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EC number: 433-400-2 | CAS number: 4245-76-5
- 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
- Study period:
- 2005-10-17 till 2006-05-11
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline-conform study under GLP without deviations
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japanese Guidelines (Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, 12 Nohsan No. 8147, Teratology
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- This study was performed in compliance with: Swiss Ordinance relating to Good Laboratory Practice, adopted May 18'" 2005 [RS 813.112.1] This Ordinance was based on the OECD Principles of Good Laboratory Practice, as revised in 1997 and adopted November 26
- Limit test:
- yes
Test material
- Reference substance name:
- -
- EC Number:
- 433-400-2
- EC Name:
- -
- Cas Number:
- 4245-76-5
- Molecular formula:
- C2H6N4O2
- IUPAC Name:
- 1-Methyl-3-nitro-guanidine
- Reference substance name:
- N-methyl-N'-nitro-guanidine
- IUPAC Name:
- N-methyl-N'-nitro-guanidine
- Details on test material:
- - Name of test material (as cited in study report): MeNigu (1-Methyl-3-nitroguanidin)
- Physical state: solid, white cristals
- Molecular weight: 118.1 g/mol
- Analytical purity: 99.7%
- Lot/batch No.: 9077154
- Expiration date of the lot/batch: June 1, 2007
- Stability under test conditions: test item in feed known to be stable for at least 3 weeks when stored at room temperature
- Storage condition of test material: at room temperature, protected from light and moisture
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: RCC Ltd Laboratory Animal Services, Füllinsdorf / Switzerland
- Age at study initiation: 10 weeks (age at pairing)
- Weight at study initiation: 186 - 225 grams (day 0 post coitum)
- Fasting period before study: not reported
- Housing: Animals were housed individually in Makrolon cages with wire mesh tops and standardized granulated softwood bedding
- Diet (e.g. ad libitum): Pelleted standard Kliba-Nafag 3433 ratlmouse maintenance diet was available ad libitum
- Water (e.g. ad libitum): Community tap water from Fullinsdorf in bottles was available ad libitum.
- Acclimation period: Seven days (minimum) prior to pairing under test conditions with an evaluation of the health status.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light / 12 hours dark
IN-LIFE DATES: From: 2005-10-25 To: 2005-11-15
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): Daily before administration
- Mixing appropriate amounts with (Type of food): The test item was weighed into a glass beaker on a tared precision balance and the vehicle was
added (wlv). Using an appropriate homogenizer a homogenous mixture was prepared. Separate formulations were prepared for each concentration.
During the daily administration period homogeneity of the test item in the vehicle was maintained using a magnetic stirrer.
- Storage temperature of food: At room temperature (17-23°C)
VEHICLE
- Justification for use and choice of vehicle (if other than water): no justification stated in the study report
- Concentration in vehicle: 0.5% in water
- Amount of vehicle (if gavage): A standard dose volume of 10 mg/kg body weight with a daily adjustment to the actual body weight was used.
- Lot/batch no. (if required): 111953524604357
- Purity: no data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples for determination of concentration, homogeneity and stability (4 hours) of the dose formulations were taken during the first week of the
administration period. Additionally, samples for determination of concentration and homogeneity were taken during the last week of the
administration period.
On each occasion three samples of approximately 2 g were taken from the top, middle and bottom of each formulation and transferred into flat
bottomed flasks. Stability samples were taken from the middle only. The samples were frozen (-25°C to -15°C) pending analysis. Analysis was performed using a method provided by the Sponsor (HPLC). The results of the Analytical Phase are presented in the attachment of the study report. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Females were housed with sexually mature males in special automatic mating cages, i.e. with synchronized timing to
initiate the nightly mating period, until evidence of copulation was observed. This system reduced the variation in the copulation times of the
different females. The females were removed and housed individually, if a) the daily vaginal smear was sperm positive or b) a copulation plug was
observed. The day of mating was designated day 0 post coitum.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. not applicable
- Further matings after two unsuccessful attempts: [no / yes (explain)] not applicable
- Verification of same strain and source of both sexes: [yes / no (explain)] Male rats of the same source and strain were used for mating only. These male rats were in the possession of RCC.
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: - Duration of treatment / exposure:
- 15 days
- Frequency of treatment:
- daily
- Duration of test:
- 21 days
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
300 mg/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- Each group consisted of 22 mated female rats.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Dose levels were based on a dose range-finding study, where treatment with MeNigu at 100, 300 and 1000 mg/kg body weight/day was well tolerated without any signs of maternal or embryo-fetal toxicity.
- Rationale for animal assignment (if not random): Mated rats were assigned to the different groups using a computer-generated random algorithm. In addition, the body weights (recorded on the day of allocation) were taken into consideration in order to ensure similar mean body weights in all groups on day 0 post coitum.
- Other:
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily
- Cage side observations checked in table p78 were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded daily from day 0 until day 21 post coitum
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: not applicable
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: gross macroscopic examination of all internal organs, with emphasis on the uterus, uterine contents, position of fetuses
in the uterus and number of corpora lutea
OTHER: - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: No data
- Number of early resorptions: No data
- Number of late resorptions: No data
- Other: - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter - Statistics:
- The following statistical methods were used to analyse body weights, food consumption, reproduction and skeletal examination data:
1. Means and standard deviations of various data were calculated and included in the report.
2. If the variables could be assumed to follow a normal distribution, the Dunnett many-one t-test, based on a pooled variance estimate, was used for
intergroup comparisons (i.e. single treatment groups against the control group).
3. The Steel test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
4. Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information. - Indices:
- none reported
- Historical control data:
- Historical control data are attached to the study report.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
FOOD CONSUMPTION
In group 4 (high dose group), mean food consumption was statistically significantly decreased throughout the treatment period compared with the control group (-10.7%). In group 3, mean food consumption was only slightly reduced (-3.6%). Mean food consumption in group 2 was not affected by the treatment with the test item.
BODY WEIGHTS
Mean body weights and body weight gains were slightly decreased in group 4 (+39.2% compared to +43.5% in the control group). The mean corrected body weight gain (corrected for gravid uterus weight) was also decreased (+4.6% compared to +7.4% in the control group). In groups 2 and 3, mean body weights were minimal lower throughout the treatment period than in the control group probably due to the smaller number of fetuses per litter (12.0 fetuses each, compared to 13.2 fetuses in the control group). This opinion is supported by the corrected mean body weight gain values, which were similar to that of the vehicle control (+7.6% and +7.9%, respectively).
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- >= 100 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOEL
- Effect level:
- >= 300 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
BODY WEIGHT
In group 4, on an individual basis, the mean fetal weights were marginally decreased (-2.1 % for male and female weights combined). As there were also lower number of fetuses per litter compared to the control, the reduced mean fetal weights was considered to be test item related.
SKELETAL EXAMINATION OF FETUSES - STAGE OF DEVELOPMENT
In group 4, when calculated on a fetus basis, skeletal examinations for the stage of development showed statistically significantly increased
incidences of non-ossified cervical vertebral bodies 2, 3 and 4. This slightly lower stage of development was considered to be a consequence
of the maternal toxicity as indicated by the reduced fetal body weights.
Effect levels (fetuses)
- Dose descriptor:
- NOEL
- Effect level:
- > 1 000 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: teratogenicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Tab. 3: Summary of significant maternal toxic effects
Observed effect | Control | Test item administration300 mg/kg bw per day | Test item administration1000 mg/kg bw per day |
Food consumption | normalized level | -3.6% | -10.7% |
Body weight gain | +43.5% | * | +39.2% |
Corrected body weight gain(corrected for gravid uterus weight) | +7.4% | - | +4.6% |
Corrected body weight gain(corrected for gravid uterus weight) | +7.9% | +7.6% | - |
* Mean body weights of dose groups 100 and 300 mg/kg bw per day were minimal lower throughout the treatment period than in the control group probably due to the smaller number of fetuses per litter. This opinion is supported by the corrected mean body weight gain values, which were similar to that of the vehicle control.
Tab. 4: Sumary of significant embryotoxic effects
Observed effect | Control | Test item administration 1000 mg/kg bw per day |
Body weight gain | normalized level | -2.4% * |
Skeletal examination | normalized level | statistically significantly increased incidences of non-ossified cervical vertebral bodies |
* Additionally smaller no. of embryos per litter, therefore considered test item related effect
Applicant's summary and conclusion
- Conclusions:
- Based on these results the NOEL for maternal organisms was considered to be 100 mg/kg body weight/day. Based on these results the NOEL for fetal organisms was considered to be 300 mg/kg body weight/day. Under the conditions described for this study MeNigu revealed no teratogenic
potential up to and including the high dose level of 1000 mg/kg body weight/day. No GHS/CLP classification of CA 2342 A under reproductive
toxicity necessary. - Executive summary:
The purpose of this study was to assess the effects of MeNigu on pregnant female rats and embryo-fetal development when administered orally, by gavage, once daily to mated female rats from day 6 through to day 20 post coitum, inclusive (OECD Guideline 414). Each group consisted of 22 mated female rats.
In order to detect effects on the pregnant female and on embryonic and fetal development, MeNigu was administered orally by gavage once daily from day 6 through to day 20 post coitum at dose levels of 0, 100, 300 and 1000 mg/kg body weight/day. A standard dose volume of 10 ml/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (carboxymethylcellulose (0.5% in water). All females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section.
At 1000 mg/kg body weight/day, mean food consumption and body weight gain were statistically significantly decreased throughout the treatment period. At 300 mg/kg body weight/day, mean food consumption was slightly reduced. At 1000 mg/kg body weight/day, the fetal body weights were slightly reduced. Furthermore, ossification of cervical vertebral bodies was slightly less advanced that in the vehicle control.
Based on these results the NOEL (no observed effect level) for maternal organisms was considered to be 100 mg/kg body weight/day. Based on these results the NOEL for fetal organisms was considered to be 300 mg/kg body weight/day. Under the conditions described for this study MeNigu revealed no teratogenic potential up to and including the high dose level of 1000 mg/kg body weight/day.
Comments on GHS/CLP-classification on reproductive toxicity:
The maternal toxicity NOEL of 100 mg/kg bw/d goes back to the slightly decreased food consumption at dose level 300 mg/kg bw/d, an effect which is considered as a minor health effect only. More clearly decreased food consumption, decreased body weight (gain) and slightly less advanced ossification of cervical vertebral bodies of the embryos were observed at the high dose level (i.e.1000 mg/kg bw/d) only. Furthermore there was the total absence of any teratogenic effects at all dose levels. Therefore it is concluded that EU or GHS classification of CA 2342 A as to its reprotoxic properties is not required.
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