of vitamin D (EFSA, 2012) + operator exposure ≤ 35% of the UL established by EFSA in 2012. This leaves a margin of ≥ 65% of the UL for additional exposure for endogenous production of cholecalciferol by sun exposure. For secondary exposure to children (toddlers approximately 1 year old), the margin is lower but still around 50% of the UL.
Chapter 4: Fate and Behaviour in the Environment
Route and rate of degradation in water Hydrolysis of active substance and No data, study waived. The substance is relevant metabolites (DT50) (state pH and hydrolytically stable due to the lack of temperature) functional groups, which can hydrolyse.
Photolytic / photo-oxidative degradation No data on photolysis; study waived (agreed of active substance and resulting relevant at WG III, 2014). metabolites
Readily biodegradable (yes/no) No (7% of CO2 yield after 28 days) Biodegradation in seawater No data, study waived. (Exposure to seawater unlikely according to uses described in the CA report).
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Non-extractable residues No data (Exposure to aquatic systems unlikely according to uses described in the CA report). Distribution in water / sediment systems No data (active substance) (Exposure to aquatic systems unlikely according to uses described in the CA report). Distribution in water / sediment systems No data (metabolites) (Exposure to aquatic systems unlikely according to uses described in the CA report).
Route and rate of degradation in soil Mineralization (aerobic) Not determined. Soil degradation study was performed with unlabelled material. Laboratory studies (range or median, with Two studies available, one is sufficiently number of measurements, with regression reliable for DT50 derivation. coefficient) Study 1. OECD 307 study with cold substance (RI = 3): SFODT50 varied from 3.4 to 8.2 days in three soils (clay loam; loamy sand, sandy loam). The absolute value of these DT50 was inconclusive due to use of cold substance (mass balance not demonstrated). Study can be used as an indication that the variability between soils is not huge (possibly less than a factor 2.4). Study 2. OECD 307 study with tritium labelled substance (RI = 2): SFODT50 = 29.3 days at 20°C in a silty clay loam, corresponding to 62.4 days at 12 °C. Regression coefficients acceptable according to FOCUS methodology (good visual fit and Chi2 3.2%). Study was used in PEC calculations. Field studies (state location, range or Field study not required: median with number of measurements) Anaerobic degradation Not applicable Soil photolysis No study available Non-extractable residues OECD 307 study with tritium labelled cholecalciferol: The non-extractable residue (NER) increases till 35% AR by day 45. Relevant metabolites - name and/or code, At least two hydroxylated cholecalciferols are % of applied active ingredient (range and formed. In total 26 metabolites are seen in LC- maximum) MS/MS chromatograms. Total metabolites (excluding NER) add up to 46% AR at day 45 (end of study). Soil accumulation and plateau No data (not applied directly to soil) concentration
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Adsorption/desorption
Ka , Kd KOC > 426580 l/kgOC at 1 µg/l (log KOC >5.63) (HPLC method, OECD 121) Kaoc , Kdoc
pH dependence (yes / no) (if yes type of dependence)
Fate and behaviour in air Direct photolysis in air Due to a low volatility (solids’ vapour pressure is 6.0 x 10–5 Pa at 25°C) significant exposure of air is unlikely. Quantum yield of direct photolysis Not determined Photo-oxidative degradation in air Photooxidation reactions (AOPWIN):
DT50OH-radical = 0.040 days (28.6 minutes) –12 3 kOH = 269.69×10 m /molecule/sec (@ OH-radical concentration 1.56×10–6/cm3 during 12 hours every day).
DT50ozone = 0.028 days (39.7 minutes) –17 3 kozone = 41.62×10 cm /molecule/sec 11 3 (@ O3-concentration 7×10 mol/cm during all 24 hours of a day). The fraction sorbed to airborne particles is estimated to be 30% (based on applicant’s vapor pressure and equation 19 in Vol IV B). The sorbed fraction may be resistant to atmospheric oxidation reactions. Volatilization Cholecalciferol has a low volatility with a measured vapour pressure of 6.0 x 10–5 Pa at 25°C and a calculated Henry’s law constant of 30.77 Pa×m3/mol 20°C. Exposure to aquatic systems is unlikely and therefore partitioning from water to air is not considered to be an important exposure pathway.
Monitoring data, if available Soil (indicate location and type of study) No monitoring data available. Surface water (indicate location and type No monitoring data available. of study) Ground water (indicate location and type No monitoring data available. of study) Air (indicate location and type of study) No monitoring data available.
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Chapter 5: Effects on Non-target Species
Toxicity data for aquatic species (most sensitive species of each group) Species Time-scale Endpoint Toxicity Fish Study waived Sufficiently reliable data for the currently applied uses are available. Waiving accepted for uses described in the CA report. Invertebrates Study waived No reliable data are available. Waiving accepted for uses described in the CA report. Algae Study waived No reliable data are available. Waiving accepted for uses described in the CA report. Microorganisms Activated sludge 3 hours Respiration EC50 > 1000 mg a.s./L (based inhibition on nominal loading rate) NOEC < 0.0005 mg a.s./L (equal to water solubility)
Effects on soil microorganisms
Nitrogen mineralization EC50 > 1000 mg a.s./kg soil dw NOEC = 1000 mg a.s./kg soil dw
Effects on earthworms or other soil non-target organisms Acute toxicity Study waived
Reproductive toxicity to Eisenia fetida LC50 > 1000 mg a.s./kg soil dw (5% peat)
NOEC = 1000 mg a.s./kg soil dw (5% peat)
Effects on terrestrial plants
Seedling emergence of Solanum EC50 = 287 mg a.s./kg soil dw (based on lycopersicum (tomato, most sensitive biomass) species) EC50 = 192 mg a.s./kg soil dw (based on
emergence) NOEC = 41 mg a.s./kg soil dw (based on biomass) NOEC = 119 mg a.s./kg soil dw (based on emergence)
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Effects on terrestrial vertebrates
Acute toxicity to birds Bobwhite quail (Colinus virginianus) LD50: >2000 mg a.s./kg bw
Mallard duck (Anas platyrhynchos) LD50: >2000 mg a.s./kg bw
Dietary toxicity to birds Bobwhite quail (Colinus virginianus) LC50 = 600 ppm (a.s.), NOEC = 93.6 ppm (a.s.)
Mallard duck (Anas platyrhynchos) LC50 = 1200 ppm (a.s.), NOEC = 93.6 ppm (a.s.) Reproductive toxicity to birds Study waived Acute toxicity to mammals LD50 dogs 10–80 mg/kg bw (low reliability) (for PNEC derivation, rat LD50 are used) Non compartment specific effects Reported cases of secondary poisoning with relevant to the food chain (secondary cholecalciferol are not known, in contrast with poisoning) other PT14 substances (e.g. AVKs) for which this is a well-documented problem. Nevertheless, secondary poisoning is theoretically predicted to be unacceptable, also for cholecalciferol. There is a need for EU- harmonised risk mitigation measures.
Effects on honeybees Acute oral toxicity Study waived Acute contact toxicity Study waived
Effects on other beneficial arthropods Acute toxicity Study waived
Bioconcentration Bioconcentration factor, aquatic (BCF) Waiving accepted for uses described in the CA report Bioaccumulation factor, terrestrial (BAFss) 0.15 (earthworms)
Chapter 6: Other End Points
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APPENDIX II: LIST OF INTENDED USES (AS PROPOSED BY THE APPLICANT WITH eCA REMARKS AND CONCLUSIONS IN THE LAST COLUMN).
The following uses are intended for the reference products: Rodent control in and around buildings by professionals and non-professionals for the purpose of the protection of public health, including13: •Prevention of transmission of disease; •Prevention of the contamination of food and feedingstuffs and other materials, at all stages of their production, storage and use; •Protection of buildings and structures including pipes, cables and overall integrity; •Protection of livestock, wild and domestic; •Social abhorrence and stigma; •Legal requirement
13 eCA comment: Only the use as biocide PT 14 rodenticide has been evaluated. Health claims and level of protection such as level of prevention of disease spreading, level of prevention of property damage, level of protection of livestock and and social abhorrence and stigma have not been assessed and verified by the eCA.
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Product Organisms Formulation Application name controlled Remarks and conclusions of the eCA of the applicants proposed intended use in column 1-7: Type Conc. of method number interval between (d-f) a.s. kind min applications (min) (i) (f-h) max
® Selontra Mice14 (e.g. RB 0.075% Baiting Up to Frequently over first The use evaluated is professional and non-professional 750 ppm Mus musculus/ (ready 40g (2 10-days and regularly control of mice and rats in and around buildings. The Soft Block domesticus/ to use units) as consumption use evaluated only includes paste bait in bait-boxes or spretus, Mus bait) every 1- continues. covered and protected bait points of a similar level of musculus 2 linear protection, placed where no food or feed item musculus). meters15 contamination is expected. General efficacy of 0.075% cholecalciferol was shown for Mus musculus domesticus and Rattus norvegicus including anticoagulant resistant strains. For individual formulations efficacy should be verified by data in the event of product approval.
® Selontra Rats14 (e.g. RB 0.075% Baiting Up to Frequently over first See above 750 ppm Rattus (ready 150g (8 10-days and regularly Soft Block norvegicus, to use units) as consumption Rattus rattus) bait) every 10 continues. linear meters15
14 eCA comment: Efficacy was not shown for Rattus rattus or for mouse strains other than Mus musculus domesticus. 15 An adequate number of baits points are used. Protected bait points are placed in appropriate positions to help prevent access by non-target animals. The number of bait points employed and the amount of product used is dependent on the treatment site; the size and severity of the infestation; the user and the user’s requirements and needs. A large number of bait points would be used on a site where immigration pressure is high, the existing infestation is heavy, and the user is professionally competent and requires maximum control. Conversely, a low number of bait points would be used in a domestic premise where the householder had sightings of a rodent pest and considered it necessary to take some action.
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Product Organisms Formulation Application name controlled Remarks and conclusions of the eCA of the applicants proposed intended use in column 1-7: Type Conc. of method number interval between (d-f) a.s. kind min applications (min) (i) (f-h) max
Harmonix House Mouse RB 0.075% Baiting Up to 20g of product must See above Rodent (Mus musculus (ready 20g be added when bait ® Paste domesticus, to use every 2- has been totally M. m. bait) 20 linear consumed within one musculus)16 meters17 control interval. Subsequent follow-up visits must to be no more than 14 days apart. Harmonix Roof Rat and RB 0.075% Baiting Up to 200g of product must See above Rodent Norway Rat (ready 200g be added when bait ® Paste (Rattus rattus, to use every 3- has been totally Rattus bait) 20 linear consumed within one norvegicus)16 meters17 control interval. Subsequent follow-up
visits must be no more than 14 days apart.
16 eCA comment: Efficacy was not shown for Rattus rattus or for mouse strains other than Mus musculus domesticus. 17 An adequate number of baits points are used. Protected bait points are placed in appropriate positions to help prevent access by non-target animals. The number of bait points employed and the amount of product used is dependent on the treatment site; the size and severity of the infestation; the user; and the user’s requirements and needs. A large number of bait points would be used on a site where immigration pressure is high, the existing infestation is heavy, and the user is professionally competent and requires maximum control. Conversely, a low number of bait points would be used in a domestic premise where the householder had sightings of a rodent pest and considered it necessary to take some action.
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