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EC number: 270-219-6 | CAS number: 68413-47-8
- 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:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 06 February 2017 to 03 April 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Dibutyl 2-[(dipropoxyphosphorothioyl)sulfanyl]succinate
- Cas Number:
- 68413-47-8
- Molecular formula:
- C18H35O6PS2
- IUPAC Name:
- Dibutyl 2-[(dipropoxyphosphorothioyl)sulfanyl]succinate
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- - Description: Light yellow, clear liquid
- Storage: Room temperature (18 - 24°C), protected from light
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at first dose: Approximately 10 weeks of age at the initiation of dose
administration.
- Weight at first dose: 326 g to 414 g and female body weights ranged from 218 g to 262 g on Study Day 0
- Housing: Clean, solid-bottom cages with bedding material (Bed O’Cobs®)
- Bedding: See above
- Feed: PMI Nutrition International, LLC Certified Rodent LabDiet® 5002 offered ad libitum
- Water: Filtered water was provided ad libitum
- Acclimation period: A minimum of 7 days
ENVIRONMENTAL CONDITIONS
- Temperature Range: 23°C ± 3°C
- Humidity Range: 50 ± 20%.
- Light Cycle: 12-hour light/12-hour dark
- Air Changes: Minimum of 10 air changes per hour
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- Test substance formulations and vehicle control were stirred continuously at room temperaturefor the duration of the dosing.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentration of test substance in dosing formulations, including the vehicle control, were assessed on the first, middle, and last formulation prepared that included all dose groups.
Four 1.0 mL samples were collected from the middle strata for concentration assessments. Two samples from each strata were analyzed to assess the concentration of the test substance in the mixtures; the remaining samples were stored refrigerated (2°C to 8°C) as backup samples.
The acceptable result for a concentration assessment is a mean concentration within 100% ± 15% (85-115%) of the target concentration. - Duration of treatment / exposure:
- Males: Two weeks before pairing up to necropsy after minimum of five weeks.
Females: Two weeks before pairing, then throughout pairing and gestation until Day 13 of lactation. - Frequency of treatment:
- Animals were dosed once daily for at least 14 days prior to mating.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 15 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Remarks:
- Females were administered the test substance at a dosage level of 150 mg/kg/day from Study Days 0–12, inclusively. On Study Day 13, the dosage level for females was reduced to 100 mg/kg/day. The dosage level for the males remained at 150 mg/kg/day.
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- Females were administered the test substance at a dosage level of 150 mg/kg/day from Study Days 0–12, inclusively. On Study Day 13, the dosage level for females was reduced to 100 mg/kg/day.
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The dosage levels were determined from results of a previous 14-day range-finding study in which the test substance
Examinations
- Observations and examinations performed and frequency:
- All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at specified intervals.
FOB and motor activity data were recorded for 5 males/group during the last week of dose administration (Study Day 27) and for 5 females/group on Lactation Day 13.
F1 clinical observations, body weights, and sexes were recorded at specified intervals and anogenital distance was recorded on Postnatal Day (PND) 1.
To reduce variability among the litters, 8 pups/litter, 4 pups/sex when possible, were randomly selected on PND 4; blood samples for possible thyroid hormone analysis were collected from the culled pups (2/litter). All F1 male pups were evaluated for areolae/nipple anlagen on PND 13. Remaining F1 pups were euthanized on PND 13; blood samples for thyroid hormone analysis were collected and selected organs were retained from 1 pup/sex/litter.
Clinical pathology evaluations (hematology, coagulation, and serum chemistry) were performed on 5 F0 animals/sex/group at necropsy. Blood samples for thyroid hormone analysis were collected from F0 males at necropsy and from F0 females on the day of the last dose (Lactation Day 13); only male samples were analyzed. F0 males were euthanized following completion of the mating period and F0 females were euthanized on Lactation Day 14 for females that delivered and Postmating Day 25 for females that failed to deliver. Complete necropsies were conducted on all F0 animals, and selected organs were weighed.
Selected tissues were examined microscopically from 5 F0 animals/sex in the vehicle control and high-dose groups. - Sacrifice and pathology:
- A complete necropsy was conducted on all F0 parental animals found dead, euthanized in extremis, or at the scheduled termination.
All F0 adults were euthanized by carbon dioxide inhalation. Males were euthanized following completion of the mating period; blood samples were collected for thyroid hormone analysis immediately prior to euthanasia.
Females that delivered were euthanized on Lactation Day 14; blood samples were collected for thyroid hormone analysis on the day prior to euthanasia - Other examinations:
- Organs were weighed from all F0 animals at the scheduled necropsies. Paired organs were weighed together. Absolute weights and organ to final body weight and brain weight ratios were reported. When organ weights could not be determined for an animal (due to weighing error, lost or damaged organ, etc.), group mean values were calculated using the available data.
- Statistics:
- All statistical tests were performed using WTDMS™. Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group. Each mean was presented with the standard deviation (S.D.), standard error (S.E.), and the number of animals(N) used to calculate the mean. Statistical analyses were not conducted if the number of animals was 2 or less. Due to the use of significant figures and the different rounding conventions inherent in the types of software used, the means, standard deviations, and standard errors on the summary and individual tables may differ slightly. Therefore, the use of reported individual values to calculate subsequent parameters or means will, in some instances, yield minor variations from those listed in the report data tables. Body weights, body weight changes, and absolute and relative organ weights were subjected to a parametric one-way ANOVA3 to determine intergroup differences. If the ANOVA revealed significant (p < 0.05) intergroup variance, Dunnett's test was used to compare the test substance-treated groups to the control group.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Adverse clinical observations at the daily examinations were noted for these two females including ataxia, tremors, hypoactivity, and/or thin body. A female in the 150/100 mg/kg/day group was euthanized in extremis on Lactation Day 1 following adverse clinical observations at the daily examinations including hypoactivity, tremors, ataxia, clonic convulsions, thin body, and red material around nose at the daily examinations.
Test substance-related increased incidences of red and/or clear material around the mouth and nose were noted for males in the 150 mg/kg/day group at approximately 1.5 hours following dose administration primarily during the last weeks of dose administration (Study Days 13–27). These observations were generally resolved by the next scheduled observations and were not considered adverse. Other clinical observations noted in the test substance-treated groups, including hair loss or scabbing on various body surfaces, occurred infrequently, at similar frequencies in the vehicle control group, and/or in a manner that was not dose-related. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Seven females in the 150/100 mg/kg/day group were found dead or euthanized in extremis during the course of the study, with 4 out of 7 attributed to the test material.
A female in the 150/100 mg/kg/day group was found dead on Gestation Day 22.This death was attributed to an intubation error and was not test substance-related.
A female in the 150/100 mg/kg/day group was inadvertently removed from the animal room, and therefore this accidental death was not attributed to test substance administration.
In the 50 mg/kg/day group, a female was euthanized in extremis on Study Day 9 with findings indicative of an intubation error (epicardial, myocardial, and pleura inflammation), and therefore this moribundity was not test substance-related. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Males:
Mean body weights and body weight gains in the 15, 50, and 150 mg/kg/day group males were unaffected by test substance administration throughout the study
Females:
Mean body weight gains in the 150/100 mg/kg/day group females were slightly lower (not statistically significant) than the vehicle control group during the premating period (Study Days 0–13). This difference was primarily due to a significantly (p < 0.05) lower mean body weight gain during Study Days 8–13. The decrements in mean body weight gain in the 150/100 mg/kg/day group were considered test substance-related, but were not of sufficient magnitude to affect mean body weights, and therefore were not considered adverse.
Mean body weights and body weight gains in the 15 and 50 mg/kg/day group females were unaffected by test substance administration during the pre-mating period. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Mean food consumption, evaluated as g/animal/day, in the 15, 50, and 150 mg/kg/day group males was similar to that in the vehicle control group throughout the study. No statistically significant differences were observed.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related higher heart weights (absolute and relative to brain and body weights) were noted in the 150/100 mg/kg/day group females. There were no histologic alterations to correlate with this finding.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- At the scheduled necropsies, review of the gross necropsy observations revealed no observations that were considered to be associated with administration of the test substance.
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no other test substance-related histologic changes. Remaining histologic changes were considered to be incidental findings or related to some aspect of experimental manipulation other than administration of the test substance. Notable findings included multiple cysts in the
kidneys, as well as bile duct dilation with peribiliary fibrosis in 2 animals. These findings were consistent with inherited polycystic kidney disease and not considered to be test substance-related. There was no test substance related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- clinical signs
- mortality
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- clinical signs
- mortality
Target system / organ toxicity
- Key result
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Based on these results, the NOAELs for systemic toxicity were considered to be 150 mg/kg/day for males, the highest dose tested, and 50 mg/kg/day for females.
- Executive summary:
The objectives of the study were to investigate the potential toxic effects of the test material when administered to rats for a minimum of 28 days and to evaluate the potential of the test substance to affect male and female reproductive performance such as gonadal function, mating behavior, and conception through day 13 of postnatal life.
Under the conditions of this screening study, no test substance-related effects were observed on F0 male and female fertility and mating indices, F0 male copulation index, F0 female conception index, gestation length, parturition, or reproductive organs at any dosage level. Therefore, dosage levels of 150 mg/kg/day for males and 100 mg/kg/day for females, the highest doses tested, were considered to be the no-observed-adverse-effect levels (NOAEL) for reproductive toxicity. Test substance-related mortality, moribundity, and adverse clinical observations (hypoactivity, tremors, ataxia, clonic convulsions, and thin body) were noted for females at 150 mg/kg/day, resulting in the reduction of the dosage level to 100 mg/kg/day on Study Day 13.
Following the reduction in dosage level for females, a single female in the 150/100 mg/kg/day group was euthanized in extremis. There were no adverse test substance-related clinical observations for males at 150 mg/kg/day or effects on body weights and food consumption for males and females at any dosage level. Test substance-related higher heart weights (absolute and relative to brain and body weights) were noted in the 150/100 mg/kg/day group F0 females. There were no adverse effects on clinical pathology parameters, thyroid hormones, or macroscopic/microscopic alterations in F0 males and females at any dosage level.
Based on these results, the NOAELs for systemic toxicity were considered to be 150 mg/kg/day for males, the highest dose tested, and 50 mg/kg/day for females. The NOAEL for neonatal toxicity was 100 mg/kg/day, the highest dose tested, based on the absence of effects on F1 offspring at all dosage levels.
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