HK1088542A - Method of dermal protection - Google Patents

Description

Skin protection method

The present invention relates to a method of skin protection, and in particular to a method of skin protection after skin contact with a composition comprising a bipyridylium herbicide.

The term "skin protection" as used herein refers to reducing the adverse consequences of contact between skin and a composition containing a bipyridylium herbicide. Such adverse consequences include, but are not limited to, skin irritation and acute transdermal toxicity. Improved skin protection may be the result of reduced skin penetration of the bipyridylium herbicide, and in addition, in general, a reduction in skin penetration is indicative of improved skin protection. It will be appreciated, however, that the present invention provides improved skin protection for bipyridylium salt herbicidal formulations which includes potential skin irritation normally present in such formulations and is independent of the mechanism by which such protection is actually achieved. In contrast to herbicidal sprays after dilution, adverse skin irritation and acute transdermal toxicity reactions typically occur upon contact, especially prolonged contact, with the herbicidal concentrate formulation prior to dilution.

Bipyridinium salt herbicides have been registered for use in agriculture for many years and can be used safely and effectively if accompanied by manufacturer's label recommendations. Proper prevention of accidental contact with the skin is recommended. The regulatory authorities have therefore evaluated the potential risks posed by skin contact with different types of compositions. In the currently available public-aware regulatory convention, skin irritation is defined in terms of the effect of exposure of the skin to agrochemical concentrate formulations over a defined period of time, typically 4 hours. The exposed surface is then decontaminated and observed at a subsequent time, classifying the skin irritation according to the regulatory standards of national or international regulatory agencies, such as the EU. Alternative methods for assessing skin irritation have been developed for regulatory purposes and may also be used to determine potential skin irritation. Transdermal toxicity is defined by the dose (mg/kg) of the agent that causes a systemic toxic response via the cutaneous route of entry. Obviously, any reduction in skin irritation or transdermal toxicity is highly desirable.

EP 0467529 describes a liquid aqueous herbicidal composition comprising a salt of paraquat or diquat or a mixture thereof in a concentration of at least 50g/l in admixture with a suspension of from 10 to 400g/l of a magnesium trisilicate, the composition further comprising an emetic and/or purgative. The magnesium trisilicate forms a gel at the pH of human gastric juice, and the specification further discloses an aqueous liquid herbicide comprising: (i) a herbicidal component comprising a salt of paraquat or diquat or a mixture thereof; (ii) a gelling agent that will gel at the pH of human gastric juice; and (iii) an emetic and/or purgative; wherein the ratio of the herbicidal component to the gelling agent is from 1: 1 to 20: 1. The object of the present invention is to reduce the possibility of harmful effects after intake of bipyridinium salts. Thus, if a certain amount of the composition of the invention is ingested, the acidity of the gastric juice (which varies over a fairly wide range, but averages about pH 1.92 for men and about 2.59 for women) will cause the composition to gel in the stomach. Increasing the viscosity of the stomach contents decreases the rate of gastric emptying. The bipyridylium herbicide will thus be trapped in the gel, which will prevent it from moving from the stomach and into the absorbed small intestine. The emetic present in the composition is absorbed relatively rapidly and will be expelled in a short time by vomiting from the gel containing the bipyridylium herbicide, thereby preventing the ingested herbicide from migrating further into the gastrointestinal tract, where absorption of the bipyridylium compound would otherwise occur. In preferred compositions, the composition contains a purgative to help clear any unabsorbed bipyridylium herbicide that has passed from the stomach into the small intestine despite the emetic effect. In the case of ingestion of the bipyridinium salt composition of the invention EP 0467259, the synergistic effect of the gelling agent, emetic and purgative (when included) will substantially reduce the absorption of the bipyridinium salt compound from the gastrointestinal tract into the bloodstream, thereby reducing the oral toxicity of the product.

The formulations described in EP 0467259 have not proven commercially viable in practice. The inclusion of a thickening or suspending agent has been found to be critical to maintaining the particles of the insoluble gelling agent, magnesium trisilicate, uniformly dispersed in the composition during storage and transport. However, purely by their nature, thickeners increase the viscosity of the composition and the balance between the problems associated with high viscosity compositions and the need to increase the viscosity to reduce the precipitated solid inorganic gelling agent has to be struck. In fact, this balance has proven to be an unpleasant compromise due to the relatively poor stability of the composition in terms of precipitated solid gelling agent, and it has also been demonstrated that excessive stickiness leads to difficulties in pouring and measuring the composition, in the spray tank it is difficult to effectively disperse the composition in water and in rinsing empty containers. Precipitation of the dispersed solid inorganic gelling agent can produce a concentration gradient of magnesium trisilicate versus emetic, so that if the components of the formulation are used in any one ratio, the relative proportions of the ingredients contained in the spray tank will not be consistent with those given, and so the safety effect will be far from optimal. The preferred thickening or suspending agent is xanthan gum sold under the tradename KELZAN, and this xanthan gum is the only suspending agent used in the examples. However, there is a short note here: other suitable suspending agents include alginates.

WO02/076212 discloses that alginate by itself is a surprisingly effective pH-sensitive gelling agent when used as a pH-sensitive gelling agent in combination with a bipyridinium salt formulation. WO02/076212 therefore discloses the use of alginate as a pH-triggered gelling agent in the preparation of a composition comprising a salt of paraquat, a salt of diquat or a mixture thereof, and the composition further comprising an emetic and/or purgative, whereby a pH-triggered gelling occurs at the pH acidity of human gastric juice.

It will be appreciated that the inventions described in EP 0467529 and WO02/076212 are fully directed to the reduction of the oral toxicity of bipyridylium salt herbicidal concentrate formulations when ingested either deliberately or accidentally. The mechanism relies on physical expulsion of the gel composition from the stomach by emetic before it is absorbed, and also by purgation to help remove any unabsorbed bipyridylium salt herbicide which, despite the emetic effect, passes from the stomach into the small intestine. We have now found that alginates have a surprising effect in reducing skin irritation and/or dermal toxicity after skin contact with a bipyridylium herbicidal composition. This effect cannot be foreseen on the basis of the teaching given in WO02/076212 and the completely different mechanism by which alginate acts on gels at gastric pH, followed by physical expulsion of vomiting.

Solid calcium alginate is used as a wound dressing, typically in the form of a non-woven sheet or a patch of fibres or cords, and is particularly useful for heavily exuding chronic wounds such as venous leg ulcers, diabetic ulcers and pressure sores. A review published on Wound Care news setter, 10 months 1998 discloses that alginate fibers absorb and interact with liquid exudates from the Wound and become hydrophilic gums. Alginates tend to maintain moisture in the wound and promote the formation of granulation tissue. Once removed, the dressing can be washed away with saline rinses.

The present invention provides a method of protecting skin following contact with a composition comprising a bipyridylium herbicide, the method comprising incorporating an alginate into the composition.

The term bipyridylium herbicide includes paraquat, diquat and mixtures of paraquat and diquat. Paraquat and diquat are typically formulated in agriculturally acceptable forms, such as water soluble salts. The compositions for use in the present invention are suitable aqueous concentrates which are diluted as required prior to application.

The aqueous composition of the invention thus suitably comprises at least 25g/l, for example at least 40g/l, of paraquat or diquat or mixtures thereof (referred to herein individually or in combination as bipyridinium salt), expressed as bipyridinium ions. The composition may comprise more than 50g/l, for example more than 100g/l, of bipyridinium ion. Although the concentration of paraquat is close to its upper limit above about 250 or 350g/l, where the stability of the composition is problematic, it is also possible to prepare compositions comprising 200g or more of paraquat per liter. Generally, the composition does not contain more than 400g/l of bipyridinium ion. Thus, typical concentrate compositions contain from 50g/l to 250g/l of bipyridinium ion.

The term alginate as used herein refers to a class of natural block copolymers extracted from seaweed consisting of uronic acid units, specifically 1-4a, L-guluronic acid and 1-4b, D-mannuronic acid linked by 1: 4 glycosidic linkages. The general structure is shown in figure 1 below.

FIG. 1 shows a schematic view of a

The ratio of mannuronic acid/guluronic acid residues (M: G) varies depending on the seaweed source. Alginates are typically classified as "high-G" or "high-M". Alginates are commonly sold as sodium salts, but different commercial grades may contain varying proportions of residual calcium ions.

The mechanism by which alginates act to achieve skin protection is not well understood and several alternative theories may be proposed by explanation. It is clear, however, that this is quite different from the "triggered gel" theory described in WO02/076212, regardless of the mechanism. First, although the skin may be somewhat acidic in some cases, it is much less acidic than stomach acid. The stomach is effectively an acidic container that receives the swallowed composition and is in contact with the highly acidic gastric fluid, the composition gel. Thereby aiding in the removal of the swallowed composition from the body by vomiting. In contrast, the skin is a neutral or only slightly acidic surface that is least likely to "trigger" any effective gelling action. Furthermore, the liquid composition will immediately start to dry when it comes into contact with the skin. The skin irritation is caused at least in part by the skin penetrating properties of the bipyridylium compound remaining dry on the skin. It is possible that the alginate has a skin protective effect on compositions dried on the skin, but it is not known how this is achieved in particular.

No connection is seen between the help of solid calcium alginate dressings to heal severely exuding chronic wounds and the skin protection effect of the present invention.

We have found that the addition of alginate does not necessarily provide significant skin protection for conventional skin irritating agrochemical compositions, and that the skin protection of alginate appears to be primarily specific to bipyridinium ion containing herbicidal compositions. The reason for this is unknown.

Examples of commercially available alginates suitable for use in the process of the invention are shown in the following table:

alginate salts	Proportion of monomers	Ca2+Content (wt.)	1% viscosity (mPas)	Approximate average molecular weight	pH of 1% solution
						MANUTEX RM	High M: G	Low Ca2+At most 0.4%	200-400	120,000-190,000	5.0-7.5
MANUTEX RD	High M: G	Low Ca2+At most 0.4%	4-15	12,000-80,0000	5.0-7.5
						KELGIN HV	High M: G	High Ca2+Maximum 1.5%	600-900	120,000-190,000	6.4-8.5
KELGIN LV	High M: G	High Ca2+Maximum 1.5%	40-80	80,000-120,000	6.4-8.5
						MANUGELGMB	High G: M	Low Ca2+，0.2-0.5％	110-270	80,000-120,000	5.0-7.5
MANUGELGHB	High G: M	Low Ca2+，0.2-0.5％	50-100	80,000-120,000	5.0-7.5
						KELCOSOL	High M: G	High Ca2+Maximum 1.5%	1000-1500	120,000-190,000	6.4-8.0

The skin protection provided is not critically dependent on the molecular weight of the alginate. The average molecular weight of the alginate is preferably from 5,000 to 250,000, such as from 10,000 to 250,000, and preferably from 10,000 to 200,000. We have found that for example the use of both MANUTEX RM (molecular weight 120,000 to 190,000) and MANUTEX RD (molecular weight 12,000 to 80,000) provides good skin protection. Mixtures of different grades of alginate may be used as desired. Under defined set conditions, the molecular weight of an alginate reflects the viscosity of its aqueous solution. Preferred alginates have an average viscosity of 2 to 2000mPas, for example 2 to 1,500mPas, especially 2 to 1000mPas, and preferably 4 to 450mPas, in a 1% aqueous solution (referred to herein as "1% solution viscosity") at 25 ℃ as measured in the LV format using a BROOKFIELD viscometer (Brookfield Engineering laboratory, Stoughton, Mass.) using 3 spindles at 60 rpm.

Particularly preferred alginates are those sold under the trade names MANUTEX RM and MANUTEX RD. MANUTEX, MANUGEL, KELGIN and KELCOSOL are trademarks of ISP. The concentration of alginate in the composition is typically in the range 1 to 50g/l, for example 3 to 50g/l, or alternatively 5 to 20g/l, and preferably 5 to 15 g/l. Higher concentrations may be used as desired, but this increases the viscosity of the composition beyond what is practically acceptable for commercial products, while concentrations below 3g/l may not provide adequate skin protection. The pH of the composition is not critical in terms of the skin protection provided by the alginate and may be used at the pH inherent in the bipyridylium composition or may be adjusted as desired to improve stability or for any other reason. Typical values for paraquat compositions are between about pH4 and pH9, for example between about pH6.5 and pH7.5, and especially about pH7. The pH of diquat is typically adjusted to between about pH5 to pH6. Conventional acids or bases such as acetic acid or sodium hydroxide may be used to adjust the pH of the composition as desired.

For most applications, a high viscosity formulation of its intrinsic pH is not desirable, and it is preferred that the viscosity of the formulation of the invention ("composition viscosity") as determined using the method of example 1 is below 300mPas, preferably below 200mPas, for example from 10 to 250mPas, and preferably from 20 to 200 mPas. It is recognized, however, that high viscosity formulations, such as those having a viscosity of 300mPas or higher, may be useful in certain applications. The viscosity of the composition will, of course, depend on the total amount of the contents, including any surfactant present.

The scope of the present invention is not limited to any particular aqueous bipyridylium salt herbicide composition. However, from the point of view of commercially advantageous concentrated formulations which usually contain conventional adjuvants or other additives, it is clearly desirable that the alginate should provide skin protection. Commercial compositions often include one or more surfactants or adjuvants in the composition to improve the biological performance of the herbicide. Such surfactants are well known to those skilled in the art and include cationic, nonionic and anionic compounds. Examples listed in EP 0467529 are disclosed and incorporated by reference. When one or more surfactants are present in the total amount of surfactants, the surfactant concentration is preferably from 25 to 200g/l of the composition, preferably from 50 to 150g/l, such as from 50 to 100g/l, especially from 50 to 70 g/l. It will be appreciated that the presence of alginate promotes skin protection of the overall composition, which includes the bipyridylium herbicide, surfactant and other components which may be present as described below. Inclusion of a surfactant to enhance biological activity may have adverse effects on the skin. However, in general, we have found that the action of alginates is primarily associated with bipyridylium salt herbicidal compositions and does not necessarily provide skin protection in the case of aqueous compositions containing only surfactants. Indeed even in the presence of alginate, bipyridinium salt compositions containing a skin irritating surfactant may exhibit a stronger skin irritating effect than corresponding compositions containing alginate without surfactant. It is important, however, that bipyridinium salt compositions containing alginate and surfactant exhibit lower skin irritation than corresponding compositions containing surfactant without alginate.

Examples of typical anionic surfactants include alkyl benzene sulfonates such as sodium or magnesium dodecyl benzene sulfonate (commercially available examples include NANSA HS 90/S); alkylethoxy carboxylates, e.g. of the formula R (OCH)₂CH₂)_nOCH₂CO₂A compound of H, wherein R ═ C₁₂-C₁₄Alkyl, and n ═ 6 to 12 (commercially available examples include EMPICOL CBF and EMPICOL CBL); c₅To C₂₀Straight-chain or branched alkyl sulfosuccinic acid disodium salts such as disodium lauryl sulfosuccinate and disodium isodecyl sulfosuccinate (commercially available from SudokuCommercially available examples include AEROSOL A268); two (C)₅To C₁₂Linear or branched) sodium alkyl sulfosuccinates such as dioctyl sodium sulfosuccinate (commercially available examples include AEROSOL OT); sodium alkyl sulfosuccinates such as sodium lauryl sulfosuccinate (commercially available examples include TEXIN 128P); naphthalene formaldehyde condensate sodium salt (commercially available examples include MORWET D425); sodium methyl oleoyl taurate (commercially available examples include ADINOL OT 64); carboxylic acid esters (commercially available examples include EURACOL M, TA); phosphate esters (commercially available examples include CRODAFOS); TEA-PEG-3 cocamide sulfate (commercially available examples include GENAPOL AMS).

Examples of typical nonionic surfactants include nonylphenol ethoxylates (commercially available examples include SYNPERONIC NP 8); block copolymers of ethylene oxide and propylene oxide (commercially available examples include SYNPERONIC PE/F88); alkylamine ethoxylates (commercially available examples include SYNPROLAM 35x15, ethmoeen C25 or T25, and NOVAMINE); ethoxylated linear alcohols (commercially available examples include LUBROL 17a 17); other alcohol ethoxylates (commercially available examples include SYNPERONIC A range (11, 15, 20, etc.), ATPLUS 245); and fatty acid ethoxylates (commercially available examples include CHEMAX). It should be noted that surfactants such as alkylamine ethoxylates are sometimes classified as cationic surfactants, but at neutral pH values they are suitably considered nonionic in most compositions of the present invention.

Examples of typical cationic surfactants include amine ethoxylates and alkoxylated diamines (commercially available examples include JEFFAMINE products).

Paraquat is the common name for 1, 1 '-dimethyl-4, 4' -bipyridinium cation. Diquat is the common name for 1, 1 '-ethylene-2, 2' -bipyridinium cation. Salts of paraquat and diquat must contain anions with sufficient negative charges to balance the two positive charges on the bipyridinium core.

Since the characteristic herbicidal action of the bipyridylium quaternary cation is independent of the nature of the associated anion, the choice of anion is a matter of convenience and can be chosen, for example, on the basis of cost. Preferred anions are salts that give suitable water solubility. Examples of anions that may be monovalent or polyvalent include acetate, benzenesulfonate, benzoate, bromide, butyrate, chloride, citrate, fluorosilicate, fumarate, fluoroborate, iodide, lactate, malate, maleate, methanesulfonate, nitrate, propionate, phosphate, salicylate, succinate, sulfate, thiocyanate, tartrate, and p-toluenesulfonate. Salts of herbicidal bipyridinium cations may be prepared from some similar anions or mixtures of different types of anions. For convenience and economy, paraquat is usually sold as paraquat dichloride, while diquat is sold as diquat dichloride.

Since the characteristic herbicidal activity of the salts of the herbicidal bipyridinium quaternary cation lies only in the cation, it is customary to use the bipyridinium quaternary cation to indicate the concentration of the active ingredient and the application rate, unless otherwise stated.

If desired, paraquat or and diquat may be used in the formulations of the invention in combination with other agrochemical active ingredients, in particular with other herbicides. Mixtures of paraquat and diquat may also be used as the agrochemical active ingredients in the present invention. Typical mixing partners suitable for mixing with paraquat and diquat in the compositions of the present invention include: ametryn, diuron, atrazine, glyphosate, butafenacil, metribuzin, prometryn, and terbuthylazine. Many other mixing partners that can be incorporated into or used in a tank mix with the compositions of the present invention are known to those skilled in the art. Representative examples include: 2, 4-D, AC304415, acetochlor, aclonifen, alachlor, amicarbazone, imazapyr, azafenidin, BAS145138, benoxacor, bentazone, Bialophos, bromoxynil, butantrin, carfentrazone, CGA 276854, clomazone, clopyralid, quinclorac, flumetsulam salt (Cloransulam), cyanazine, dicamba, dichloropropylamine, dichlorsulam, diflufenzopyr, dimethenamid, fenclorim, fentrazamide, florasulam, flufenacet, flumetsulam, flumiclorac, flumioxazin, fluroxypyr, foramsulfuron, furazolidone, glufosinate, halosulfuron, imazasulfuron, imazapyr, imazaquin, imazamox, iosulfuron, isoxapyroxafen, MCPA, metosulam, MCPA, metosulam, Metolachlor, metosulam, MON4660, nicosulfuron, NOA-402989, pendimethalin, flumsulfuron, flumetsulam, prosulfuron, pyridate, rimsulfuron, S-dimethenamid, sethoxydim, S-glufosinate, simazine, Slurtamone, S-metolachlor, sulcotrione, glyphosate, terbutryn, thifensulfuron-methyl and triflusulfuron-methyl.

It will be appreciated that while the novel methods of the present invention provide improved skin protection, the compositions used in the methods of the present invention will also typically be formulated to reduce the consequences of accidental or deliberate ingestion and will therefore typically comprise a conventional emetic.

A variety of known emetics may be used in the compositions used in the methods of the present invention. However, the preferred emetic is the compound disclosed in UK patent No.1507407 for the formulation of bipyridinium salt herbicides, and a particularly preferred emetic is 2-amino-6-methyl-5-oxo-4-n-propyl-4, 5-dihydro-5-triazolo [1, 5-a ] -pyrimidine.

The amount of emetic used in the composition will vary depending on the particular type of emetic, but when the emetic class disclosed in UK patent No.1507407 is used, the concentration of emetic is preferably from 0.1 to 5g per litre of composition. For a composition containing 200g of bipyridinium salt compound per liter, the concentration is 1.0 to 2.0g/l, and particularly preferably 1.5 to 2.0g/l of emetic.

For some applications, the compositions of the present invention may also additionally comprise a purgative, such as magnesium sulfate.

When magnesium sulfate is used, the concentration of magnesium sulfate is preferably from 10 to 400g/l of the composition, and more preferably from 10 to 100g/l, based on the weight of dry magnesium sulfate without hydrated water. Higher concentrations of magnesium sulphate, for example up to 400g/l, may be used and may continue to improve the purgative effect, but such high levels of magnesium sulphate may have an adverse effect on formulation stability. The compositions used in the method of the invention may also contain conventional additives such as odorants (warning agents), for example the pyridine derivatives described in UK patent No.1406881, or n-pentanoic acid. The composition may also contain pigments or dyes to impart a characteristic color to the composition.

The compositions used in the process of the invention can be prepared simply and conveniently by mixing the components. The solid alginate may be added to an aqueous solution of the bipyridylium salt, or the alginate may be first mixed into water and subsequently added to an aqueous solution of the bipyridylium salt.

The invention is illustrated by the following examples in which all parts and percentages are by weight unless otherwise indicated. The concentration of the auxiliaries is given in each case by weight of the composition employed. When the concentration is below 100%, the concentration of the adjuvant in the composition is given. For example, the product NANSA HS90/S is provided as a 90% by weight solution of sodium dodecylbenzenesulfonate.

In example 1, the skin irritation effect was measured using regulation Protocol OECD 404 and 402, which have been published for implementation. In the examples that follow, skin irritation was determined using the in vitro Skin Irritation Function Test (SIFT) based on the electrical resistance of the ex vivo mouse skin, and in the in vitro model, the test was based on the skin penetration of the chemical to be tested itself. This test to reduce the amount of animals required for the test is described in "preliminary studies of the in vitro Skin Irritation Function Test (SIFT) to prevent acute skin irritation in vivo: results and evaluation of ECVAM Phase III, Diot, Esdaile, Fasano, Manning and Owen, in vitro toxicology 17(2003)123- "136", incorporated herein by reference. The document reports phase III efficacy tests with different chemicals. The SIFT test results are expressed as k Ohms of resistance after 20 hours of exposure to the test composition. Any magnitude of decrease in resistance indicates the degree of skin irritation.

The SIFT protocol identifies changes in skin barrier function following topical exposure of skin to potential skin irritants. Since disruption of this barrier promotes skin penetration, it is also highly desirable to determine the penetration of the test chemical itself in this in vitro model. The SIFT test is therefore modified to include the measurement of bipyridyl chemicals such as paraquat. The procedure was performed as described in Heylings et al, supra, except that the radioisotope-labeled paraquat was added to the quantified solution prior to application to the skin. The quantitative preparation is tested for homogeneity to ensure that the radiolabel is fully dispersed in the preparation in the test system and has sufficient specific activity to allow appropriate measurements to be made. At a time point 4 hours after topical skin exposure, a sample of the saline receiver fluid was collected, which flowed across the inner face of the skin, and the amount of paraquat that had penetrated the skin at that time point was determined using liquid scintillation counting. The model was confirmed by means of in vivo assays performed by conventional OECD protocol tests, which showed that the smaller the amount of paraquat that penetrated the skin, the less the in vivo skin irritation response. The composition performance test was performed in this in vitro SIFT protocol, in terms of the ability of the new composition to reduce the penetration of paraquat, compared to its corresponding control. Thus percentage values below 100 indicate a potential advantage. Two additional internal positive and negative controls included in the test confirmed that the device and skin patch were entirely suitable. The standards used were the skin irritant, sodium lauryl sulfate (positive control) and untreated skin (negative control), as described by Heylings et al. Generally, we have found that compositions comprising paraquat and alginate reduce the penetration of paraquat through the skin compared to compositions that do not comprise alginate. In vivo experiments demonstrated that the compositions comprising alginate were less irritating to the skin than compositions without alginate.

Example 1

The composition prepared for use in the method of the invention (composition 1) had the following composition:

components	Concentration of
		Paraquat dichloride	200g/l (Paraquat ion)
SYNPROLAM 35X15	31g/l
		AEROSOL OT-B	22.35g/l
MANUTEX RM	10g/l
		Magnesium sulfate containing 1.5 moles of hydrated water	74g/l
Acetic acid	To pH6.5-7.5
		Emetic agent: 2-amino-6-methyl-5-oxo-4-n-propyl-4, 4-dihydro-5-triazolo [1, 5-a ]]Pyrimidines	1.5g/l
Coloring agent	2.5g/l
		Defoaming agent	0.25g/l
Odorant	0.1g/l
		Water (W)	To 1 liter

AEROSOL OT-B contains 85% sodium dioctyl sulfosuccinate and 15% sodium benzoate. SYNPROLAM 35X15 is a compound of the formula R-N (CH)₂CH₂O)_xH(CH₂CH₂O)_yAlkylamine ethoxylate of H, wherein the sum of x and y is 15, and R ═ C₁₃-C₁₅. Manutexrm is a high M alginate with a low calcium content (up to 0.4%) and a 1% solution viscosity of 200 to 400 mPas.

At 25 ℃ for 300s^-1("composition viscosity") the viscosity of the composition was measured using a Paar Physica HaakeMCl + high shear Rheometer and found to be 68.0 mPas.

The above compositions were evaluated for skin irritation and transdermal toxicity using published regulated protocol OECD 404 and 402. This shows a significant reduction in skin irritation and transdermal toxicity compared to the data for the commercial paraquat product without alginate.

Examples 2 to 6

In this example, alginate was added to the composition as shown in table 2.

TABLE 2

Components	Concentration of
		Paraquat dichloride	100g/l (Paraquat ion)
Genamin T-150	15.5g/l
		NANSA 1169-A	31.6g/l
Magnesium sulfate containing 1.5 molecules of hydrated water	74g/l
		Acetic acid	To pH6.5-7.5
Emetic agent: 2-amino-6-methyl-5-oxo-4-n-propyl-4, 5-dihydro-5-triazolo [ l, 5-a]-pyrimidines	1.5g/l
		Coloring agent	2.5g/l
Defoaming thorn	D.5g/l
		Odorant	10g/l
Water (W)	To l liter

NANSA 1169-A is a 30% w/w aqueous solution of sodium dodecylbenzenesulfonate. GenaminT-150 is divided intoSubformulae can be written as R-N (CH)₂CH₂O)_xH(CH₂CH₂O)_yH, an alkylamine ethoxylate, wherein the sum of x and y is 15, and R is tallow.

The actual alginate added, the alginate concentration and the skin irritation value of the resulting composition as measured using the SIFT test are shown in table 3. In Table 3, the skin irritation values are determined as percent reduction in skin irritation (as determined by skin penetration of paraquat) relative to corresponding commercial standards containing 100g/l paraquat and no alginate. Values below 100% indicate reduced skin irritation relative to the standard. Values are the average of a minimum of six observations in the SIFT protocol.

TABLE 3

Example Nos. all contain 100g/l of paraquat	Alginate salts	Alginate concentration (g/l)	Relative skin irritation value for Paraquat skin penetration%
				2	MANUTEX RM	7	85％
MANUTEX RD	7
		3	MANUTEX RM		5	76％
MANUTEX RD	5
			4	MANUTEX RM	3.5		63％
MANUTEX RD	3.5
		5		MANUTEX RM	7	47％
6	MANUTEX RD		7				77％

Examples 7 to 19

In Table 4, the skin irritation values were determined as a percentage reduction in skin irritation (as measured by skin penetration of paraquat) relative to a related commercial standard comprising 200g/l paraquat and no alginate. Values below 100% indicate reduced skin irritation relative to the standard. Values are the average of a minimum of six observations in the SIFT protocol.

TABLE 4

Components		Example No. 2
								7	8	9	10
Paraquat dichloride		200g/l (Paraquat ion)	200g/l (Paraquat ion)	200g/l (Paraquat ion)	200g/l (Paraquat ion)
						Emetic agent		0.5g/l	1.5g/l	1.5g/l	1.5g/l
NANSA 1169A		63.3g/l	63.3g/l	63.3g/l	63.3g/l
						GENAMIN T150		31g/l	31g/l	31g/l	31g/l
MANUTEX RM		9g/l	9g/l	9g/l	9g/l
						Magnesium sulfate 1.5H2O		74g/l	74g/l	74g/l	74g/l
Defoaming agent		0.25g/l	0.25g/l	0.25g/l	0.25g/l
						Coloring agent		2.5g/l	2.5g/l	2.5g/l	-
Odorant		0.1g/l	0.1g/l	0.1g/l	0.1g/l
						Acetic acid		To pH6.5-7.5	To pH9	To pH5	To pH6.5-7.5
Water (W)		To 1 liter	To 1 liter	To 1 liter	To 1 liter
						Skin irritation value of Paraquat skin penetration%		60％	58％	57％	52％

Components		Example No. 2
							11	12	13
Paraquat dichloride		200g/l (Paraquat ion)	200g/l (Paraquat ion)	200g/l (Paraquat ion)
					Emetic agent		1.5g/l	1.5g/l	1.5g/l
NANSA 1169A		-	63.3g/l	-
					GENAMIN T150		31g/l	-	-
MANUTEX RM		9g/l	9g/l	9g/l
					Magnesium sulfate 1.5H2O		74g/l	74g/l	74g/l
Defoaming agent		0.25g/l	0.25g/l	0.25g/l
					Coloring agent		2.5g/l	2.5g/l	2.5g/l
Odorant		0.1g/l	0.1g/l	0.1g/l
					Acetic acid		To pH6.5-7.5	To pH6.5-7.5	To pH6.5-7.5
Water (W)		To 1 liter	To 1 liter	To1 liter
					Relative skin irritation value (%) -based on paraquat skin penetration		52％	26％	14％

Example 14

Example 14 further illustrates that the addition of alginate to paraquat reduces skin irritation. In this example, the relative skin irritation values are expressed as a percentage of the values obtained for the exact corresponding alginate-free composition.

Components		Example No. 2
					14
Paraquat dichloride		200g/l (Paraquat ion)
			Emetic agent		0.5g/l
BioSoft SDBS 30LA		86g/l
			GENAMIN T150		43g/l
MANUTEX RM		9g/l
			Magnesium sulfate heptahydrate		123.74g/l
Defoaming agent		0.5g/l
			Coloring agent		2.5g/l
Odorant		0.1g/l
			Acetic acid		To pH6.5-7.5
Water (W)		To 1 liter
			Relative skin irritation value (%) -based on paraquat skin penetration		78％

BioSoft SDBS 30LA is a 30% w/w aqueous solution of sodium dodecylbenzenesulfonate.

Claims (15)

1. A method of protecting skin following contact with a composition comprising a bipyridylium herbicide, the method comprising incorporating an alginate into the composition.

2. The method according to claim 1, wherein the bipyridylium herbicide is a paraquat salt.

3. The method according to claim 1, wherein the bipyridinium herbicide is a diquat salt.

4. The method according to claim 1, wherein the bipyridylium herbicide is a mixture of a paraquat salt and a diquat salt.

5. A process according to any preceding claim, wherein the composition is an aqueous concentrate composition comprising at least 25g/l bipyridinium ion.

6. The method according to claim 5, wherein the composition comprises from 50g/l to 250g/l of bipyridinium ion.

7. A process according to any preceding claim, wherein the alginate has an average molecular weight of from 5,000 to 250,000.

8. The method according to claim 7, wherein the average molecular weight is from 10,000 to 200,000.

9. The method according to any one of claims 1 to 6, wherein the alginate has a 1% solution viscosity of from 2 to 2000 mPas.

10. The method according to claim 9, wherein the 1% solution viscosity of the alginate is from 2 to 1,500 mPas.

11. A method according to any preceding claim, wherein the concentration of alginate in the composition is from 1 to 50 g/l.

12. A method according to claim 11, wherein the concentration of alginate in the composition is from 5 to 15 g/l.

13. A method according to any preceding claim, wherein the composition comprises one or more surfactants.

14. A method according to any preceding claim, wherein the composition comprises an emetic.

15. A method according to any preceding claim, wherein the composition comprises a purgative.