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EC number: 249-528-5 | CAS number: 29232-93-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Version / remarks:
- 1984
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.36 (Toxicokinetics)
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 85-1 (Metabolism and Pharmacokinetics)
- GLP compliance:
- yes
Test material
- Reference substance name:
- Pirimiphos-methyl
- EC Number:
- 249-528-5
- EC Name:
- Pirimiphos-methyl
- Cas Number:
- 29232-93-7
- Molecular formula:
- C11H20N3O3PS
- IUPAC Name:
- O-2-(diethylamino)-6-methylpyrimidin-4-yl O,O-dimethyl phosphorothioate
Constituent 1
- Radiolabelling:
- yes
Test animals
- Species:
- rat
- Strain:
- other: Alpk:APfSD
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 mg/kg bw (total dose)
- Dose / conc.:
- 50 mg/kg bw (total dose)
- Dose / conc.:
- 250 mg/kg bw (total dose)
- Dose / conc.:
- 1 mg/kg bw/day
- Remarks:
- 14 days non-radiolabelled test substance and 1 day radiolabelled test substance
Results and discussion
Any other information on results incl. tables
The test substance is rapidly and
extensively absorbed from the gastrointestinal tract following gavage
administration of doses of 1, 50 or 250 mg/kg bw and repeated doses of 1
mg/kg bw/day (Table 2. the results at 50 mg/kg bw seem anomalous and are
used for comparison with bile-duct cannulated rats only). Excretion is
rapid, predominantly in the urine (>70%) at 48 hours, with approximately
50 % of the administered dose present in 12 hour urine samples. Some of
the radiolabel present in faeces is due to biliary excretion. Overall
the extent of absorption is considered to be >80% based on the
radioactivity found in the urine of animals dosed with a single dose of
1 or 250 mg/kg bw and the repeat dose at 1 mg/kg bw/d (>60%) plus the
significant level of radioactivity found in the bile of animals dosed
with a single dose of 50 mg/kg bw (17%). Variations in the levels of
radiolabel in consecutive faecal samples indicated that test substance
metabolites were subject to entero-hepatic circulation, which was more
predominant in females and animals receiving repeated doses. This was
consistent with the data from bile-duct cannulated animals, but could
also involve deposition and release
in adipose tissue. Two days after dosing, less than 2% of the
administered dose remained in the carcass and tissues, though abdominal
fat had particularly high concentrations in females dosed with 250 mg/kg
bw. Other than a marked increase in deposition in fat at 250 mg/kg bw,
the results were essentially independent of dose level and duration.
Indications of a sex difference in some aspects of the toxicokinetics of
the test substance were consistent with metabolite data.
Table 2. Urine, faecal and tissue levels (means) in Alpk rats following administration of the test substance.
Dose |
1 × 50 |
1 × 1 |
1 × 250 |
Repeat (14 + 1) × 1 mg/kg bw/d |
||||
Male |
female |
male |
female |
male |
female |
Male |
female |
|
Urine 12h (% of dose) |
33 |
28 |
59 |
46 |
53 |
50 |
54 |
57 |
Urine 12h - cannulated (% of dose) |
22 |
7 |
NP |
NP |
NP |
NP |
NP |
NP |
Urine 48h non-cannulated (including terminal cage wash) (% of dose) |
50 |
49 |
72 |
64 |
70 |
79 |
69 |
73 |
Urine 48h - cannulated (including terminal cage wash) (% of dose) |
38 |
33 |
NP |
NP |
NP |
NP |
NP |
NP |
Faeces 12h (% of dose) |
6 |
11 |
11 |
16 |
10 |
3 |
12 |
11 |
Faeces 12h - cannulated (% of dose) |
2 |
<1 |
NP |
NP |
NP |
NP |
NP |
NP |
Faeces 48h non-cannulated (% of dose) |
22 |
22 |
- |
- |
- |
- |
- |
- |
Faeces 48 h - cannulated (% of dose) |
30 |
16 |
- |
- |
- |
- |
- |
- |
Total excretion 48 h (% of dose) |
71 |
68 |
95 |
93 |
95 |
93 |
98 |
94 |
Total excretion 48 h - cannulated (% of dose) |
85 |
69 |
NP |
NP |
NP |
NP |
NP |
NP |
|
|
|
|
|
|
|
|
|
Bile 6h (% of dose) |
9 |
4 |
NP |
NP |
NP |
NP |
NP |
NP |
Bile 12h (% of dose) |
14 |
11 |
NP |
NP |
NP |
NP |
NP |
NP |
Bile 48h (% of dose) |
17 |
21 |
NP |
NP |
NP |
NP |
NP |
NP |
|
|
|
|
|
|
|
|
|
Tissue + carcass day 2 (% of dose) |
NP |
NP |
0.3 |
1.3 |
0.7 |
1.9 |
0.8 |
1.0 |
|
|
|
|
|
|
|
|
|
Liver day 2 (mg equiv./g) |
NP |
NP |
0.004 |
0.003 |
1.2 |
1.1 |
0.005 |
0.003 |
Kidney day 2 (mg equiv./g) |
NP |
NP |
0.003 |
0.004 |
1.2 |
1.5 |
0.004 |
0.004 |
Abdominal fat day 4 (mg equiv/g) |
NP |
NP |
0.004 |
0.009 |
5.6 |
56.0 |
0.007 |
0.011 |
Brain day 2 (mg equiv./g) |
NP |
NP |
0.001 |
0.001 |
0.2 |
0.3 |
0.001 |
0.001 |
Blood day 2 (mg equiv./g) |
NP |
NP |
0.002 |
0.002 |
1.1 |
1.1 |
0.002 |
0.003 |
Plasma day 2 (mg equiv./g) |
NP |
NP |
0.001 |
0.001 |
1.1 |
0.7 |
0.001 |
0.001 |
Heart day 2 (mg equiv./g) |
NP |
NP |
0.001 |
0.001 |
0.4 |
0.4 |
0.001 |
0.001 |
Pooled samples of urine, bile and faeces from the studies were examined for the presence of metabolites using a variety of chromatography techniques, mass spectroscopy (MS) and nuclear magnetic resonance spectroscopy (NMR). A total of 20 metabolites were detected, 13 of which were characterised. In most groups, >75% of the administered dose was characterised.Absorbed test substance is extensively metabolised, with no parent compound found in either urine or bile. Administration of a single dose or 15 doses of the test substance at 1 mg/kg bw produced a similar metabolic profile in both sexes with the main reactions being i) cleavage of the ester bond followed by glucuronidation or N-dethylation (M3, M11) or ii) O-demethylation (M6) followed by N-dethylation. Administration of 50 or 250 mg/kg bw indicated saturation in females of the pyrimidinyl esterase and the N-dethylation of M6. This difference in metabolism may be linked with the high levels of radiolabel in abdominal fat of females administered 250 mg/kg bw. Several metabolites retain functional groups consistent with cholinesterase inhibiting potential (M5). There was no direct evidence, in the samples analysed, of transformation to test substance oxon, though other oxons were detected in urine.
Table 3. Main metabolites in urine, faeces and bile (means; % of administered dose) in Alpk rats following administration of the test substance.
Dose
|
1 × 50 |
1 × 1 |
1 × 250 |
Repeat (14 + 1) × 1 mg/kg bw/d |
||||
Metabolite# |
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
Urine |
|
|
|
|
|
|
|
|
parent |
N.D. |
N.D. |
N.D. |
N.D. |
N.D. |
N.D. |
N.D. |
N.D. |
M1 |
1 |
5 |
3 |
4 |
7 |
9 |
3 |
6 |
M3 |
14 |
5 |
28 |
28 |
15 |
8 |
30 |
28 |
M11 |
1 |
<1 |
2 |
1 |
1 |
N.D. |
1 |
1 |
De-ethyl M6 |
12 |
7 |
8 |
5 |
24 |
13 |
10 |
10 |
M6 |
1 |
11 |
N.D. |
2 |
3 |
35 |
N.D. |
2 |
M12 |
2 |
1 |
5 |
4 |
4 |
3 |
8 |
5 |
O-Glucuronide of M1 |
3 |
2 |
4 |
4 |
5 |
6 |
1 |
5 |
ethoxy-glucuronide of M12 |
<1 |
<1 |
3 |
1 |
1 |
- |
2 |
2 |
Faeces |
|
|
|
|
|
|
|
|
parent |
29 |
15 |
13 |
15 |
4 |
3 |
15 |
5 |
M1 |
N.D. |
N.D. |
N.D. |
N.D. |
N.D. |
N.D. |
1 |
1 |
M3 |
N.D. |
N.D. |
2 |
3 |
6 |
5 |
7 |
3 |
M11 |
N.D. |
N.D. |
6 |
5 |
5 |
2 |
5 |
3 |
O-Glucuronide of M1 |
N.D. |
N.D. |
N.D. |
1 |
3 |
1 |
1 |
1 |
Bile |
|
|
|
|
|
|
|
|
parent |
N.D. |
N.D. |
- |
- |
- |
- |
- |
- |
M5 |
3 |
2 |
- |
- |
- |
- |
- |
- |
M1 |
1 |
1 |
- |
- |
- |
- |
- |
- |
M3 |
2 |
1 |
- |
- |
- |
- |
- |
- |
M11 |
<1 |
N.D. |
- |
- |
- |
- |
- |
- |
De-ethyl M6 |
3 |
2 |
- |
- |
- |
- |
- |
- |
M6 |
<1 |
<1 |
- |
- |
- |
- |
- |
- |
M12 |
<1 |
N.D. |
- |
- |
- |
- |
- |
- |
O-Glucuronide of M1 |
6 |
12 |
- |
- |
- |
- |
- |
- |
N.D. - Not Detected
Applicant's summary and conclusion
- Conclusions:
- Excretion is rapid, predominantly in the urine (>70%) at 48 hours, with approximately 50 % of the administered dose present in 12 hour urine samples. Some of the radiolabel present in faeces is due to biliary excretion. Overall the extent of absorption is considered to be >80% based on the radioactivity found in the urine of animals dosed with a single dose of 1 or 250 mg/kg bw and the repeat dose at 1 mg/kg bw/d (>60%) plus the significant level of radioactivity found in the bile of animals dosed with a single dose of 50 mg/kg bw (17%). Variations in the levels of radiolabel in consecutive faecal samples indicated that the test substance metabolites were subject to entero-hepatic circulation, which was more predominant in females and animals receiving repeated doses. This was consistent with the data from bile-duct cannulated animals, but could also involve deposition and release in adipose tissue. Two days after dosing, less than 2% of the administered dose remained in the carcass and tissues, though abdominal fat had particularly high concentrations in females dosed with 250 mg/kg bw. Other than a marked increase in deposition in fat at 250 mg/kg bw, the results were essentially independent of dose level and duration. Indications of a sex difference in some aspects of the toxicokinetics of the test substance were consistent with metabolite data.
Absorbed test substance is extensively metabolised, with no parent compound found in either urine or bile. A total of 20 metabolites were detected, 13 of which were characterised. In most groups, >75% of the administered dose was characterised. - Executive summary:
The basic ADME of the test substance, following single and repeat dosing, was investigated in Alpk:APfSD rats in a series of studies performed between 1996 and 1998.All studies were performed according to GLP and the following Guidelines without significant deviations:- 87/302/EEC B.36 / OECD 417 (1984) / FIFRA § 85-1. All studies used unlabelled material of 99.6% purity and 2-14C-pyrimidyl labelled material of >98% purity and specific activity of 2.15 GBq/mMol. Doses were administered by gavage in corn oil. Urine samples were taken at 6, 12, 24, 36 and 48 hours after the 14 C dose, with faecal samples taken at 12, 24, 36 and 48 hours. Bile samples were taken on eight occasions between 2 and 48 hours after dosing. Animals were sacrificed at 48 hours (except 50 mg/kg bw non-cannulated animals - 72 hours) and samples of cage washes, blood and a range of tissues taken. Samples were analysed by liquid scintillation counting following appropriate processing. Autoradiography was performed on animals sacrificed 6 or 24 hours after a dose of 1 mg/kg bw.
The test substance is rapidly and extensively absorbed from the gastrointestinal tract following gavage administration of doses of 1, 50 or 250 mg/kg bw and repeated doses of 1 mg/kg bw/d (Table 2. the results at 50 mg/kg bw seem anomalous and are used for comparison with bile-duct cannulated rats only). Excretion is rapid, predominantly in the urine (>70%) at 48 hours, with approximately 50 % of the administered dose present in 12 hour urine samples. Some of the radiolabel present in faeces is due to biliary excretion. Overall the extent of absorption is considered to be >80% based on the radioactivity found in the urine of animals dosed with a single dose of 1 or 250 mg/kg bw and the repeat dose at 1 mg/kg bw/d (>60%) plus the significant level of radioactivity found in the bile of animals dosed with a single dose of 50 mg/kg bw (17%). Variations in the levels of radiolabel in consecutive faecal samples indicated that the test substance metabolites were subject to entero-hepatic circulation, which was more predominant in females and animals receiving repeated doses. This was consistent with the data from bile-duct cannulated animals, but could also involve deposition and release in adipose tissue. Two days after dosing, less than 2% of the administered dose remained in the carcass and tissues, though abdominal fat had particularly high concentrations in females dosed with 250 mg/kg bw. Other than a marked increase in deposition in fat at 250 mg/kg bw, the results were essentially independent of dose level and duration. Indications of a sex difference in some aspects of the toxicokinetics of the test substance were consistent with metabolite data.
Pooled samples of urine, bile and faeces from the studies were examined for the presence of metabolites using a variety of chromatography techniques, mass spectroscopy (MS) and nuclear magnetic resonance spectroscopy (NMR). A total of 20 metabolites were detected, 13 of which were characterised. In most groups, >75% of the administered dose was characterised.Absorbed test substance is extensively metabolised, with no parent compound found in either urine or bile. Administration of a single dose or 15 doses of the test substance at 1 mg/kg bw produced a similar metabolic profile in both sexes with the main reactions being i) cleavage of the ester bond followed by glucuronidation or N-dethylation (M3, M11) or ii) O-demethylation (M6) followed by N-dethylation. Administration of 50 or 250 mg/kg bw indicated saturation in females of the pyrimidinyl esterase and the N-dethylation of M6. This difference in metabolism may be linked with the high levels of radiolabel in abdominal fat of females administered 250 mg/kg bw. Several metabolites retain functional groups consistent with cholinesterase inhibiting potential (M5). There was no direct evidence, in the samples analysed, of transformation to test substance oxon, though other oxons were detected in urine.
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