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EC number: 240-815-0 | CAS number: 16752-77-5
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 983
- Report date:
- 1983
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The purpose of this study was to determine the toxicity and the teratogenic potential of the test substance in the rabbit. Solutions of the test substance in deionized water were administered by gavage on days 7 through 19 of presumed gestation to artificially inseminated rabbits at dosages of 0 (vehicle), 2, 6 and 16 mg/kg/day at a dosage volume of 5 mL/kg/day. Rabbits were observed for signs of agent effect, abortion or delivery. Body weights were recorded. Does which aborted were killed, examined, and observed uterine contents were recorded. Does which were found dead were similarly examined. On day 29 of presumed gestation, surviving female rabbits were killed, the abdomen of each was opened, and the uterus wag examined. Each fetus or delivered pup was weighed and subsequently examined for gender and for gross external, visceral and skeletal alterations.
- GLP compliance:
- yes
Test material
- Reference substance name:
- Methomyl
- EC Number:
- 240-815-0
- EC Name:
- Methomyl
- Cas Number:
- 16752-77-5
- Molecular formula:
- C5H10N2O2S
- IUPAC Name:
- (E)-[1-(methylsulfanyl)ethylidene]amino N-methylcarbamate
- Test material form:
- solid: crystalline
Constituent 1
- Specific details on test material used for the study:
- Methomyl
Lot#: INX-1179-255
Purity: 98.7%
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Dutchland Laboratories, Inc., Swampbridge Road, Box 139A, Denver, Pennsylvania
- Age at study initiation: Approximately 28 weeks
- Weight at study initiation: 3.14 to 4.71 Kg
- Housing: Female rabbits were housed in vertical order according to dosage and insemination groups. Housing units consisted of eight individual stainless steel cages (5 square feet of floor area with 16 inch height per individual cage).
- Diet: Certified rabbit chow #5322, approximately 180 g each per day
- Water: ad libitum
- Acclimation period: Approximately 7 weeks
ENVIRONMENTAL CONDITIONS
- Temperature: 17.7-22.2°C
- Humidity: 30-80%
- Air changes: 12-15 per hr
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: deionized water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Solutions of the test substance in reverse osmosis processed deionized water (R.O. water) a were prepared daily prior to use. Concentrations, calculated on the basis of the active ingredient were selected to provide 5 mL/kg dosage volume to rabbits in all dosage groups.
VEHICLE
- Concentration in vehicle: 0.4, 1.2 and 3.2 mg/mL for dosages of 2, 6 and 16 mg/kg respectively - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure: Artificial insemination
- Verification of same strain and source of both sexes: yes
- Day of artificial insemination is referred to as day 0 of pregnancy - Duration of treatment / exposure:
- GD 7 to GD 19
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 2 mg/kg bw/day
- Dose / conc.:
- 6 mg/kg bw/day
- Dose / conc.:
- 16 mg/kg bw/day
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dosages evaluated in this study were selected on the basis of an initial toxicity assessment and a pilot evaluation.
In the initial toxicity assessment, one female rabbit (not inseminated) was administered a single 24 mg/kg/day dosage of the test substance to determine if a rabbit could tolerate the agent at the maximum dosage proposed for the preliminary study. In the preliminary study four artificially-inseminated rabbits were assigned to each dosage group, and the test substance was administered at dosages of 8, 16 or 24 mg/kg/day on days 7 through 19 of presumed gestation.
The 24 mg/kg/day dosage was lethal. Two rabbits in this dosage group died on day 7 of presumed gestation at approximately 10 and 30 minutes post dosage. Dosage-dependent clinical signs observed for surviving rabbits included ataxia, decreased motor activity, body jerks, tremors, vocalization (16 and 24 mg/kg/ day dosage groups), salivation, clonic convulsions, dyspnea, pin-point pupils, tales and reluctance to use hindlimbs (24 mg/kg/day dosage group). Pregnancy occurred in 4, 2, 1 and 3 rabbits in the control, low, middle and high dosage groups, respectively. Of these, one control rabbit aborted, and two high dosage group rabbits died. Maternal body weight and caesarean-sectioning data were inconclusive. The single surviving pregnant rabbit in the high dosage group had a larger number of resorptions and fewer live fetuses, as compared with control group rabbits, a possible agent-related effect. All fetuses from litters of does given test substance appeared normal at gross external examination. Two fetuses, one from each of two control litters, were hydrocephalic (domed heads).
Examinations
- Maternal examinations:
- OBSERVATIONS: Female rabbits were observed for physical signs and/or general appearance several times during the prestudy period and on days 0, 3 and 6 of presumed gestation. Observations for physical signs of agent effect, abortion and/or viability were made several times each day during the administration period (days 7 through 19 of presumed gestation) and daily during the post administration period (days 20 through 29 of presumed gestation).
BODY WEIGHT
- Time schedule for examinations: Day after arrival, once weekly during the acclimation period, on days 0 and 6 of presumed gestation, and daily during the administration period (days 7 through 19 of presumed gestation) and Post administration period (days 20 through 29 of presumed gestation) .
FOOD CONSUMPTION: During the study rabbits were observed for anorexia.
POST-MORTEM EXAMINATIONS
- Sacrifice on gestation day # 29
- Organs examined: Lungs, uterus and gross lesions - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Weight of each live fetus
- Number of corpora lutea
- Number of implantations
- Number and location of early and late resorptions
- Number and location of all live and dead fetuses
- Other: Any gross anomaly - Fetal examinations:
- - External examinations: Yes
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Statistics:
- Maternal physical sign data and the incidence of pregnancy and abortion were analyzed using Fisher's exact test.
The one-way analysis of variance was used to evaluate average body weights of rabbits assigned to the four dosage groups on days 0 and 6 of presumed gestation. Maternal body weight data for days 0, 7, 11, 15, 20, 24, 29 and 29C (corrected) of pregnancy a were analyzed using Bartlett's test of homogeneity of variances, and either the one-way analysis of variance or the Mann-Whitney U test. If Bartlett's test was positive (P ≤0.05), then the Mann-Whitney U test was used to analyze the data by testing each group individually against the control dosage group.
If Bartlett's test was negative (P >0.05), then the one-way analysis of variance was used to analyze the data. If the F-ratio was positive (P ≤0.05), then Dunnett's test was used to test each group individually against the control dosage group.
Data obtained during Caesarean-sectioning and for malformations and variations was evaluated using Jonckheere's test with the population of affected fetuses per litter considered to be the basic experimental unit. If Jonckheere's test was positive (P ≤0.05), and if there were fewer than 75% ties in a group, then the Mann-Whitney U test was used to analyze the data by testing each group individually against the control dosage group. If Jonckheere' s test was positive (P ≤0.05), and if there were more than 75% ties in a group, then Fisher's exact test was used with fixed point censoring to evaluate the data.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- CNS stimulation occurred for high dosage group rabbits and was considered to be an effect of the test substance. Dosage-dependent increases (P =0.047 to P <0.0001) in incidence of tremors, hyperactivity, body jerks, excess salivation, aggressive behavior (stamping of hind feet), hyperpnea, and convulsions were observed for high dosage group rabbits, as compared with control. Dosage-dependent increased incidences were also observed for ataxia, impaired or lost righting reflex, self-inflicted or spontaneous lesions, dyspnea, hyper sensitivity, pin-point pupils and vocalization. These incidences were not significantly different (P >0.05) from those observed for control rabbits.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Test substance related deaths occurred for one rabbit in the 6 mg/kg/day dosage group and 7 (P =0.003) rabbits in the 16 mg/kg/ day dosage group. These deaths generally followed observed evidence of central nervous system (CNS) stimulation.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- A small, dosage-related increase (P <0.05) in maternal body weight gain occurred between days 0 and 29 of gestation; however, only the gain of the high dosage group differed significantly from the control value. This difference was due to the decreased incidence of anorexia of the dams of the high dosage group during the latter portion of gestation.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Postmortem observations included a perforated stomach and evidence of excess salivation in the middle dosage group rabbit. Excess salivation was also observed for high dosage group rabbits, and the incidence was significantly increased (P =0.008), as compared with the control group.
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- As compared with the control group, the incidence of anorexia was significantly decreased (P =0.009) for rabbits in the high dosage group. This observation was considered to be a rebound in feed consumption after the dosage period. During the last part of gestation, spontaneous anorexia did occur among the control, low and middle dosage group rabbits.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- The incidence of pregnancy and number of corpora lutea per dam were similar for all dosage groups.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- The incidence of implantations per dam were similar for all dosage groups.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- The incidence of resorptions per dam were similar for all dosage groups.
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- The incidence of pregnancy per dam were similar for all dosage groups.
Effect levels (maternal animals)
- Remarks on result:
- other: maternal toxicity was expressed as death and CNS stimulation
Results (fetuses)
- Fetal body weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A dosage-related increase in average fetal body weight occurred; the difference from the control value was statistically significant only for the middle (P =0.025) and high (P =0.003) dosage groups. This increase in fetal body weight was not considered to be an adverse effect, since it was not observed to be due to the presence of edema. It probably was due to increased feed consumption of the dams during the latter part of gestation.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Administration of 2, 6 and 16 mg/kg/day dosages of the test substance to does did not result in adverse effects on embryo/ fetal viability or fetal sex ratio. Similarly, no gross external, soft tissue or skeletal malformations, developmental variations or variations due to retarded development observed for fetuses were attributed to administration of the test substance to the does.
Effect levels (fetuses)
- Key result
- Remarks on result:
- other: Administration of aqueous solutions of the test substance to pregnant rabbits at dosages of 2, 6 and 16 mg/kg/day on days 7 through 19 of gestation was neither teratogenic nor embryo-fetal toxic, even in the presence of maternal toxicity.
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Administration of aqueous solutions of the test substance to pregnant rabbits at dosages of 2, 6 and 16 mg/kg/day on days 7 through 19 of gestation was neither teratogenic nor embryo-fetal toxic, even in the presence of maternal toxicity.
- Executive summary:
The purpose of this study was to determine the embryofetal toxicity and the teratogenic potential of the test substance in the rabbit. Solutions of the test substance in reverse osmosis processed deionized water were administered by gavage on days 7 through 19 of presumed gestation to artificially-inseminated rabbits which had been randomly assigned to each of four dosage groups (20 rabbits/group).
The test substance as administered to rabbits at dosages of 0 (vehicle), 2, 6 and 16 mg/kg/day (calculated as the active ingredient) at a dosage volume of 5 mL/kg/day.
Agent-related deaths occurred for one rabbit in the 6 mg/kg/day dosage group and seven (P =0.003) rabbits in the 16 mg/kg/ day dosage group. These deaths generally followed observed evidence of central nervous system (CNS) stimulation.
One low dosage group rabbit aborted on day 27 of gestation, and one middle dosage group rabbit delivered on day 29 of gestation. These occurrences were considered to be spontaneous.
CNS stimulation occurred for high dosage group rabbits and was considered to be an effect of the test agent. Dosage-dependent increases (P =0.047 to P <0.0001) in incidence of tremors, hyperactivity, body jerks, excess salivation, aggressive behavior (stamping of hind feet), hyperpnea, and convulsions were observed for high dosage group rabbits, as compared with control. Dosage-dependent increased incidences were also observed for ataxia, impaired or lost righting reflex, self-inflicted or spontaneous lesions, dyspnea, hyper sensitivity, pin-point pupils and vocalization. These incidences were not significantly different (P >0.05) from those observed for control rabbits.
Postmortem observations included a perforated stomach and evidence of excess salivation in the middle dosage group rabbit. Excess salivation was also observed for high dosage group rabbits, and the incidence was significantly increased (P =0.008), as compared with the control group.
As compared with the control group, the incidence of anorexia was significantly decreased (P =0.009) for rabbits in the high dosage group. This observation was considered to be a rebound in feed consumption after the dosage period. During the last part of gestation, spontaneous anorexia did occur among the control, low and middle dosage group rabbits.
A small, dosage-related increase (P <0.05) in maternal body weight gain occurred between days 0 and 29 of gestation; however, only the gain of the high dosage group differed significantly from the control value. This difference was due to the decreased incidence of anorexia of the dams of the high dosage group during the latter portion of gestation.
A significant decrease (P =0.024) in maternal body weight was observed among the dams in the 2 mg/kg/day dosage group on days 0 to 7, as compared with that for the control group. This decrease was not test substance-related, since it occurred before the dosage period.
The incidence of pregnancy and number of corpora lutea, implantations and resorptions per dam were similar for all dosage groups.
A dosage-related increase in average fetal body weight occurred; the difference from the control value was statistically significant only for the middle (P =0.025) and high (P =0.003) dosage groups. This increase in fetal body weight was not considered to be an adverse effect, since it was not observed to be due to the presence of edema. It probably was due to increased feed consumption of the dams during the latter part of gestation.
Administration of 2, 6 and 16 mg/kg/day dosages of the test substance to does did not result in adverse effects on embryo/ fetal viability or fetal sex ratio. Similarly, no gross external, soft tissue or skeletal malformations, developmental variations or variations due to retarded development observed for fetuses were attributed to administration of the test substance to the does.
On the basis of these data, administration of aqueous solutions of the test substance to pregnant rabbits at dosages of 2, 6 and 16 mg/kg/day on days 7 through 19 of gestation was neither teratogenic nor embryo-fetal toxic, even in the presence of maternal toxicity. The maternal toxicity was expressed as death and CNS stimulation.
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