polymeric zinc propylenebis(dithiocarbamate);propineb (ISO)

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

July-1994 to May-1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Objective of study:

absorption

distribution

excretion

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Version / remarks:

1984

Deviations:

no

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Limited
- Weight at study initiation: Males: 188-282 g, Females: 192-204 g
- Housing: Throughout the study period the animals used for the blood kinetics studies were housed individually in polypropylene and stainless steel cages with raised wire mesh floors to inhibit coprophagy. Animals used for the excretion studies were housed individually in all-glass metabolism cages specifically designed for the separate, quantitative collection of urine and faeces.
- Diet: Standard laboratory diet (SDS Rat and Mouse Maintenance Diet No. 1, Special Diets Services, Essex, UK) was available ad libitum.
- Water: Domestic water was available ad libitum.
- Acclimation period: 7 days
- Health status: Animals were carefully observed during the acclimation period to ensure that they were in good health and suitable for inclusion in the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24°C
- Humidity (%): 33-59%
- Photoperiod (hrs dark / hrs light): 12 h light/dark cycle

Route of administration:

oral: gavage

Vehicle:

other: 0.5% aqueous gum tragacanth

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: [14C]-Propineb (15.22 mg premix, equivalent to 13.25 mg of test substance) was accurately weighed into a 50 mL volumetric flask. The flask was made up to volume with 0.5% aqueous gum tragacanth, and placed into an ultrasonic bath for ca 10 min until a homogeneous suspension appeared to have formed. The dose suspension was then transferred to a conical flask and kept mixing on a magnetic stirrer throughout dose administration. The formulated dose was administered to the animals as soon as possible after preparation.

Duration and frequency of treatment / exposure:

single application

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

1 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

Sixteen male and 8 female

Control animals:

no

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, expired air, blood, plasma, serum, heart, lungs, spleen, kidneys, liver, perirenal fat, testes/ovaries, gastrointestinal tract plus contents, uterus, muscle (leg), brain, thyroids, adrenals, skin remaining carcass, bone mineral, bone marrow, cage washes
- Time and frequency of sampling: Urine: 0-6 h and 6-24h post dose, then at 24 h intervals up to 168 h post dose
Faeces: at 24 h intervals up to 168 h post dose
expired air: at 24 h intervals for the first 48 h post dose tissue: 168 h after dosing
blood: 0.25, 0.5, 1, 2, 4, 6, 8, 24 and 48 hours post dose for blood kinetic; 168 hours post dose for excretion kinetics and tissue retention

ANALYTICAL METHOD
- Complete description including:
thin layer chromatography (TLC): Pooled urine and faeces extracts were analysed by thin-layer chromatography (TLC) and were applied in a 1.5 cm band to silica gel plates (Kieselgel 60F2S4, layer thickness 0.25 mm). All samples were underspotted and run alongside a mixture of the supplied non-radiolabelled reference standards. Samples were applied along the origin marked at 2 cm and run over a distance of 15 cm. Two solvent systems were used, these were as follows:
Solvent System 1 - Chloroform:Methanol:Water; 65:25:4 v/v/v
Solvent System 2 - IsopropanohAmmonia (25%):Water; 75:15:15 v/v/v
The position of each of the supplied non-radiolabelled reference standards were visualised by either quenching under u.v. light, spraying with ninhydrin or by staining with iodine. Radioactive areas of the TLC plates were quantified using a Phosphor Image Analyser (Molecular Dynamics, Model 455A), and the relative % of each radioactive area determined by peak integration. The radioprofile obtained from each sample was evaluated by matching the position of the radioactive areas on TLC plates with the positions of the supplied non-radiolabelled reference standards. It should be noted however that radioprofiling using one dimensional TLC where many components are present may give rise to radiochemical peaks containing more than one component.

Liquid scintillation analysis: All samples were analysed for 5 min using a scintillation analyser (Canberra Packard Limited) with automatic quench correction using an external standard method.
Representative blank samples were analysed and their values subtracted from the biological sample measurements. The activity in each sample was expressed as net d.p.m. A limit of reliable determination of 30 d.p.m. above background has been instituted in these laboratories. If results arise from data 10-30 d.p.m. above background the fact has been noted in the Results section. Similarly, the fact has been noted if results arise from data less than 10 d.p.m. above background.

Combustion analysis: Samples for combustion were weighed into combustocones (Packard Instrument Company Limited) and combusted using a Packard Tri-Carb 306 Automatic Sample Oxidiser. The resultant 14CO2 was absorbed in Carbo-Sorb® and mixed automatically with Permafluor®E"1" scintillation fluid. Combustion efficiency and carry-over were checked routinely several times throughout each production run. The mean combustion efficiency was shown to be greater than 97% throughout the experimental period.

Type:

excretion

Results:

49.35% and 52.52% during 168 h post dose in urine of male and female rats, respectively;
46.39% and 44.65% during 168 h post dose in faeces of male and female rats, respectively

Details on absorption:

Low dose (1 mg/kg bw): Following administration of [14C]-Propineb, mean concentrations of total radioactivity in whole blood were generally higher in female rats. The mean whole blood concentration time curve, however, followed a similar pattern in both male and female rats.
Absorption was rapid with the mean maximum concentration of total radioactivity in whole blood observed at 2 h (males) and 4 h (females) post dose, representing 0.324 µg equiv./g (range 0.278-0.363 µg equiv./g) and 0.424 µg equiv./g (range 0.375-0.446 µg equiv./g) in male and female rats, respectively. Mean concentrations of total radioactivity in whole blood thereafter declined, representing 0.028 µg equiv./g (range 0.020-0.036 µg equiv./g) and 0.041 µg equiv./g (range 0.028-0.058 µg equiv./g) at 24 h post dose in male and female rats, respectively. Thereafter mean concentrations of total radioactivity in whole blood declined more slowly, representing 0.013 µg equiv./g (range 0.012-0.014 µg equiv./g) and 0.032 µg equiv./g (range 0.015-0.045 µg equiv./g) at 48 h post dose in male and female rats, respectively.
High dose (100 mg/kg bw): Following administration of [14C]-Propineb to male rats, absorption was rapid with the mean maximum concentration of total radioactivity in whole blood observed at 4 h post dose representing 25.2 µg equiv./g (range 21.6-27.0 µg equiv./g). Mean concentrations of total radioactivity in whole blood thereafter declined, representing 4.2 µg equiv./g (range 2.6-7.1 µg equiv./g) at 24 h post dose. Thereafter mean whole blood concentrations of total radioactivity declined more slowly representing 1.1 µg equiv./g (range 0.8-1.5 µg equiv./g) at 48 h post dose.

Details on distribution in tissues:

Low dose (1 mg/kg bw): Mean tissue residues at 168 h post dose accounted for 0.47% (range 0.41-0.57%) and 0.52% (range 0.46-0.63%) of the administered dose in male and female rats, respectively, the majority of which was associated with the residual carcass.
Highest mean concentrations of total radioactivity at 168 h post dose were found in thyroid glands, representing 3.135 µg equiv./g (range 0.882-7.060 µg equiv./g) and 2.853 µg equiv./g (range 1.073-5.774 µg equiv./g) in male and female rats, respectively. All other tissues and organs investigated contained mean concentrations of total radioactivity lower than in whole blood (male and female: 0.007 µg/g), except for kidneys (males = 0.051 µg equiv./g, females = 0.038 µg equiv./g), adrenals (males = 0.015 µg equiv./g, females = 0.021 µg equiv./g), liver (males = 0.012 µg equiv./g, females = 0.009 µg equiv./g) and lungs (males and females = 0.008 µg equiv./g).
The tissue distribution of total radioactivity at 168 h post dose was independent of gender.

High dose (100 mg/kg bw): Mean tissue residues in male rats at 168 h post dose accounted for 0.63% (range 0.49-0.78%) of the administered dose, the majority of which was associated with the residual carcass.
Highest mean concentrations of total radioactivity at 168 h post dose were found in thyroid glands representing 113.75 µg equiv./g (range 101.51-139.83 µg equiv./g). All other tissues and organs investigated contained mean concentrations of total radioactivity lower than in whole blood (0.57 µg equiv./g), except for kidneys (1.66 µg equiv./g), skin (1.50 µg equiv./g), adrenals (1.00 µg equiv./g), bone marrow (0.94 µg equiv./g), liver (0.78 µg equiv./g) and lungs (0.73 µg equiv./g).

Details on excretion:

Low dose (1 mg/kg bw): Following administration of [14C]-Propineb, urinary excretion accounted for a mean of 49.35% (range 45.67-53.40%) and 52.52% (range 48.01-56.84%) of the administered
dose during the 168 h post dose period in male and female rats, respectively. During the same period, a mean of 46.39% (range 40.72-55.11%) and 44.65% (range 37.95-50.11%) of the administered dose was recovered in faeces in male and female rats, respectively. Expired 14CO2 was a minor route of elimination in male and female rats accounting for a mean of 1.47% (range 1.30-1.59%) and 2.01% (range 1.80-2.34%) of the administered dose, respectively over the first 48 h post dose. Radioactivity in the non 14CO2 volatile trap was below the limit of reliable determination in all animals investigated over this period. Excretion was rapid and essentially complete by 48 h post dose, with a mean of 100.42% (range 94.30-104.07%) and 101.00% (range 97.36-103.46%) of the administered dose excreted in male and female rats, respectively during this period. The routes and rates of excretion were essentially independent of gender. The mean total excreted during 168 h post dose in male and female rats was 101.87% (range 95.94-105.03%) and 102.08% (range 98.53-104.41%) of the administered dose, respectively. The mean total recovered during the same period was 102.36% (range 96.52-105.45%) and 102.61% (range 99.04-104.87%) of the administered dose in male and female rats, respectively.
High dose (100 mg/kg bw): Following administration of [14C]-Propineb to male rats, urinary excretion accounted for a mean of 50.19% (range 41.97-59.13%) of the administered dose during 168 h post dose, while faecal elimination accounted for a mean of 40.79% (range 32.66-44.90%) of the administered dose during the same period. Expired 14C02 was a minor route of elimination accounting for a mean of 2.83% of the administered dose (range 1.21-7.42%) over the first 48 h post dose. Radioactivity in the non 14CO2 volatile trap was below the limit of reliable determination in all animals investigated over this period. Excretion was rapid and essentially complete by 48 h post dose, with a mean of 96.99% (range 94.44-100.55%) of the administered dose excreted during this period. The mean total excreted during 168 h post dose was 98.62% (range 96.87-102.96%) of the administered dose. The mean total recovered during the same period was 99.26% (range 97.48-103.74%) of the administered dose.

Details on metabolites:

Pooled 0-24 h Urine:
[14C]-Propineb was extensively metabolised in both male and female rats, since no unchanged Propineb was detected in urine. Similar metabolite profiles were found in the urine of male and female rats at the low dose level (1 mg/kg). BNF 5547 I (propylene thiourea) and propylendiamine co-chromatographed with radioactive peaks in both TLC systems, accounting for ca 45% and 5% of the urinary radioactivity, respectively. At least 9 other radioactive metabolites were present. Most accounted for less than 10% of the applied radioactivity.
At the high dose level (100 mg/kg), absorbed [14C]-Propineb was again extensively metabolised. The radioprofile obtained in urine for male rats, compared to the corresponding profile at the low dose level showed no new radioactive components to be present. BNF 5547 I (propylene thiourea) and propylendiamine co-chromatographed with radioactive peaks in both TLC systems, accounting for ca 40% and 30% of the urinary radioactivity, respectively. At least 4 other radioactive metabolites were present, each accounting for less than 10% of the applied radioactivity. Compared to the low dose level, the relative proportions of propylene thiourea and propylendiamine had changed with fewer unknown radioactive metabolites present.
PU (propylene urea) may also have co-chromatographed with radioactive peaks in both TLC systems at both dose levels. Due to this reference standard running in close proximity to BNF 5547 I (propylene thiourea) the radioactivity associated with propylene urea is not known.

Pooled 0-24 h Faeces:
The extraction efficiency from pooled faeces homogenates at the low and high dose level was 24% and 40%, respectively. This low extraction efficiency may be explained by the presence of unabsorbed parent test material which is insoluble in solvent. The radioprofile obtained in faeces extracts following oral administration at the low dose level (1 mg/kg) was essentially independent of gender, however an additional radioactive peak accounting for ca 15% of the applied radioactivity was observed in female animals. BNF 5547 I (propylene thiourea) and BNF 5547 B (4-methylimidazoline) co-chromatographed with radioactive peaks in both TLC systems, accounting for ca 20% and 30% of the applied radioactivity, respectively. At least 6 other radioactive metabolites were present. Most accounted for less than 20% of the applied radioactivity.
At the high dose level (100 mg/kg) the radioprofile obtained in the faeces extract from male rats compared to the corresponding profile at the low dose level showed no new radioactive components to be present. BNF 55471 (propylene thiourea) and BNF 5547 B (4-methylimidazoline) co-chromatographed with radioactive peaks in both TLC systems, accounting for ca 50% and ca 6% of the applied radioactivity, respectively. At least 3 other radioactive metabolites were present, most accounting for less than 20% of the applied radioactivity. Compared to the low dose level, the relative proportions of propylene thiourea and 4-methylimidazoline had changed with fewer unknown radioactive metabolites present.

Conclusions:

Following a single oral administration of [14C]-Propineb, excretion was rapid, with the routes and rate of excretion essentially independent of gender and dose. Based on urinary excretion alone, at least 50% of the administered dose was absorbed. Expired 14CO2 accounted for only ca 2% of the administered dose and recovery of radioactivity was complete.

The concentration of total radioactivity in tissues at 168 h post dose was very low. Highest concentrations of total radioactivity were observed in the thyroid, with mean concentrations approximately 400 and 200 times higher than in whole blood at the low and high dose, respectively. The mean tissue concentrations of total radioactivity obtained at each dose level did not always reflect the difference in dose level.

Absorbed [14C]-Propineb was extensively metabolised with the metabolite profiles in urine and extracts from faeces essentially independent of gender at the low dose. At the high dose, no new radioactive metabolites were observed. Co-chromatography in 2 TLC systems suggested propylene thiourea and propylendiamine were present in urine and propylene thiourea and 4-methylimidazoline in faeces extracts. Many other minor unknown radioactive metabolites were also present.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Remarks:

Metabolism study

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

10-February-1995 to 09-October-1997

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to other study

Objective of study:

metabolism

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Principles of method if other than guideline:

Guideline not stated (comparable to OECD 417).

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

refer to study M-052831-01-1

Route of administration:

oral: gavage

Vehicle:

other: 0.5% gum tragacanth

Duration and frequency of treatment / exposure:

single application

Dose / conc.:

1 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on study design:

refer to study M-052831-01-1

Details on dosing and sampling:

refer to study M-052831-01-1

Type:

metabolism

Results:

Absorbed [14C]propineb was extensively metabolized, mainly via PTU (propylene thiourea) and PDA (propylendiamine) (metabolites found in urine and faeces); metabolism was comparable for males and females and was generally independent of the dose.

Details on absorption:

Not assessed in this study.

Details on distribution in tissues:

Not assessed in this study.

Details on excretion:

Total excreta (urine and faeces) were in the range of 91-97% of the administered dose.

Toxicokinetic parameters:

other: Study with focus on metabolism, no further data on absorption given.

Metabolites identified:

yes

Details on metabolites:

The degradation of [14C]propineb proceeds mainly via PTU (propylene thiourea) and also via PDA (propylendiamine). PTU is further metabolized or degraded via three pathways. The first one leads to PU and to a small amount of 2-methoxy-4-methylimidazoline. The second leads to 2-methyhnercapto-4-methylimidazoline. Finally, PTU is transformed via 2-sulfonyl-4-methylimidazoline to 4-methylimidazoline and to N-formyl-PDA. The pathways leading to PU and N-formyl-PDA are assumed to be the major routes of PTU degradation.

Independent of dose level and gender, PTU (propylene thiourea) was the main metabolite identified in native urine. Other main metabolites were PU (propylene urea) and 4-methylimidazoline. PDA (propylendiamine) was found to be a major metabolite exclusively in high dose level urine. Minor metabolites were 2-methylmercapto-4-methylimidazoline, N-formyl-PDA and 2-sulfonyl-4-methylimidazoline.

Low dose level native urine showed only slight sex differences with male urine containing one additional unknown metabolite and female urine showing a higher amount of PTU (about 31% female versus about 25% male of renal radioactivity). About 55 % of the renal radioactivity was identified.

High dose level native urine contained a high amount of PDA (about 20% of renal radioactivity) which was not present in low dose level urine. PTU (about 25%) was in the same range in the high and low dose urine whereas in the high dose group PU (about 14%) was distinctly higher and 4-methylimidazoline (about 5%) distinctly lower. One additional unknown metabolite was also present. About 69% of the renal radioactivity was identified.

Native urine was combined, lyophilized and the residue was extracted with methanol. This methanol fraction was subjected to fractionation by micropreparative HPLC and TLC. It was demonstrated by this procedure that PTU degraded to 4-methylimidazoline and to other more polar degradation products. A major degradation product, N-formyl-PDA, was purified by HPLC and eventually identified by mass spectroscopy.

Faeces were extensively extracted with methanol and acid. Whereas total extraction efficiency (methanol plus acidic extracts) for low dose level faeces was about 70%, it was about 85% for high dose level faeces. However, the relative amount (%) of metabolites identified in extracted faecal radioactivity was rather low with about 27-30% (acidic extracts) and about 23-29% (methanol extracts) for low dose level faeces and about 25% (acidic extracts) and about 32%
(methanol extracts) for high dose level faeces.

The methanol extracts of low dose level faeces showed no difference between male and female rats. The high dose methanol extracts showed two new unknown minor metabolites and the amount of 4-methylimidazoline was higher (about 21% as compared to about 13-15 % in methanol extracts of low dose level faeces). Acidic extracts of low dose level faeces differed in PTU (17% female versus 10% male) and in 4-methylimidazoline (2% female versus 8% male).
Acidic extracts of high dose level faeces differed only in the amount of PDA with was 15% compared to about 9-11% in low dose level extracts.Generally, the amount of PTU in all dose levels and gender was rather low with about 1-3% in methanol extracts and about 8-17% in acidic extracts. Strikingly, 4-methylimidazoline, a degradation product of PTU, was the main metabolite in methanol extracts where the amount of PTU was lowest. Therefore it is assumed that PTU degraded to an unknown extent during the extensive extraction procedure. PDA (about 9-15%) was detected exclusively in the acidic
extracts of all dose levels.

Total radioactivity excreted via urine and faeces was in the range of 91-97 % of administered dose. Total metabolites identified were about 34% (low dose, male), about 38% (low dose, female) and about 45% (high dose, male) of the administered dose. PTU was found to be the major metabolite with about 14-19% of administered dose, followed by 4-methylimidazoline with about 8-10% and PU with about 5-9%. In the high dose level group, PDA was found to be the
second major metabolite with about 12% of administered dose whereas in low dose level groups, PDA accounted for only about 1-2% of administered dose.

Taking into account the identified metabolites and degradation products, the main pathway of transformation of propineb proceeds via PTU. A second important pathway leads to PDA. Whereas PDA seems to be an end-product in urine and faeces, PTU appeared to be further transformed through 3 pathways. The first one leads to PU, a small part of which is methylated to 2-methoxy-4-methylimidazoline, the second leads to 2-methylmercapto-4-methylimidazoline, a minor methylated metabolite of PTU. The third pathway transforms PTU by stepwise oxidation of the sulfur via 2-sulfonyl-4-methylimidazoline to 4-methylimidazoline and finally to N-formyl-PDA.

Conclusions:

Absorbed [14C]propineb was extensively metabolized with the metabolite profiles in native urine independent of gender at the low dose. Co-chromatography in 3 TLC systems suggested PTU (propylene thiourea), PU (propylene urea) and 4-methylimidazoline as major metabolites. 2-Memylmercapto-4-methylimidazoline, N-formyl-propylendiamine and 2-sulfonyl-4 methylimidazoline were suggested to be minor metabolites. Other unknown metabolites were also present. At the high dose, native urine showed additionally PDA (propylendiamine) as a major metabolite. At the low dose about 50-56% of the analyzed radioactivity was identified, at the high dose 69%.

Faeces were extensively extracted with methanol and acid resulting in an extraction efficiency of about 68-85%. PTU, PU and 4-methylimidazoline were identified. The amount of PTU and PU was low as compared to urine values. PDA was identified exclusively in the acidic extract. 2-Amino-3-ureidopropane, a degradation product of 2-methylmercapto-4-methylimidazoline and of 2-methoxy-4-methylimidazoline, was found to be a minor metabolite. Generally, there seemed to be no difference between dose and gender, except that the amount of 4-methylimidazoline was higher at the high dose level. About 25-30% of the extracted faecal radioactivity was identified in the acidic extracts and 23-32% in the methanol extracts.

Total excreta (except 14CO2) were in the range of 91-97% of the administered dose. Total identified metabolites were in the range of 34-45% with PTU as the major metabolite accounting for 14-19%. PU accounted for 5-9%, 4-methylimidazoline for 8-10% and PDA (in the high dose level group) for about 12 %. Total unknowns (radioactive residue) were in the range of 46-62%.

It was shown in this study that the major metabolite PTU was subject to intensive degradation leading to numerous degradation products. N-formyl-PDA was identified as a degradation product. It is very likely that the original amount of PTU in native urine and in faeces was much higher. Storage, fractionation steps and TLC reduced the amount of PTU more or less distinctly.

The degradation of [14C]propineb proceeds mainly via PTU and also via PDA. PTU is further metabolized or degraded via three pathways. The first one leads to PU and to a small amount of 2-methoxy-4-methylimidazoline. The second leads to 2-methyhnercapto-4-methylimidazoline. Finally, PTU is transformed via 2-sulfonyl-4-methylimidazoline to 4-methylimidazoline and to N-formyl-PDA. The pathways leading to PU and N-formyl-PDA are assumed to be the major routes of PTU degradation.

Description of key information

Based on the urinary excretion alone, at least 50% of an administered oral dose of propineb was absorbed. Following administration of 1 mg [¹⁴C]propineb/kg bw, mean concentrations of total radioactivity in whole blood were generally higher in female rats. The mean whole blood concentration time curve, however, followed a similar pattern in both male and female rats. At both dose levels (1 mg and 100 mg/kg bw), absorption was rapid with the mean maximum concentration of total radioactivity in whole blood at 2-4 hours post dose in male and female rats.

Following administration at the low dose (1 mg/kg bw), urinary excretion accounted for a mean of approximately 50% and 53% of the orally administered dose over 168 hours in male and female rats, respectively. During the same period, a mean of approximately 46% and 45% was recovered in faeces in male and female rats, respectively. Expired ¹⁴CO₂ was a minor route of elimination in male and female rats accounting for a mean of 1.5 % and 2 % of the administered dose, respectively, over the first 48 hours post dose. Excretion was rapid and essentially complete by 48 hours post dose with the routes and rates of excretion independent of gender. At the high dose level (100 mg/kg bw), urinary and faecal excretion over 168 hours post dose accounted for a mean of approximately 50% and 41% of the administered dose, respectively. Expired ¹⁴CO₂ was a minor route of elimination accounting for a mean of approximately3 % of the administered dose over the first 48 hours post dose. The mean total amount excreted over 68 hours post dose was approximately 99% of the oral dose.

The radioactivity levels (TRR) in tissues of female and male Wistar rats at 168 hours post dose of 1 or 100 mg [¹⁴C]propineb/kg bw were very low, accounting for less than 1% of the administered dose. In the low dose groups, highest mean TRR were found in the thyroids, accounting for 3.315 and 2.853 μg eq/g in male and female rats, respectively. All other tissues and organs contained mean TRR levels lower than in whole blood (0.007 μg eq/g), except the kidneys, adrenals, liver and lungs. The tissue distribution of total radioactivity was independent of gender. In the high dose group (100 mg/kg bw), highest mean concentrations of TRR were found in the thyroids of male rats, representing 113.75 μg equ/g. All other tissues and organs investigated contained mean TRR levels lower than in whole blood (0.57 μg eq/g), except the kidneys, skin, adrenals, bone marrow, liver and lungs. Although no repeated dosage was performed in these experiments - based upon the low residues in the individual tissues and organs of the body after single dosage (with the exception of the increased concentration in the thyroid) - there is no risk of a significant bioaccumulation after repeated dosage. 

Orally absorbed [¹⁴C]propineb was extensively metabolized with the metabolite profiles in native urine independent of gender at the low dose. Co-chromatography in 3 TLC systems suggested PTU (propylene thiourea, M01), PU (propylene urea, M02) and 4-methylimidazoline (MI, M03) as major metabolites. 2-Methylthio-4-methylimidazoline (MMMI, 2-methylmercapto-4-methylimidazoline, M08), N-formyl-PDA (M07) and PTU-S-trioxide (2-sulfonyl-4-methylimidazoline, SMI, M06) were suggested to be minor metabolites. Other unknown metabolites were also present. At the high dose, native urine showed additionally PDA (M04) as a major metabolite. At the low dose about 50-56% of the analyzed radioactivity was identified, at the high dose 69%.
Faeces were extensively extracted with methanol and acid resulting in an extraction efficiency of about 68-85%. PTU (M01), PU (M02) and 4-methylimidazoline (M03) were identified. The degradation of [14C]propineb proceeds mainly via PTU (M01) and also via PDA (M04). Whereas PDA (M04) seems to be an end-product in urine and faeces, PTU (M01) appeared to be further transformed through three pathways. The first one leads to PU (M02), a small part of which is methylated to 2-methoxy-4-methylimidazoline (M09), the second leads to 2-methylthio-4-methylimidazoline (M08), a minor methylated metabolite of PTU (M01). The third pathway transforms PTU (M01) by stepwise oxidation of the sulfur via 2-sulfonyl-4-methylimidazoline (M06) to 4-methylimidazoline (M03) and finally to N-formyl-PDA (M07). The pathways leading to PU (M02) and N-formyl-PDA (M07) are assumed to be the major routes of PTU (M01) degradation.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In the EFSA conclusion on propineb (EFSA, 2016), the adsorption values were derived following the Guidance on dermal absorption (EFSA PPR Panel, 2012). Based on the toxicokinetic studies, an oral absorption value of 60% was set for propineb. This value is taken over for the current assessment. The agreed dermal absorption values for propineb are 0.1% for the concentrate and 0.7% for the dilution. Therefore, for the current assessment a value of 1% as worst case is chosen. In absence of data on absorption via the inhalation route a default value of 100% is assumed.