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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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 970
- Report date:
- 1970
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- no
- Remarks:
- Study performed before GLP
- Limit test:
- no
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
Test animals
- Species:
- rat
- Strain:
- other: SPF
- Remarks:
- Wistar-derived
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: young adult
- Weight at study initiation: males: 268 - 367 g, females: 220 - 295 g
- Housing: housed five per cage in Wilmslow-type mobile rat units. The cages were constructed of 19 gauge galvanised wire mesh (1 cm2) on three sides and floor with a solid back, and measured 33 x 27.5 x 13.5 cm. They were suspended over collecting trays lined with absorbent paper and attached to each cage was a food hopper of capacity 300 g, and two water bottles each of capacity 225 mL.
- Diet: stock diet, ad libitum
- Water: ad libitum
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- maize oil
- Details on oral exposure:
- DIET PREPARATION
All diets consisted of 77 parts of the stock diet, 18 parts of malt extract and 2 parts of maize oil with test substance, all by weight, to which was added 600 mL of water and the whole diet mixed mechanically for ten minutes after which it was moulded into pieces 3 - 6 cm in length and 1 cm diameter in a meat extruder. The experimental diets were identical with the control except that the appropriate quantities of the test material were incorporated into the diet before mixing. - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- Continuous
Doses / concentrationsopen allclose all
- Dose / conc.:
- 8 ppm
- Remarks:
- Dietary equivalent to 0.4 mg/kg bw/day in males and females
- Dose / conc.:
- 80 ppm
- Remarks:
- Dietary equivalent to 4 mg/kg bw/day
- Dose / conc.:
- 360 ppm
- Remarks:
- Dietary equivalent to 18 mg/kg bw/day
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, plain diet
- Details on study design:
- The animals on the various dose levels were introduced into the experiment over a period of two weeks, five animals from each group being introduced daily.
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS:
- Time schedule: daily
BODY WEIGHT:
- Time schedule for examinations: at the beginning and at weekly intervals during the study
FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
HAEMATOLOGY:
- Time schedule for collection of blood: pre-experimentally, at the mid point of the feeding study and immediately prior to killing the animals
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: five males and five females per dose group
- Parameters checked: haemoglobin concentration, packed cell volume, mean corpuscular diameter, reticulocyte count, total and white cell counts, differential white cell counts, platelet counts and clotting function tests (prothrombin index and Kaolin/Cephalin time)
CLINICAL CHEMISTRY:
- Time schedule for collection of blood: once a week for five weeks pre-experimentally and then at one and two weeks after commencement of dosing followed by sampling at fortnightly intervals to the end of the experimental period
- Time schedule for collection of brains: at the end of dosing
- Animals fasted: Not specified
- How many animals: 5 rats from each group
- Parameters checked: erythrocyte, plasma and brain cholinesterase activity
- Sacrifice and pathology:
- GROSS PATHOLOGY:
At the end of the 90-day treatment period 20 males and 20 females from each group were killed with halothane and an immediate full post-mortem examination made. The remaining five male and five females in each group were treated in the same way after a four-week recovery period on normal diets. Organ weights were recorded and organ:body weight ratios calculated for five male and five female animals selected from each group. These calculations were made for liver, heart, lungs, adrenals, kidneys and spleen.
HISTOPATHOLOGY:
The following organs were examined: liver, kidney, spleen, heart, lung, adrenal, gonads, thymus, thyroid, pancreas, stomach, duodenum, jejunum, ileum, caecum, colon, salivary gland, brain (cerebrum, cerebellum and pons) and spinal cord.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- All the animals survived the 90-day test period with the exception of one control male which died after four weeks from wounds received during fighting and one male on 360 ppm in the diet, which died of respiratory disease at nine weeks.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The mean body weights show that the weight gain in all test groups is comparable with the control group, with the exception of the females in 80 and 360 ppm groups. These animals showed a reduced weight gain of 18 and 21 % respectively when compared with the control animals.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- The female rats in 80 and 360 ppm groups showed a reduced food utilisation of 18 and 30 % respectively when compared with the control value.
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The activity of plasma cholinesterase was inhibited in 80 and 360 ppm groups to the extent of 40% in the males and 60% in the females in 80 ppm group, and 65% in the males and 80% in the females in 360 ppm, the inhibition becoming apparent after two weeks, but remaining constant to the end of the experimental period. The activities returned to normal within one week after cessation of dosing. No inhibition was seen at the lowest dose level (8 ppm). Inhibition of erythrocyte cholinesterase activity was seen in 360 ppm group only, and achieved 30% in the males and 50% in the females after two weeks on the test diets. This degree of inhibition persisted for the remainder of the experimental period and activity returned to normal during the four-week recovery period. Inhibition of brain cholinesterase activity occurred in the female rats of 80 and 360 ppm groups achieving a level of 40% in 360 ppm group. Recovery does not appear to be complete after four weeks. The male animals in 360 ppm group showed a tendency to inhibition of this activity, but this inhibition did not achieve statistical significance.
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No abnormalities attributable to the test material were seen. The male animals which died showed evidence of bleeding from the lacerations and bronchopneumonia in the lungs.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- (=NOEL)
- Effect level:
- 8 ppm
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical biochemistry
- Remarks on result:
- other:
- Remarks:
- Dietary equivalent to 0.4 mg/kg bw/day for both males and females
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 80 ppm
- System:
- central nervous system
- Organ:
- brain
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Table 1. Food consumption and body weight gain in female rats
Dose (ppm) |
0 |
8 |
80 |
360 |
0 |
8 |
80 |
360 |
|
Males |
Females |
||||||
Body weight gain |
||||||||
Starting weight |
307.9 |
308.6 |
308.0 |
311.3 |
250.2 |
250.2 |
250.0 |
260.4 |
Terminal weight |
437.2 |
437.4 |
446.4 |
439.3 |
285.3 |
285.3 |
278.8 |
288.0 |
Weight gain |
129.3 |
128.8 |
138.4 |
128.0 |
35.1 |
35.1 |
26.8 |
27.6 |
Food consumption |
||||||||
Food consumption per rat (g) |
1561 |
1487 |
1502 |
1520 |
1193 |
1201 |
1155 |
1216 |
Food intake per gram body weight (g) |
12.1 |
11.6 |
10.9 |
11.9 |
34.0 |
34.2 |
40.1 |
44.1 |
Table 2. Lymphocyte counts following exposure to the test substance
Dose (ppm) |
Time |
Distribution 10-3mm3(mean ±SD) |
|||
Males |
Females |
||||
Total WBC |
Lymphocytes |
Total WBC |
Lymphocytes |
||
0 |
Pre-exposure |
8.32±0.59 |
6.45±0.55 |
6.68±1.23 |
5.73±1.14 |
Mid-exposure |
7.30±1.30 |
5.78±1.36 |
6.36±1.54 |
5.24±1.36 |
|
Terminal |
6.02±0.44 |
4.86±0.52 |
5.16±1.09 |
4.29±1.01 |
|
8 |
Pre-exposure |
6.56±1.45 |
5.30±1.23 |
6.28±2.34 |
5.28±2.16 |
Mid-exposure |
6.62±1.85 |
5.69±1.59 |
6.14±1.27 |
5.29±1.52 |
|
Terminal |
5.46±1.53 |
4.39±1.48 |
5.12±1.50 |
3.96±1.45 |
|
80 |
Pre-exposure |
6.86±2.39 |
5.59±2.00 |
6.78±1.79 |
5.69±1.42 |
Mid-exposure |
6.48±1.57 |
5.51±1.49 |
5.86±1.21 |
4.78±1.11 |
|
Terminal |
5.64±1.63 |
4.40±1.20 |
4.62±1.12 |
3.91±0.97 |
|
360 |
Pre-exposure |
7.68±1.74 |
6.11±1.63 |
6.88±1.87 |
5.54±2.16 |
Mid-exposure |
5.78±1.95 |
4.72±1.41 |
6.04±1.61 |
4.76±1.49 |
|
Terminal |
6.02±1.57 |
4.77±1.70 |
4.30±0.83 |
3.42±0.63 |
Table 3. Cholinesterase activities (means, absolute and % inhibition) in rats (~5/group) fed diets containing the test substance.
Week |
1 pre- |
1 |
2 |
6 |
12 |
1 recovery |
4 recovery |
Dose (ppm) |
|
|
|
|
|
|
|
Erythrocyte |
|
|
|
|
|
|
|
Males 0£ |
1.0 |
1.0 |
0.9 |
1.4 |
1.3 |
0.9 |
1.1 |
8 (% inhibition§) |
+27 |
+20 |
+11 |
5 |
+8 |
+31 |
+20 |
80 (% inhibition§) |
+31 |
+6 |
+10 |
21 |
+11 |
+13 |
+5 |
360 (% inhibition§) |
+17 |
+8 |
34 |
60 |
11 |
34 |
+16 |
|
|
|
|
|
|
|
|
Females 0£ |
1.2 |
1.0 |
1.2 |
1.4 |
1.2 |
1.0 |
1.1 |
8 (% inhibition§) |
1 |
+28 |
3 |
5 |
14 |
+11 |
+4 |
80 (% inhibition§) |
14 |
+35 |
1 |
24 |
22 |
6 |
+3 |
360 (% inhibition§) |
18 |
5 |
48 |
51 |
60 |
29 |
22 |
Brain |
|
|
|
|
|
|
|
Males 0# |
N.P. |
N.P. |
N.P. |
N.P. |
30.6 |
N.P. |
30.5 |
8 (% inhibition§) |
N.P. |
N.P. |
N.P. |
N.P. |
+3 |
N.P. |
+2 |
80 (% inhibition§) |
N.P. |
N.P. |
N.P. |
N.P. |
1 |
N.P. |
+9 |
360 (% inhibition§) |
N.P. |
N.P. |
N.P. |
N.P. |
12 |
N.P. |
14 |
|
|
|
|
|
|
|
|
Females 0# |
N.P. |
N.P. |
N.P. |
N.P. |
31.8 |
N.P. |
31.4 |
8 (% inhibition§) |
N.P. |
N.P. |
N.P. |
N.P. |
6 |
N.P. |
+1 |
80 (% inhibition§) |
N.P. |
N.P. |
N.P. |
N.P. |
20 |
N.P. |
21 |
360 (% inhibition§) |
N.P. |
N.P. |
N.P. |
N.P. |
42 |
N.P. |
35 |
N.P. - not performed
£-umoles/ml/min
#- delta pH/g/h
§compared with control values rather than pre-test values for the group
+ increase in cholinesterase activity compared with the control
Applicant's summary and conclusion
- Conclusions:
- The NOAEL is 8 ppm, dietary equivalent to 0.4 mg/kg bw/day, based on brain cholinesterase activity inhibition in female rats.
- Executive summary:
In a non-GLP compliant study which was similar to OECD 408 (pre-GLP and pre-guideline), groups of 25 male and 25 female SPF Wistar-derived, pathogen free rats were maintained for 90 days on diets containing 0, 8, 80 and 360 ppm test substance (dietary equivalent to 0.4, 4, 18 mg/kg bw/day). Animals were observed for clinical signs, body weight, food consumption. Blood samples for haematology were taken from 5/sex/group pre-dosing, mid-term and at week 12. Plasma and erythrocyte cholinesterase activities were determined pre-dosing, at weeks 1, 2, 4, 6, 8, 10 and 12 and at weeks 1 and 4 of the recovery period. Brain cholinesterase measurements were performed at terminal sacrifice. At the end of the 90-day treatment period 20 males and 20 females from each group were killed with halothane and an immediate full post-mortem examination made. The remaining five male and five females in each group were treated in the same way after a four-week recovery period on normal diets. Organ weights were recorded and organ:body weight ratios calculated for five male and five female animals selected from each group. These calculations were made for liver, heart, lungs, adrenals, kidneys and spleen.
All the animals survived the 90-day test period with the exception of one control male which died after four weeks from wounds received during fighting and one male on 360 ppm in the diet, which died of respiratory disease at nine weeks. The mean body weights show that the weight gain in all test groups is comparable with the control group, with the exception of the females in 80 and 360 ppm groups. These animals showed a reduced weight gain of 18 and 21 % respectively when compared with the control animals. The female rats in 80 and 360 ppm groups showed a reduced food utilization of 18 and 30 % respectively when compared with the control value. No adverse effects were observed in the haematological parameters, gross or microscopic pathology. The activity of plasma cholinesterase was inhibited in 80 and 360 ppm groups to the extent of 40% in the males and 60% in the females in 80 ppm group, and 65% in the males and 80% in the females in 360 ppm, the inhibition becoming apparent after two weeks, but remaining constant to the end of the experimental period. The activities returned to normal within one week after cessation of dosing. No inhibition was seen at the lowest dose level (8 ppm). Inhibition of erythrocyte cholinesterase activity was seen in 360 ppm group only, and achieved 30% in the males and 50% in the females after two weeks on the test diets. This degree of inhibition persisted for the remainder of the experimental period and activity returned to normal during the four-week recovery period. Inhibition of brain cholinesterase activity occurred in the female rats of 80 and 360 ppm groups achieving a level of 40% in 360 ppm group. Recovery does not appear to be complete after four weeks. The male animals in 360 ppm group showed a tendency to inhibition of this activity, but this inhibition did not achieve statistical significance.
Under the conditions of this study, the NOAEL is 8 ppm, dietary equivalent to 0.4 mg/kg bw/day, based on brain cholinesterase activity inhibition in female rats.
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