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EC number: 204-500-1 | CAS number: 121-82-4
- 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
![](https://chesar.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1 March 1978 to 29 February 1980
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: This study was performed before GLP and OECD guidelines. However the method used is similar to to OECD 414.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 980
- Report date:
- 1980
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Perhydro-1,3,5-trinitro-1,3,5-triazine
- EC Number:
- 204-500-1
- EC Name:
- Perhydro-1,3,5-trinitro-1,3,5-triazine
- Cas Number:
- 121-82-4
- Molecular formula:
- C3H6N6O6
- IUPAC Name:
- 1,3,5-trinitro-1,3,5-triazinane
- Test material form:
- solid: crystalline
- Details on test material:
- - Name of test material (as cited in study report): RDX, heaxhydro-1,3,5-trinitro-1,3,5-triazine
- Molecular formula (if other than submission substance):C3H6N6O6
- Molecular weight (if other than submission substance): 222.26
- Smiles notation (if other than submission substance):N(=O)(=O)N(CN(N(=O)(=O))CN1N(=O)(=O))C1
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type: Explosive
- Physical state: crystal
- Analytical purity: 88.6% +/- 0.9%
- Impurities: 2.2% +/- 0.1% water and 9% HMX
- Lot/batch No.: HOL 43537
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Well known breeder
- Housing: Animal were usually housed together in plastic shoebox cages witb corn cob bedding
- Diet (e.g. ad libitum): ad libitum)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: one week
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 1% methylcellulose and 1% polysorbate 80 in water
- Details on exposure:
- Before preparation of the suspension, bulk RDX was crushed by hand. A concentrated suspension was prepared by hand mixing and diluted to proper concentrations with magnetic stirring. The vehicle was 1% methylcellulose and 1% polysorbate 80 (Tween 80, Lot No. 766613 or Lot No. 781666, Atlas Chemical Industries) ("MCTW") in water. Maintaining uniform suspensions was not always easy. Freeze-thaw cycles helped, especially with the more concentrated suspensions.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- A variety of dosage preparation were assayed for RDX content. Some of these were trial mixes to develop methods and check stability of the preparation. Others were actual dosage preparations, spot checks, rather than a systematic assay. Sample aliquots were diluted with acetone to give a concentration of ~ 15 mg RDX/mL and assayed by HPLC-UV.
- Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: until evidence of mating
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged : the male was removed from the cohabitation cage - Duration of treatment / exposure:
- Rats were dosed by gavage on days 6 through 19 of gestation
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0.2 mg/kg/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
2 mg/kg/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
20 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 24 female rats per dose for all treated groups except for the highest dose group which contained 25 female rats
- Control animals:
- yes, concurrent vehicle
- other: Positive control 350mg/kg hydroxyurea given on Day 6 followed by vehicle on Day 7 to Day 12
- Details on study design:
- - Dose selection rationale: based on a rat range finding study performed by gavage with 10, 20, 40 and 80 mg RDX/kg/day.
All rats given a RDX dose of 80 or 40mg/kg/day died following convulsions. Inspection of the uterus at the time of death indicated that all dams in the 40 mg/kg/day but not in the 80 mg/kg/day dose group had hemorrhages around implantation sites or detached feto-placental units. Similar effects were not observed at lower doses with full-term dams. With the exception of one dam given 20 mg/kg/day which exhibited some of the jerking movements, no effects were seen in dams given 10 or 20 mg/kg/day when compared with dams given the suspension medium without RDX. An indication of morbidity was evident in the weight gain of these dams. Mean values for the treatment weight change (difference between gravid day 20 and day 6 bodyweight) were 91 or 86 g for dams given 10 or 20 mg/kg/day versus 126 g for the control. No indications of an adverse effect on fetal development was observed. This range finding teratology study in rats suggests that at dosage levels of 20 mg/kg/day RDX a consistent adverse effect on maternal weight gain and intrauterine effects may be observed. As a result of this study, three dose levels of RDX (i.e., 0.2, 2, and 20 mg/kg/day) were selected for the full-scale study.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: on gestation days, 6, 7, 9, 11 and 19
FOOD CONSUMPTION : Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- the viscera examined grossly - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: one third of the viable fetuses per litter
- Skeletal examinations: Yes: two third of the viable fetuses per litter - Statistics:
- Data were analyzed by a nonparametric rank test. The level of significance was selected a p<0.05 unless otherwis indicated. The litter was considered the experimental unit of observation. For example, the percent of fetuses with a given anomaly was calculated for each litter. These percentages were then analysed by a non parametric rank test.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
MORTALITY:
Mortality was observed in 6 of 25 dams treated with 20 mg/kg/dayof RDX and occurred between the 11th and the 14th day of gestation. Chronic convulsions occurred in four dams before death.
NEUROTOXICITY
Neurotoxic signs of RDX were observed in 18 of the 25 dams treated with 20 mg/kg/day. These animals showed hyperactivity and other central nervous system related stimulations including convulsions. The appearance of neurotoxic signs in these animals normally occurred on the second day of dosing and then diminished in frequency after the eighth day of dosing. At a dose level of 2.0 mg/kg/day only one female exhibited convulsion during the period of dosing. Convulsions were also observed in one female receiving 350 mg/kg/day of hydroxyurea. There were no neurotoxic signs observed in any females receiving either the vehicle or 0.2 mg RDX/kg/day during the dosing period of day 6-19 of gestation.
LIVER WEIGHT
The absolute liver weight was significantly reduced in dams treated vith 20 mg/kg/day of RDX. There were no meaningful changes in liver weight in dams treated vith low dose levels of RDX or hydroxyurea.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 2 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes. Remark: (Embryotoxic effects)
Details on embryotoxic / teratogenic effects:
EMBRYOTOXICITY
There were no meaningful changes in number of implants, viable and dead fetuses when the data obtained from treated animals were compared with control animals. High incidence of earlier resorption was noted in surviving animal treated with RDX at 20 mg/kg/day. However, it is difficult to evaluate the significance of this parameter based on only surviving dams.
TERATOGENIC EFFECTS
The external, soft tissue and skeletal anomalies detected in fetuses from rats following oral administration of RDX at 0.2, 2.0, 20.0 mg/kg/day were found to be similar to control rats receiving vehicle only. Hydroxyurea, serving as positive control, produced high incidences of Hydroencephales (soft tissue anomaly), cleft palate, abnormal snout, absence of eye bulges (external anomalies), anomalies of snout, mandible, cranium, vertebrae, sternebrae, axial skeleton and ribs as compared with vehicle or RDX treated rats.
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 2 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: embryotoxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 20 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- 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
See Table 1 below for data on RDX treatment in rats |
Table 1 Effect Of Hydroxyurea And RDX Administration During Gestation On Maternal Welfare In Rats
aAdministered 350 mg/kg/day on gestational day 6, vehicle on days 7 -12 bDay 20 weight - day 0 weight -weight of reproductive tract and contents
See table 2 below for details on embryo toxicity.
Table 2 Embryo Toxicity
|
Applicant's summary and conclusion
- Conclusions:
- In this rat teratogenicity study the high dose (20 mg/kg/day) of RDX produced maternal toxicity (neurotoxicity, including convulsions), some maternal deaths and embryotoxicity. The embryotoxicity could be solely the result of the convulsions and consequent hypoxia/transient anoxia. The lower doses (0.2 and 2.0 mg/kg/day) had no adverse effects. Therefore the maternal and developmental NOAEL is 2.0 mg/kg/day. The teratology NOAEL is 20 mg/kg/day.
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