DEFRA commission PS2108

Towards cost effective registration of natural semiochemicals for crop protection in the UK

PSD considerationof pre-submission edition of a dossier submitted to support the inclusion of a semiochemical in Annex I of Council Directive 91/414/EECand product approval in the UK.

METHYL SALICYLATE

October 2006

1

Methyl salicylate

Background information

Notifier / Rothamsted
Active substance name: / Methyl Salicylate
Product name(s) (if different): / Not known (unformulated?)
Function (eg Herbicide, insecticide) / Insect repellant
What is the intended use? (attach GAP table if appropriate)
Control of aphids in cereal crops via a slow release formulation of the vapour.
Is the substance also approved for a different use? (food, feed additive, biocide / Medicinal and flavouring agent
(see * below)
Grade of active? / Food/Feed/Trade/not given– not given
Grade of product? / Food/Feed/Trade/not given – n/a
Does the active/product occur naturally? / Yes (it is involved in host plant location by Rhopalosiphum padi).
How does it occur? (eg in soil, as plant) / From plants
Is there a summary dossier? / Yes
Have example labels been provided? (Give location) / No
Have previous national or international evaluations been included in the dossier, (eg EPA, ECFA, JMPR, check CIRCA for EPA evaluation) Including from OECD countries / Some info from NIST/EPA database (IIA 2.5.1/04) and from National Toxicology Programme by NTIS (IIA 2.5.1/05 and 06).
Have any database searches been included and if so what search terms were used?
Please refer to pages 7-12 of Annex 1 Project Report to PS2108 for further details.
Are any tests/studies still Ongoing/not fully complete? If so which ones
No (JSC have however highlighted on p33 of the overview report a list of possible studies that could be done together with costings).

(* The dossier contains the following details about use of methyl salicylate:

’’Methyl salicylate is also known as: ‘Oil of wintergreen’ which is a common ingredient for liniments, ointments and essential oils used in self-treatment of musculoskeletal pain. Its pleasant smell also encourages its use to flavour confectionery.’’ (IIA 5.9.2/01 - 2001).

‘’The two chief uses of methyl salicylate are as a flavouring agent and as a rubefacient and counterirritant. As a flavouring agent it is found in candies, cough drops, lozenges, chewing gum, toothpastes, mouth washes, root beer and such medications as aromatic cascara sagrada. As a rubefacient and counterirritant it is the active ingredient of a variety of liniments and other topical products designed to relieve muscle and joint aching’’. (IIA 5.9.2/09 - 1979))

Identity:

Active substance (and any alternative names):

Brief Summary of Data Provided:
Eg: Method of manufacture,
Technical specification of active substance,
Minimum purity,
Formulation details,
Chemical name(s) of constituent(s)
Methyl salicylate is employed as the major component of a fully definable essential oil (oil of wintergreen) and acts as an indicator of plant stress, and therefore non-host status, thereby reducing aphid colonisation of, for example, cereal crops.

Molecular and structural formula, molecular mass

Molecular formula: / C8H8O3
Structural formula: /
Molecular mass: / 152.15
Common name, IUPAC and CA chemical names, CAS, EINECS, ELINCS numbers, molecular formula, mass and structural formula provided.
No information provided on the specification of purity, identity of isomers, impurities etc, analytical profile of batches, or whether any toxicologically relevant impurities had been identified (Document J not available).
JSC note that ‘ultimately, this section will need to address the profile of the commercial materials and those materials used to generate data within the published reports’.
Have sufficient data been provided to allow an appropriate risk assessment on the active substance and product to be performed?
Basic information on common name, IUPAC and CA chemical names, CAS, EINECS, ELINCS numbers, molecular formula, mass and structural formula has been provided.
No information provided on the specification of purity, identity of isomers, impurities etc, analytical profile of batches, or whether any toxicologically relevant impurities had been identified (Document J not available).
Further information required:
(State timescale if Appropriate)
Good information on characterisation of the material is required to GLP to include.
  • Clarification on whether methyl salicylate is an extract or synthesized chemical.
  • Where relevant, information on how the preparation in question compares with those used or evaluated elsewhere e.g in food manufacture, pharmacy or aroma therapy.
  • In line with OECD guidance, PSD would consider 3 batch analysis adequate to demonstrate consistency in production (unless the three batches indicated considerable batch to batch variation in which case standard 5 batches would be required).

Physical and chemical properties:

Active substance (and any alternative names):

Brief Summary of Data Provided:
Eg: Description of physical state and odour,
n-octanol water partition coefficient,
solubility,
stability in water/rate of hydrolysis,
storage stability,
flammability/explosivity etc,
stability in air
ease of handling,
Information has been submitted on melting point, boiling point, relative density, vapour pressure, Henry’s law constant, physical state, odour, UV/Vis (as) etc, solubility in water, partition co-efficient n-octanol water, hydrolysis rate at pH 4, 7 and 9, direct phototransformation, dissociation constant, autoflammability, flash point.
None of the information has been generated to GLP. Very few studies provide details on the method used (Column 2) and test material purity (Column 3).
No information on quantum yield (UV wavelength max is 310 nm), estimate of photochemical oxidative degradation (Atkinson equation), solubility in organic solvents, explosive and oxidising properties and surface tension.
No AIII data – p27 of the overview report clearly states that the compound is not formulated.
Have sufficient data been provided to allow an appropriate risk assessment on the active substance and product to be performed?
Information has been submitted on a range of properties. No information on quantum yield (although this may not be required if fate evaluation concludes that there is no contamination of the environment from use of the impregnated strips), estimate of photochemical oxidative degradation (Atkinson equation), solubility in organic solvents, explosive and oxidising properties and surface tension.
Further information required:
(State timescale if Appropriate)
  • Further detail required on which studies were performed with pure or technical material.
  • Expert statements should be acceptable to address the points regarding oxidative and explosive properties. Bretherick's Handbook of Reactive Chemical Hazards (Hardcover) by Peter Urben (Editor, 7th Edition) may be a useful reference.
  • An Atkinson calculation needs to be carried out. If >2days then long range transport will need to be considered.

Uses and further information (please also refer to section on Efficacy):

Brief Summary of Data Provided:
Eg Uses,
Mode of action and effect,
Metabolites and degradation,
Safety data sheet,
Method, timing and rate of application,
Waiting periods, limitations etc,
Instructions, label and packaging,
Storage, transport, containment etc
Disposal and emergency procedures.
Methyl salicylate is referred to by JSC as ‘an unformulated volatile compound which occurs naturally and is released only into the air from impregnated plastic strips suspended around cereal crops’.
GAP table is attached to this document and includes two other application methods in addition to the impregnated strips (which do not appear to be mentioned elsewhere in the submission) and also gives information on impregnation concentrations. JSC note that ‘use scenarios are selected which have proven efficacy and known commercial interest’.
p27 of the overview report clearly states that the compound is not formulated so the AIII package would be limited to studying the release of the compound from its plastic strip applicator system. No label has been provided for the impregnated strips.
No details have been provided on possible metabolites although Section 3.5.3 in Document MII states that ‘Gentisic acid has also been detected in a number of tissues, together with a number of conjugated metabolites of both compounds. Methyl salicylate is the active semiochemical and both salicylic acid and gentisic acid are biologically inactive (as semiochemicals) degradation products.’
Have sufficient data been provided to allow an appropriate risk assessment on the active substance and product to be performed?
Further information/clarification on the proposed GAP/application method(s) is required, for example it is not clear how the impregnated strips are ‘activated’ and whether they are held within a dispenser and how may strips are to be used per hectare. Such information will help to determine possible exposure routes (use in a greenhouse would simplify the risk assessment in many areas).
Further consideration of possible metabolites would also be useful.
Further information required:
(State timescale if Appropriate)
  • Clarification of the intended use and GAP.
  • How are the impregnated strips ‘activated’ (this also applies to the other methods of application if they are also under consideration). Are they held in a dispenser? What do the strips consist of?
  • How many strips are needed per hectare?
  • Further commentneeded on possible metabolites and their potential activity (particularly as salicylic acid is purported to be an elicitor itself).

Methods of Analysis:

Brief Summary of Data Provided:
Eg: methods for
Parent active substance (including significant impurities and additives),
Metabolites,
Residues of parent and metabolites in soil, water, crops, animal products,
Product impurities and additives
No information is available.
JSC note that work is underway on methods for identifying and analysing semiochemicals which will be used to validate and support the specification of the technical material at a time when a decision is taken to move to the commercial phase and to gain registration.
No methods for the determination of residues in crops or the different environmental compartments (soil, water, air) are available. Where scientific arguments can be provided to demonstrate no exposure, analytical methods might not be required.
Have sufficient data been provided to allow an appropriate risk assessment on the active substance and product to be performed?
With regard to determining the content of the active substance and relevant impurities in the technical specification validated methods will be needed where the technical specification is supported by batch analysis data.
The method for the technical specification is likely to be suitable for the post-registration method but will require validation.
From a plant perspective if there is no expected exposure to the crop then a method to determine residues in the treated crop will not be required.
If the material is to be applied via a dispenser for example and it can be established then no contamination of soil, groundwater and surface water occurs then it may be possible to present arguments to waive the need for methods for these areas.
Methods for body fluids and tissues, only required if active substance is classified as toxic or highly toxic.
It is noted that this is a relatively volatile compound and that a method for air has been developed. The specific requirement for validation is dependent on whether exposure via air (to operators and/or the environment) will occur.
Further information required:
(State timescale if Appropriate)
The need for further information is subject to the outcome of consideration of each of the points above.

Mammalian toxicology/operator exposure:

Brief Summary of Data Provided:
Eg: Acute Studies; oral, inhalation, percutaneous,
Long term studies; oral, inhalation
Reproductive studies: Genotoxicity, Teratogeneticity
Cacinogenicity and neurotoxicity studies,
Opex: Operator, worker, bystander
NB if the substance is already used in food/feed these may not be required.
Two reports are to GLP but the remainder varied much in quality.
Information has been submitted to address the main areas of tox.
No information provided on exposure to operators, workers or bystanders.
According to the physchem section methyl salicylate is relatively volatile , vapour pressure is >1 x 10-2 Pa (4.6 Pa) thereby requiring an acute inhalation toxicity study.
Have sufficient data been provided to allow an appropriate risk assessment on the active substance and product to be performed?
Overall the information provided is limited. In general information is required on acute toxicity of the active substance (this can then be calculated for a formulation), mutagenicity and argumentation for not needing long-term studies.
According to the OECD guidance document if the substance is part of a well-known group of substances (ie. an SCLP); or it is present below background levels or within levels used in other scenarios with significant human exposure then there is no need for further data to that mentioned in the paragraph above.
However, in the case of methyl salicylate, JECFA (Joint FAO/WHO Expert Committee on Food Additives) has carried out a full assessment of this compoundas a food flavouring and has derived an ADI, therefore there is no need for the use of ‘a threshold of toxicological concern’. It may also be possible to calculate an AOEL from this report which will allow us to assess operator exposure by comparing the AOEL to the amount of the active substance on the impregnated strip.
The information provided on dermal and inhalation toxicity is sufficient for classification at present (no obvious requirement for classification).
Further information required:
(State timescale if Appropriate)
Although the information provided is limited it is considered sufficient when taken together with the JECFA evaluation and should allow a conventional assessment to be carried out.

Residues:

Brief Summary of Data Provided:
Eg
Crop metabolism data,
Residue definition,
Residue trials, feeding studies,
Effects of processing
Effect of waiting periods on residues (eg withholding/re-entry)
Estimation of consumer exposure
Methyl salicylate is not intended for application directly to the crop (it is intended to be suspended in the crop following impregnation onto materials such as plastic strips) and so no residues information has been provided.
Have sufficient data been provided to allow an appropriate risk assessment on the active substance and product to be performed?
Agree that as there is no direct application to the crop no residues information is required.
Further information required:
(State timescale if Appropriate)
No further information required at this stage.

Environmental Fate and Behaviour:

Brief Summary of Data Provided:
NB – Consider whether the intended use will result in release into the environment
Eg
For both parent and metabolites:
Soil: degradation; Field, Lab and lysimeter studies, Soil accumulation
Water: groundwater and surface water, PECs leaching, photo degradation,
Air: route of travel, degradation
Due to the intended use (impregnated strips suspended in the crop) the main route of environmental exposure is expected to be volatilisation into the atmosphere.
The summaries of the ready biodegradability reports do not indicate which environmental compartment was tested.
Have sufficient data been provided to allow an appropriate risk assessment on the active substance and product to be performed?
Incorporation into plastic strips avoids some fate-related requirements. However we support JSC’s view that further consideration of the potential for methyl salicylate to contaminate soil and water is required, for example can it be washed off the plastic application strips.
As the main route of environmental exposure will be volatilisation into the atmosphere, data on the fate and behaviour of methyl salicylate in air, along with data on levels released into the atmosphere will be required. Vapour pressure and Henry’s law constant data are available. As stated previously an Atkinson calculation is required to establish the potential for long-range transport.
There should be consideration of the expected fate and behaviour of any metabolites / degradation products of potential environmental relevance / concern.
A future issue to be aware of is the preparation of a FOCUS guidance document for air. This indicates that for a substance which is likely to be volatile possible deposition on soil and surface water, where it may contribute to the loading in these compartments, may need to be taken into account.
Further information required:
(State timescale if Appropriate)
  • Can methyl salicylate be washed off the plastic application strips?
  • If so, are data available on the amounts likely to be washed off following a typical rainfall event?
  • Could the sticks on which the lures are suspended in the field fall over to allow direct exposure of the chemical to soil and/or water bodies?
  • How long are the plastic strips expected to be effective in the field?
  • An Atkinson calculation needs to be carried out. If >2days then long range transport will need to be considered.
  • Consideration of the expected fate and behaviour of any metabolites / degradation products of potential environmental relevance / concern.

Ecotoxicology:

Brief Summary of Data Provided:
NB Consider whether the intended use will result in non-target organisms being exposed
Eg: Toxicity and risks to the following:
Birds
Aquatic organisms
Terrestrial vertebrates (Mammals)
Bees
Non-target arthropods
Earthworms
Soil macro organisms
Soil micro organisms
Very little information was found on methyl salicylate (bees and earthworms only).
Is this semio chemical likely to work on other insects (eg. beneficial ones?)
Honeybees and NTAs – the risk to honeybees and NTAs must be addressed, except where use is in situations where there is no exposure.
Need classification and labelling?
Have sufficient data been provided to allow an appropriate risk assessment on the active substance and product to be performed?
Further ‘study’ details required for honeybee and earthworm information.
We note JSC’s comment on honey bees and non-target arthropodsand the need for information to address whether behaviour or reproduction would be affected (particularly if exposure is likely to exceed natural background levels). The information presented on bees indicates no adverse effects so provided application is kept localised in dispensers then there should be no problem for other non-target arthropods. A clear understanding of how methyl salicylate works would help in constructing cases for not conducting certain studies.
The need for further data on earthworms is dependent on the Atkinson calculation and also whether it can be shown that methyl salicylate cannot reach the soil by the application method proposed.
Acute toxicity studies on aquatic organisms (fish, invertebrates and algae) will be required for hazard classification purposes.
If it is found that methyl salicylate can be washed off the plastic strips and be present in soil at greater than background levels then information on effects on soil micro-organisms will be required.
Further information required:
(State timescale if Appropriate)
  • Further ‘study’ details required for honeybee and earthworm information.
  • Information to address whether behaviour or reproduction would be affected (particularly if exposure is likely to exceed natural background levels) – depends on the method of application).
  • Acute toxicity studies on aquatic organisms (fish, invertebrates and algae) for hazard classification purposes.
  • Possible information on soil micro-organisms (depends on further fate assessment).

Efficacy (please also refer to section on Uses and further information):