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4.8 Dodine (084)(R)**

R-residue and analytical aspects

** Evaluated within the Periodic Review Programme of the Codex Committee on Pesticide Residues


Dodine, 1-dodecylguanidinium acetate (dodecylguanidine monoacetate), is a fungicide and bactericide registered for foliar use on pome fruits, stone fruits including cherries, and nuts including walnuts.

Dodine is the only active substance from the guanidine family, which was first evaluated in 1974 for toxicology and residues by the JMPR and subsequently in 1976 and 1977. The latest toxicology review was in 2000. It was listed under the Periodic Review Programme at the 30th Session of the CCPR (ALINORM 99/24) for review by the 2001 JMPR but was re-scheduled for 2003.

The 2000 JMPR allocated an acceptable daily intake for humans of 0-0.1 mg/kg bw and an acute reference dose of 0.2 mg/kg bw.

The 1977 JMPR considered that a feeding study with large animals to determine whether feeding apple pomace and grape pomace would contribute residues to meat and milk was still desirable.

The manufacturer supplied information on identity, methods of analysis, use pattern, metabolism in plants and farm animals, residue trials on apples, pears, cherries, peaches and plums, storage stability in analytical samples, effects of processing on residues and fate in the environment.

In addition, information on GAP was provided by the governments of France and The Netherlands.

Dodine is currently formulated as wettable powders, suspension concentrates and wettable granules. It is a slightly yellow fine powder with low solubility in water (<1g/l) and organic solvents. Dodine is not considered fat-soluble, as its log octanol/water partition coefficient is 0.96.

Animal metabolism

The metabolism of radiolabelled dodine has been investigated in rats and a lactating goat. The metabolic pathway in both rats and goat suggests that dodine is extensively metabolized by both species by initially forming a carboxylic acid chain with the elimination of urea and a consequent series of 2-carbon degradation cycles, consistent with the beta oxidation pathway used by mammals to degrade medium to long chain fatty acids.

Rat metabolism was reviewed by the 2000 JMPR. Cumulative excretion in urine and faeces was reported as being above 90% of the dose. Absorbed dodine is extensively metabolized in rats. Four metabolites were seen in urine: hydroxydodecylguanidine, the main metabolite, urea, and two unidentified metabolites which appeared to be a mixture of carboxylic acid products arising from oxidation of the alkane side chain.

In a lactating goat dosed orally for five consecutive days with [14C]dodine at the mean equivalent dietary level of 12.8 ppm by gelatin capsule, dodine was extensively metabolized. Sixty eight per cent of the dose was excreted in urine (38%), faeces (30%) and milk (0.05%). Less than 1% of the dose remained in the tissues. Dodine was a minor component in all edible tissues and no parent compound was present in milk. In the dosed goat, 14C levels were much higher in kidney and liver (0.168 mg/kg and 0.109 mg/kg as dodine) than in muscle or fat (0.02 mg/kg-0.008 mg/kg as dodine). Hexylguanidine carboxylic acid, octylguanidine carboxylic acid and dodecylguanidine carboxylic acid were identified but none exceeded 0.001 mg/kg dodine equivalents in the foreleg muscle or 0.05 mg/kg in the liver and kidney; urea was present in all edible tissues and milk (from <0.01 mg/kg dodine equivalents in milk and muscle to <0.017 mg/kg in liver and kidney).

Plant metabolism

Plant metabolism studies on apples, strawberries and pecan trees were reported. In apples and strawberries, the parent compound was the main component of the residue; metabolism appeared to be more active in nuts with dodine and guanidine being the main residues found in kernels. In apples much of the residue remained in the peel. The metabolism of dodine was found to be essentially similar among the plants tested. Degradation of dodine in fruits is a relatively slow process, occurring by successive oxidation and hydrolysis to CO2 and ammonia; guanidine and urea are intermediate degradation products.

After three foliar applications of [14C]dodine to field grown apple trees at a rate of 0.108 kg ai/hl each, radioactive residues at mature harvest (7 days after the third application) were mainly located in the apple peel (82.3% of the TRR). Dodine accounted for 72 to 89% of the TRR extracted from apple peel and pulp. Several minor metabolite fractions were observed, all below 0.01 mg/kg except one compound tentatively identified as guanidine, found at 0.017 mg/kg dodine equivalents.

After four foliar applications of [14C]guanidine dodine to strawberries at 3.12 kg ai/ha, radioactive residues in mature fruit harvested 14 days after the third and fourth applications represented 4.3 to 6.8 mg/kg dodine equivalents. Unchanged dodine accounted for >85% of the TRR in washed strawberries. Several metabolite fractions were observed, all below 0.01 mg/kg dodine equivalents except one at 0.05 mg/kg. No major metabolite was found, although urea and guanidine were identified as possible metabolites. In rinses (2.5% of the TRR), the parent was also the major component of the residue. No degradation product occurred at >0.01 mg/kg dodine equivalents.

After three foliar applications of [14C]dodine to pecan trees during the growing season at 0.2 kg ai/hl, a low level of the applied dodine reached the kernels. Kernels isolated from mature pecans contained 0.114 mg/kg radioactive residues, composed of guanidine (0.041 mg/kg expressed as dodine, 36% of the TRR) and dodine (0.015 mg/kg, 13.2% of the TRR). Twenty per cent of the TRR (0.023 mg/kg dodine equivalents) was associated with the free fatty acid fraction.

Most of the parent compound undergoes extensive metabolism to guanidine, followed by subsequent metabolism to 14CO2 and NH3. Carbon dioxide is assimilated into the metabolic pool. The very high proportion of lipid in the kernels is consistent with incorporation of 14CO2 into the fatty acid fraction.

Immature pecans (including shells and hulls) harvested before the second application (60 days after the first) contained 2.152 mg/kg TRR, dodine (0.976 mg/kg, 43.2% of the TRR) and guanidine (0.326 mg/kg dodine equivalents, 14.4% of the TRR) being the main compounds. Two unidentified metabolites, putative oxidation products of dodine, accounted for 0.2 mg/kg dodine equivalents (9.3% of the TRR) and 0.288 mg/kg dodine equivalents (13% of the TRR).

Environmental fate


The Meeting received information on the degradation of dodine under aerobic conditions in a number of soils, on soil photolysis and on field dissipation.

Aerobic soil degradation of dodine is rapid; the calculated half-lives ranged from 3 to 10 days in the tested soils. This degradation ultimately results in the formation of carbon dioxide without the formation of any other significant degradation products or persistent unextractable residues.

Field experiments confirmed that dodine is not a persistent compound and has a rather short half-life ranging from 6 to 18 days at four locations; it did not move down the soil profile. Dodine did not undergo significant photolysis on soil surfaces.

It is suggested that the degradation of dodine in the environment is mainly microbial.

Analytical methods

The Meeting received a description and validation of analytical method 45137 for dodine in fruit crops. The method is based on GC with mass-selective detection (MSD) and achieved an LOQ of 0.05 mg/kg in apples, plums, peaches, pears and cherries, and 0.1 mg/kg in wet apple pomace.

Dodine is extracted from the fruit by homogenization with methanol and the solution is filtered and brought to a volume. An aliquot is cleaned up by liquid-liquid partition and the dodine is derivatizated by refluxing for two hours with hexafluoroacetylacetone in 1-chlorobutane. The solvent is evaporated and the samples are dissolved in cyclohexane for GC-MSD.

Wet apple pomace samples from the metabolism study with [14C]dodine were extracted and analysed by method 45137 giving an average value of 2.15 mg/kg. The average value obtained by LSC after re-extraction according to the apple method was 1.95 mg/kg, which is close to method 45137.

Stability of residues in stored analytical samples

The Meeting received information on the stability of dodine in various substrates at freezer temperatures.

In the two studies conducted to examine the stability of dodine residues under deep freezer storage conditions, no significant degradation of dodine was observed, for the duration of the study, in any of the substrates analysed.

The Meeting concluded that dodine was stable up to 18 months in apple, cherry, peach, apple juice and wet apple pomace samples when stored frozen.

Definition of the residue

Dodine was the main identified component (in samples containing ³0.05 mg/kg) detected in edible portions in plant metabolism studies, representing 80.6% of the extracted TRR in apple pulp, 86.5% of the extracted radioactivity of washed strawberries and 13.2% of the TRR in mature pecan kernels. No major metabolite was identified except in pecan kernels where guanidine represented 36% of the TRR but only 0.041 mg/kg.

In the metabolism study on a lactating goat dosed orally dodine represented less than 1% of the TRR in edible tissues and was not identified in milk. The major metabolites of dodine identified in tissues and milk, resulting from beta oxidation, were hexylguanidine carboxylic acid, octylguanidine carboxylic acid and dodecylguanidine carboxylic acid, each representing less than 0.05 mg/kg dodine equivalents.

The Meeting concluded that dodine residues, both for compliance with MRLs and for the estimation of dietary intakes should be defined as dodine.

The definition applies to both plant and animal commodities.

Results of supervised trials

Supervised trials with the foliar application of WP and SC formulations to apples, pears, peaches, cherries and plums were reported from Europe (Belgium and France) and the USA.

In all supervised trials reported from France on pears, residues were measured on fruit taken just before the last application as well as just after it. The first residue expressed as a percentage of the second provides an indication of the contribution of previous applications to the final residue in the case of multiple applications. The average carryover of 48% (range 16%-91%) suggests that the number of applications may have an influence on the final residue at harvest. Decline studies on both apples and pears suggest that dodine has an average half-life of about 20 days after multiple applications. It is therefore considered that 2 applications will be likely to produce a higher residue level than one application and would provide reliable information for estimating residue levels.

Trials were not reported on strawberries or grapes for which CXLs exist at 5 mg/kg for both commodities. The Meeting agreed to recommend withdrawal of these CXLs.

Apples. Field data were reported from France and the USA.

GAP for France is 0.7 kg ai/ha with a PHI of 28 days for SC formulations and allows a maximum of four applications. Seventeen supervised residue trials in France complied with the French PHI and application rate but would probably have produced lower residues than expected as the interval between the penultimate and last applications was generally longer than intended. The residues at mature harvest were 0.07, 0.12, 0.14 (2), 0.16, 0.17 (2), 0.23, 0.25, 0.31, 0.32, 0.34, 0.39, 0.49, 0.59, 0.61, 0.87.

GAP in the USA specifies foliar application of 0.75 to 2.2 kg ai/ha with a PHI of 7 days for the WP formulation, with no information on the maximum number of applications. Thirteen trials in the USA complied with US GAP; the residues were 0.88, 1.03, 1.10, 1.14, 1.32, 1.43, 1.44, 1.55, 1.73, 1.85, 2.01, 2.28 and 2.35 mg/kg.

The Meeting decided to use only the US trials in the evaluation because the two populations of results were considered to be different.

Pears. Field data were reported from Belgium, France and the USA.

GAP for France is the same as for apples. Fourteen supervised trials in France matched French GAP. The residues in rank order were 0.16, 0.18, 0.25, 0.26, 0.29, 0.31, 0.37, 0.40, 0.61, 0.54 (2), 0.6, 0.61 and 1.3 mg/kg.

GAP for Belgium is 1 kg ai/ha for SC formulations and allows three or four applications. Two Belgian trials supported the Belgium use pattern and the residues were 0.37 and 0.45 mg/kg.

GAP from the USA is for foliar application at 1.5-2.25 kg ai/ha with a PHI of 7 days for the WP formulation. Seven trials in the USA accorded with US GAP. The residues in rank order were 0.50, 1.68, 1.71, 1.74, 1.82, 1.94 and 2.43 mg/kg.

The Meeting decided to use only the US trials in the evaluation because the results from Europe and the USA were considered to be from different populations with higher residues in the US trials.

As the use patterns of dodine on pears and apples were considered similar in terms of PHIs and dose rates, the Meeting agreed to combine the results from the US trials for estimating a maximum residue level for pome fruits.

The combined residues in the 20 trials were 0.50, 0.88, 1.03, 1.10, 1.14, 1.32, 1.43, 1.44, 1.55, 1.68, 1.71, 1.73, 1.74, 1.82, 1.85, 1.94, 2.01, 2.28, 2.35 and 2.43 mg/kg.

The Meeting agreed to recommend the withdrawal of the existing separate CXLs of 5 mg/kg for apples and pears and made a new recommendation for pome fruits of 5 mg/kg, and estimated an STMR of 1.70 mg/kg and an HR of 2.43 mg/kg.

Cherries. Field trials were reported from France. Dodine is not registered in France on for use on cherries. Two of the French trials could be evaluated against Spanish GAP (0.05-0.08 kg/hl, 15 days PHI, no information on the maximum number of applications allowed) for foliar applications of the SC formulation. The results were 0.14 (2) mg/kg.

Dodine is registered in the USA at a dose rate of 0.75-1.5 kg for foliar applications but no current PHI was provided. GAP in Canada is 1.5 kg/ha by foliar application with a WP formulation and a PHI of 7 days but no information was provided on the maximum number of applications. The six US trials were evaluated against Canadian GAP. The results in rank order were 0.34, 1.08, 1.15, 1.27, 1.4 and 2.11 mg/kg.

The Meeting decided to use the results of US trials in the evaluation and agreed to recommend withdrawal of the current CXL of 2 mg/kg for cherries to be replaced by 3 mg/kg, and estimated an STMR and an HR of 1.21 mg/kg and 2.11 mg/kg respectively, both expressed on the whole fruit as no information was available on the edible portion.

Peaches and nectarines. Field trials on peaches were reported from France and the USA.

Five of the 7 supervised residue trials reported from France complied with the current French GAP of 0.9 kg ai/ha by foliar application of an SC formulation with a 60-day PHI (last treatment at the end of flowering). The results were <0.05 mg/kg in whole fruit and <0.05(2), 0.05 and 0.07 mg/kg (in pulp.

Nine supervised trials reported from the USA complied with the current US GAP of 1.5-3 kg ai/ha by foliar application with a WP formulation and a PHI of 15 days. The results in rank order were 0.46, 0.48, 0.68, 0.77, 1.27, 1.65, 1.77, 2.50 and 3.71 mg/kg.

The results from the US trials were evaluated. The Meeting confirmed the previous recommendation for an MRL of 5 mg/kg, now a CXL, and estimated an STMR of 1.27 mg/kg and an HR of 3.71 mg/kg (both expressed on whole fruit as no information was available on the edible portion).

The Meeting agreed to extrapolate the recommendations to nectarines as current GAP for peaches applies to nectarines in the USA.

Plums. Field trials were reported from the USA. Dodine is not registered for use on plums in the USA, so the trials could not be evaluated.


One processing study was reported from the USA on apples. The residue in processed fractions was determined after six foliar applications to apple trees, each at the nominal rate of 7.3 kg ai/ha. Samples taken at 7 days PHI were processed the next day into fresh unclarified juice and wet pomace using procedures closely simulating commercial practices.

Dodine in the processed fractions was determined by the current validated method and the results show that the residue concentrates in the wet pomace (processing factor of 5.11) with very little found in the juice (processing factor 0.09).

These processing factors were applied to the STMR of the raw commodity to estimate STMR-Ps of 8.69 mg/kg and 0.15 mg/kg in wet apple pomace and apple juice respectively.

Farm animal dietary burden

The Meeting estimated the dietary burden of dodine residues in farm animals on the basis of the feeding stuffs listed in appendix IX of the FAO manual.

Wet apple pomace might be used as feed for diary and beef cattle. As this is a processed commodity the STMR-P estimated by the Meeting was used for the estimation of both the maximum and the median farm animal dietary burdens.

Farm animal dietary burden




Dry matter

Residue on dry basis mg/kg

Percent of diet

Residue contribution

Beef cattle

Dairy cattle

Beef cattle

Dairy cattle













The dodine dietary burdens for animal commodity MRL and STMR estimations (residue levels in animal feed expressed on dry weight) are beef cattle 8.7 ppm, dairy cattle 4.4 ppm.

Farm animal feeding studies

No animal feeding study was provided. However in the metabolism study on a lactating goat dosed orally for five consecutive days with a calculated mean daily dose of 12.8 ppm and slaughtered approximately 23 h after the last dose (the plasma peak was reached 8 h after the last dose), dodine is not considered fat-soluble. The Meeting therefore expected that on the basis of the current calculated dietary burdens, residues of dodine would be low in the edible tissues, organs and milk of beef or dairy cattle ingesting 8.7 ppm or 4.4 ppm dodine respectively.

Maximum residue levels in animal commodities

In the absence of an animal feeding study and method of analysis for dodine in animal products, the Meeting did not estimate a maximum residue level or STMR for animal products.



1. A method of analysis in animal products.
2. A farm animal feeding study.


Long-term intake

The International Estimated Daily Intakes of dodine, based on the STMRs estimated by the Meeting for pome fruits (apple and pear), peach, nectarine and cherry and on STMR-P for apple juice were within the range 0-2% of the maximum ADI of 0.1 mg/kg bw (JMPR 2000) for the five GEMS/Food regional diets (Annex 3).

The Meeting concluded that the intake of residues of dodine resulting from the uses considered by the JMPR is unlikely to present a public health concern.

Short-term intake

The International Estimated Short Term Intakes (IESTIs) for dodine were calculated for commodities for which STMRs or HRs were estimated by the current Meeting.

On the basis of the acute reference dose of 0.2 mg/kg bw allocated in 2000, the estimated intakes based on the HRs estimated by the Meeting for apple, pear, peach, nectarine and cherry were in the range 6%-30% of the acute RfD for the general population and 20%-80% of that for children up to 6 years (Annex 4).

The Meeting concluded that the short-term intake of residues of dodine resulting from the uses considered by the JMPR is unlikely to present a public health concern.

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