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EC number: 203-103-0 | CAS number: 103-34-4
- 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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- December 1, 1987 - June 9, 1988
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 988
- Report date:
- 1988
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
- Deviations:
- yes
- Remarks:
- 50 metaphase cells were observed per animal (instead of 100).
- GLP compliance:
- yes
- Type of assay:
- chromosome aberration assay
Test material
- Reference substance name:
- Di(morpholin-4-yl) disulphide
- EC Number:
- 203-103-0
- EC Name:
- Di(morpholin-4-yl) disulphide
- Cas Number:
- 103-34-4
- Molecular formula:
- C8H16N2O2S2
- IUPAC Name:
- 4-(morpholin-4-yldisulfanyl)morpholine
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River laboratories, Kingston, New York
- Age at study initiation: 61 days
- Weight at study initiation: males = 139-158g, females = 104-122g
- Assigned to test groups randomly: [no/yes, under following basis: ]
- Fasting period before study: 18 hours prior dosing
- Housing: individually in stainless steel wire mesh cages
- Diet (e.g. ad libitum): Wayne Rodent Blox, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: 4 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- Corn oil
- Details on exposure:
- Volume of administration = 10 ml/kg
- Duration of treatment / exposure:
- a single exposure
- Frequency of treatment:
- a single exposure
- Post exposure period:
- 6, 18 and 30 hrs
Doses / concentrations
- Remarks:
- Doses / Concentrations:
2800 mg/kg bw
Basis:
actual ingested
- No. of animals per sex per dose:
- 5 animals / sexe / group
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Cyclosphosphamide (20 ml/kg)
Examinations
- Tissues and cell types examined:
- Animals were sacrified at 6, 18 and 30 hours after dosing. 2/3h prior sacrifice, each animal was given a single peritoneal dose of colchicine at 4 mg/kg bw to arrest dividing cells in metaphase. A total of 500 well spred, intact metaphase cells were scored for the presence of chromosome aberration per experiment treatment point (50/animal) by 2 invertigators (25 each/animal).
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION:
Based on the results of the preliminay study and in discussion with the Sponsor, a dose of 2800 mg/kg was selected as an estimate of the maximum tolerated dose for evaluation in the metaphase analysis assay.
DETAILS OF SLIDE PREPARATION:
Slides were coded randomly by study number and number and letter designation by a person not involved in the actual scoring of the slides. The code was kept in the QAU's file until ail slides were evaluated. Ail animais were coded as a single set with no indication of dose or time of harvest. Following scoring of ail slides, data were decoded and placed into groups for statistical analysis.
METHOD OF ANALYSIS:
A total of 500 well spread, intact metaphase cells (if possible) were scored for the presence of chromosome aberration per experimental treatment point (50 per animal) by two investigators (25 each per animal). Cells were located by systematic searching of the slide under low power (20X-40X) magnification. Cells judged acceptable for analysis based on cell morphology and total centromere number were then further analyzed with a 100X oil immersion objective where abnormalities were detected and classified. Vernier coordinates were recorded for the first and last metaphase scored, as well as for any abnormal metaphases (including gaps) observed. The centromere number was recorded for all cells analyzed. Ail slides were scored for chromosome damage using a Nikon Optiphot microscope. - Evaluation criteria:
- not precised
- Statistics:
- Mean number of aberrations per cell per rat (50 cells per rat) were analyzed for statistically significant increases in chromosome aberration by a one-way analysis of variance (ANOVA). Each sampling Lime was analyzed separately as compared to its concurrent vehicle control group. The CP group was not included in the ANOVA. Data from this group were analyzed separately by a one-tailed t test comparing CP with the 18 heur vehicle contrai. The mean and standard deviation of aberrations/tell were also determined for each group of rats (500 tells; 50 tells per rat). The number of aberrant metaphases was analyzed by Chi-square analysis for statistically significant increases. Statistical significance was determined at the p < or =0.05 probability level.
Results and discussion
Test results
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- yes
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY : 2 adult male and 2 adult female rats (55 days old)
- Dose range: 2800 mg/kg bw
Due to the pharmacotoxic signs observed at this dose, 2800 mg/kg was selected as an estimation of the maximum tolerated dose.
RESULTS OF DEFINITIVE STUDY
Pharmacotoxic Effects of Treatment:
No pharmactoxic signs of treatment were observed in animals administered Sulfasan R immediately after dosing. Pharmacotoxic signs observed prior to colchicine administration in all groups treated with Sulfasan R were as follows :
-6 Hour Croup - (observed approximately 4 hours after dosing):
All rats had exhibited diarrhea, piloerection, decreased body tone, abnormal gait and a brownish discoloration on forepaws and around oral-nasal region. Four males and two females had an abnormal stance and arched back. Five males and two females had decreased activity and three females had body drop. One male died just prior to harvest. Gross necropsy of this animal revealed mottled lungs. This male was replaced by an other rat which also exhibited signs common to those in this group. Males in this group lost an average of 1.2 grams while the females gained 0.6 grams average from the original fasted weights.
-18 Hour Group - (observed approximately 16 hours after dosing):
All-rats exhibited diarrhea, decreased body tone, abnormal gait, abnormal stance, piloerection, arched back, and a brownish discoloration on forepaws and around nasal-oral region. Three females and four males exhibited chromodacryorrhea and one male and two females had lacrimation. Males and females bath lest an average of 5.2 grams from the initial fasted weights.
-30 Hour Group (observed approximately 28 hours after dosing):
Al rats had an abnormal gait, abnormal stance, decreased body tone, piloerection, arched back and a brownish discoloration on forepaws and around nasal-oral region. Additional signs observed in this group in one or more animais include diarrhea, decreased activity, chromodacryorrhea and pour grooming. Males lost an average of 3.6 grams by this time while females gained 2.2 grams average as compared to the original fasted weights.
-No pharmacotoxic signs were observed in rats administered the vehicle or positive controls with the exception of two males and one female in the 6 hour corn oil group which exhibited diarrhea prior to colchicine administration.
Males in the 6 hour corn oil group had an average weight loss of 1.4 grams white the females gained 0.6 grams average. In the 18 hour corn oil group, by sacrifice time, the males had an average weight gain of 6.4 grams while the females gained an average of 10 grams from the initial fasted weights. In the 30 hour corn oil group, males gained 9 grains average and the females gained 6 grams average.
Positive control males had an average gain of 6.4 grains and females gained an average of 7.6 grams compared to the initial fasted weights.
Summary of Metaphases scored: A total of 500 metaphases/group (50/rat) were. analysed in each group, except for the Cl) group in which a total of only 460 metaphases were analysed.
Proportion of Cells with Aberrations: The proportion of cells with one or more aberrations (1 aberration or greater) was analyzed by Chi-square analysis by comparing the number of cells with aberrations versus the number of normal cells in each treatment group versus the vehicle control. Each time of sacrifice was analyzed separately and groups within each sacrifice time were compared individually to the vehicle control. Cells with gaps only were net considered aberrant for this analysis. A statistically significant increase (p < 0.01) was detected with the positive control CP group at the 18 hour sacrifice. No other significant differences were noted.
Analysis of Aberrations per Cell: The mean number of aberrations per cell per animal were analyzed for statistically significant increases by a one-way ANOVA for each time interval. Data reflect the total number of aberrations seen in all cells scored per group. No statistically significant differences (p < 0.05) from the vehicle controls were detected by this analysis in animals treated with Sulfasan RR.
Animals treated with CP gave a statistically significant (p < 0.01) increase in the number of aberrations. In this group 139 metaphases were severely damaged. These metaphases could not accurately be scored due to multiple aberrations with tangles (134 metaphases) and/or partially shattered chromosomes (5 metaphases). This metaphase population comprised 23.2% of ail metaphases scored in the CP group. These cells were noted on the scoring sheets but were not included in the total of 460 metaphases analyzed statistically.
Any other information on results incl. tables
Table : Results of in vivo test
Compound |
dose |
Harvest time |
# rats |
# metaphases analyzed |
Aberrations/group |
Corn oil |
10 ml/kg |
6 hr |
10 |
500 |
2 |
DTDM |
2800 mg/kg |
6 hr |
10 |
500 |
5 |
Corn oil |
10 ml/kg |
18 hr |
10 |
500 |
2 |
DTDM |
2800 mg/kg |
18 hr |
10 |
500 |
5 |
Positive control |
20 mg/kg |
18 hr |
10 |
460 |
1719 |
Corn oil |
10 ml/kg |
30 hr |
10 |
500 |
2 |
DTDM |
2800 mg/kg |
30 hr |
10 |
500 |
6 |
Applicant's summary and conclusion
- Conclusions:
- DTDM was judged negative in its ability to induce structural chromosomal aberrations to the hemopoietic cells of the rat bone marrow under the experimental conditions of this assay.
- Executive summary:
This study was designed to evaluate the potential of 4,4'-dithiodimorpholine (Sulfasan R) to induce structural chromosomal aberrations in the hemopoietic cells of the rat bonemarrow when administered by oral gavage. Sulfasan R was evaluated in a preliminary study at a dose of 2800 mg/kg of body weight. Due to the pharmacotoxic signs observed in this dose group, 2800 mg/kg was selected as anestimation of the maximum tolerated dose.
Sulfasan R (2800 mg/kg) and the vehicle control (corn oil) wereadministered in single oral doses to three groups of Fisher 344 rats per eachtreatment level and sacrificed 6, 18 and 30 hours after dosing. An extragroup of rats was dosed with the positive control, Cyclophosphamide (CP; 20mg/kg) and sacrificed 18 hours later. Approximately two hours prior to eachsacrifice, animals were administered colchicine at 4 mg/kg of body weight toarrest tells in metaphase. At the appropriate time, animals were sacrificedand both femurs were removed from each animal and metaphase slides prepared.Slides were stained, coded and scored for chromosomal aberrations.
Ail rats dosed with Sulfasan R {2800 mg/kg) exhibited from mild to severepharmacotoxic signs at all time intervals evaluated. These observations suggest that Sulfasan R was evaluated near the maximum tolerated dose.
A total of 50 metaphase cells were analyzed for each animal (when possible) for the presence of chromatid and chromosome type aberrations.Aberrations were classified according to type on a standard scoring sheet and the number of aberrations in each cell tabulated. The number of centromeresin each cell was counted and recorded.
Data were evaluated for statistically significant increases inaberrations per cell in treatment groups as compared tothevehicle controlgroups. The proportion of aberrant metaphases was also evaluated forstatistically significant increases over the vehicle control groups. Datawere evaluated separately for each harvest interval.
The positive control article, CP, resulted in significant increases inthe incidence of chromosome aberrations and in the proportion of metaphases with one or more aberrations.
No statistically significant increases in the incidence of aberrations orin the number of cells with one or more aberrations were observed in animals treated with Sulfasan R at a dose of 2800 mg/kg at any of the three sampling times evaluated. Therefore, under the conditions of thisassay, Sulfasan R was not clastogenic to the hemopoietic cells of the rat bone marrow.
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