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EC number: 258-508-5 | CAS number: 53378-51-1
- 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
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2012-2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
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)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Sodium O,O-diisobutyl dithiophosphate
- EC Number:
- 258-508-5
- EC Name:
- Sodium O,O-diisobutyl dithiophosphate
- Cas Number:
- 53378-51-1
- Molecular formula:
- C8H18NaO2PS2
- IUPAC Name:
- sodium O,O-diisobutyl dithiophosphate
- Test material form:
- other: 51 % w/w solution in water, stabilized with X % NaOH
- Details on test material:
- - Substance type: Liquid
- Physical state: Light brown liquid
- Molecular formula (if other than submission substance): C8H18NaO2PS2
- Molecular weight (if other than submission substance): 264
- Smiles notation (if other than submission substance): CC(C)COP(=S)([S-])OCC(C)C.[Na+]
- InChl (if other than submission substance): InChI=1/C8H19O2PS2.Na/c1-7(2)5-9-11(12,13)10-6-8(3)4;/h7-8H,5-6H2,1-4H3,(H,12,13);/q;+1/p-1
Constituent 1
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, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: Males/females: Both 59 days
- Weight at study initiation: Males: 272.2 g to 299.9 g, Females: 210.4 g to 233.6 g
- Fasting period before study: 16 hours
- Housing: kept individually in MAKROLON cages (type III plus)
- Diet (e.g. ad libitum): Commercial ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany; served as food ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 55% ± 15%
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg b.w./day - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- For the analysis of the test item-vehicle mixtures samples of approx. 2 x 1 mL were taken at the following time points and stored at ≤ minus 20°C until analysis at LPT:
- Start of treatment period:
Concentration and stability:
Immediately after preparation of the test item vehicle mixtures as well as 8 and 24 hours after storage of the test item preparations at room temperature:
3 samples/dose level group (groups 2 to 4)
Number of samples: 3 x 3 = 9
Homogeneity:
At start of administration, during (middle) administration and before administration to the last animal of each dose level group:
3 samples/dose level group (groups 2 to 4).
Number of samples: 3 x 3 = 9
- End of treatment period:
Concentration:
During treatment with the test item always before administration to the last animal/dose level group:
1 sample/dose level group (groups 2 to 4).
Number of samples: TD 26 (1 x 3) = 3
Number of samples: TD 39 (1 x 3) = 3
Sum of all samples: 24, sum of all aliquots: 48
The samples were labelled with the study number, test item, test species, type of sample, aliquot number, concentration, test day, sampling time and date. - Duration of treatment / exposure:
- Males: The daily administration of the test item started two weeks before mating and lasted until the day before sacrifice (considering a minimum total dosing period of at least 28 days).
Females: The daily administration of the test item started two weeks before mating and lasted up to at least day 3 of lactation. - Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Dose / conc.:
- 600 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10 male and 10 female
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: See supporting study: 14-DAY DOSE-RANGE-FINDING STUDY OF IBP1-Na (DANAFLOATTM 245) BY ORAL ADMINISTRATION TO RATS
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least daily, the frequency was increased when signs of toxicity were observed.
Cage side observations included skin/fur, eyes, mucous membranes, respiratory and circulatory systems, somatomotor activity and behavior patterns. The onset, intensity and duration of any signs observed were recorded.
Individual animals were observed before and after dosing at each time of dosing for any signs of behavioral changes, reaction to treatment or illness.
In addition, animals were checked regularly throughout the working day from 7:00 a.m. to 3:45 p.m. On Saturdays and Sundays animals were checked regularly from 7:00 a.m. to 11:00 a.m. with a final check performed at approximately 3:30 p.m.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least daily, the frequency was increased when signs of toxicity were observed.
Additionally, once before the first exposure (to allow within-subject comparisons) and once a week thereafter, detailed clinical observations were made in all animals outside the home cage in a standard arena and at the same time, each time preferably by observers unaware of the treatment. Signs noted included changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g. lacrimation, piloerection, pupil size, and unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behavior (e.g. self-mutilation, walking backwards) were also recorded.
Dated and signed records of appearance, change, and disappearance of clinical signs were maintained on clinical history sheets for individual animals.
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal was recorded on a weekly or daily basis throughout the experimental period with the exception of the mating period.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the premating period
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: 5 male and 5 female animals from each group
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the premating period
- Animals fasted: Yes
- How many animals: 5 male and 5 female animals from each group
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
All superficial tissues were examined visually and by palpation and the cranial roof removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral midline incision and skin reflection all subcutaneous tissues were examined. The condition of the thoracic viscera was noted with due attention to the thymus, lymph nodes and heart. The abdominal viscera were examined before and after removal; the urinary bladder was examined externally and by palpation. The gastro-intestinal tract was examined as a whole and the stomach and caecum were incised and examined. The lungs were removed and all pleural surfaces were examined under suitable illumination. The liver and the kidneys were examined. Any abnormalities in the appearance and size of the gonads, adrenals, uterus, intra-abdominal lymph nodes and accessory reproductive organs were recorded.
HISTOPATHOLOGY: Yes - Statistics:
- Toxicology and pathology data were captured, whenever possible, using the departmental computerized systems (Provantis® Integrated preclinical software, version 8.2.0.8, Instem LSS Ltd.). Raw data not fully compatible with the computerized
systems were maintained on paper according to appropriate SOPs. The test item-treated groups (2 to 4) were compared with the control group (1). The following statistical methods were used: STUDENT's t-test All numerical functional tests (p ≤ 0.01)
Multiple t-test based on DUNNETT, C. W. New tables for multiple Comparisons with a control Biometrics, 482-491 (Sept 1964) Body weight / Food consumption / Haematology / Clinical chemistry / Absolute and realtive organ weights (p ≤ 0.05 and p ≤ 0.01)
For all numerical values (e.g. body weight, food consumption and organ weight data) homogeneity of variances was tested by using the BARTLETT chi-square test. If the variances were homogeneous, the DUNNETT test (p ≤ 0.01) was used to compare the experimental groups with the control group. In case of heterogeneity of variances, the STUDENT's t-test was carried out; limit of significance was p ≤ 0.01. Exact test of R. A. FISHER Histopathology (p ≤ 0.05) For the comparison of classification measurements (for example the Fertility Index) the FISHER's exact test, n < 100 or chi2-test with Yates' correction for continuity, n ≥ 100 (p ≤ 0.05 and p ≤ 0.01) were employed. These statistical procedures were used for all data. Significantly different data were indicated in the tables of the report. The mean values and standard deviations were calculated to the highest possible degree of accuracy and then rounded to the reported number of decimal places. Hence, deviations to the last decimal place of up to 1 may occur caused by rounding.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At the intermediate and the high dose level (200 and 600 mg IBP1-Na/kg b.w./day) a slight to extreme salivation was noted in nearly all animals, with a higher incidence at the high dose level. Piloerection and an increased water consumption were noted for a few animals of the intermediate and the high dose group, which is most like related to the alkalinity of the substance.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- No test item-related premature death was noted.
One male animal from the intermediate dose group (200 mg IBP1-Na/kg b.w./day) died prematurely on test day 32. The examination of the aninmal at autopsy and at histopathology revealed changes in the cardia part of the stomach (forestomach), which were also found in further animals of the intermediate and the high dose group and which are considered as to be test item related. However, the death of this animal was most likely referred to heart failure indicated by a severely increased heart weight. The death is therefore regarded to be spontaneous. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- A slight reduction in body weight was noted until the end of the study on test day 38 for the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day). Body weight at autopsy was reduced accordingly.
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Examination of the haematological and biochemical parameters revealed statistically significant changes in the male and female animals of the high dose group (600 mg IBP1-Na/kg b.w./day), which were considered as to be test item-related.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Males: A statistically significant increase in the plasma activity of ALAT and ASAT, a decrease of the chloride concentration and a decrease in the globulin concentration leading to an increase in the albumin/globulin ratio were noted in the high dose group.
Females: At the intermediate and the high dose level statistically significant dose dependent minor decreases of the chloride and sodium concentration were noted. At the high dose level the ASAT activity was increased. - Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- The neurological screening revealed a slight reduction for the hindlimb grip strength of the male and female animals of the high dose group (600 mg IBP1-Na/kg b.w./day).
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Examination of the organ weights revealed a slightly statistically significant increase in the relative liver weight of the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day).
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Macroscopic inspection at autopsy revealed test item related changes in the cardia part of the stomach from animals of the intermediate dose group (200 mg IBP1- Na/kg b.w./day) and in the cardia part of the stomach from 1 female animal of the high dose group (600 mg IBP1-Na/kg b.w./day).
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- The histopathological examination revealed test item related changes in the forestomach from male and female rats of the intermediate and the high dose group (200 and 600 mg IBP1-Na/kg b.w./day) in form of hyperplasia and hyperkeratosis of the squamous cell epithelium, infiltration with neutrophilic granulocytes, granulation tissue and ulcerations.
Additionally, test item-related changes were noted in the liver in the form of a slight centrilobullar hepatocellular hypertrophy at 600 mg/kg bw/day.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: systemic effects
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The following no-observed-adverse-effect levels were noted for the test substance:
Effects on the F0-generation
NOAEL (no-observed-adverse-effect level): 200 mg IBP1-Na/kg b.w./day, p.o.
Effects on reproduction
NOAEL (no-observed-adverse-effect level): 600 mg IBP1-Na/kg b.w./day, p.o.
Remark: The test substance as produced and marketed contains NaOH due to the production method. - Executive summary:
The toxicity of the substance was assessed in a Combined Dose Toxicity Study with the Reproductive/Developmental Screening Test according to OECD 422 (adopted 22 march 1996). Doses of 0 (control), 60, 200 and 600 mg/kg bw/day was administered by gavage to 10 Crl: CD(SD rats/sex/dose. Male rats were dosed daily for 37 days, female rats were dosed daily starting two weeks before mating and continued to a least day 3 of lactation.
The following no-observed-adverse-effect levels were noted for the test substance:
Effects on the F0-generation
NOAEL (no-observed-adverse-effect level): 200 mg IBP1-Na/kg b.w./day, p.o.Effects on reproduction
NOAEL (no-observed-adverse-effect level): 600 mg IBP1-Na/kg b.w./day, p.o.
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