Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 222-883-3 | CAS number: 3648-18-8
- 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
Immunotoxicity
Administrative data
Description of key information
The immunotoxicity caused by Dioctyltin is an acute effect, The value acute is missing in selection possibilities for time frame of effect
LOAEL Dioctyltin oxide 11.8 mg/kg/day => LOAEL DOTL 3.9 mg/kg/day
Key value for chemical safety assessment
Effect on immunotoxicity: via oral route
Link to relevant study records
- Endpoint:
- immunotoxicity
- Remarks:
- acute
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1992
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: no glp, no guideline study, well documented
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- no guideline required
- GLP compliance:
- no
- Limit test:
- no
- Species:
- other: rodent and human
- Strain:
- other: not relevant
- Sex:
- not specified
- Route of administration:
- other: not relevant
- Vehicle:
- other: not relevant
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- not relevant
- Frequency of treatment:
- not relevant
- No. of animals per sex per dose:
- not relevant
- Conclusions:
- After activation of NR3C1 the DNA fragmentation (via duming of IL-6) of thymocytes tbeginns within a hour and cells lysis follows 3 top 5 hours later.
This results in thymus atrophy, depletion of lymphocytes - Executive summary:
Destruction of thymus cells was one of the earliest observed properties of adrenal glucocorticoids. The cells affected are primarily immature, CD4/CD8 double-positive lymphocytes. This process has been clearly shown in vivo and in vitro to be apoptosis, as characterized by cell shrinkage, membrane alterations, nuclear collapse and chromatin fragmentation into oligonucleosomes. Glucocorticoid-induced thymocyte death requires new mRNA and protein synthesis. A beginning has been made in identifying the genes involved in thymocyte apoptosis. A case is made for the death of unselected thymocytes in vivo being regulated by endogenous glucocorticoids.
- Endpoint:
- immunotoxicity
- Remarks:
- other: gene expression, thymus, IL-6
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2008
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: no glp, no guideline, well documentation
- Qualifier:
- no guideline required
- Executive summary:
Thymopoiesis is essential for development and maintenance of a robust and healthy immune system. Acute thymic atrophy is a complication of many infections, environmental stressors, clinical preparative regimens, and cancer treatments used today. This undesirable sequela can decrease host ability to reconstitute the peripheral T cell repertoire and respond to new antigens. Currently, there are no treatments available to protect against acute thymic atrophy or accelerate recovery, thus leaving the immune system compromised during acute stress events. Several useful murine models are available for mechanistic studies of acute thymic atrophy, including a sepsis model of endotoxin-induced thymic involution. We have identified the IL-6 cytokine gene family members (i.e., leukemia inhibitory factor, IL-6, and oncostatin M) as thymosuppressive agents by the observation that they can acutely involute the thymus when injected into a young, healthy mouse. We have gone on to explore the role of thymosuppressive cytokines and specifically defined a corticosteroid-dependent mechanism of action for the leukemia inhibitory factor in acute thymic atrophy. We also have identified leptin as a novel, thymostimulatory agent that can protect against endotoxin-induced acute thymic atrophy. This review will highlight mechanisms of stress-induced thymic involution and focus on thymosuppressive agents involved in atrophy induction and thymostimulatory agents that may be exploited for therapeutic use.
- Endpoint:
- immunotoxicity
- Remarks:
- other: gene expression
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 2010
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: no glp, no guideline study, well documanted
- Qualifier:
- no guideline required
- Principles of method if other than guideline:
- Reagents
Mouse monoclonal antibodies specific for cytokeratin and isotype
IgG were purchased from Dako (Carpinteria, CA). Neutralizing
anti-IL-6 was from R&D Systems (Minneapolis, MN). Alexa Fluor
488-conjugated goat anti-mouse IgG was from Invitrogen Corp.
(Carlsbad, CA). Recombinant mouse cytokine IL-6 was from Pepro-
Tech, Inc. (Rocky Hill, NJ). Jak2 inhibitor AG490 was from Sigma–
Aldrich Co. (St. Louis, MO) and dissolved in dimethylsulfoxide
(DMSO).
Cell culture
Fresh, discarded thymus tissue was taken from healthy children
during corrective cardiovascular surgery and from thymo-thymectomies
of patients with thymoma. The study protocol was approved
by Human Experiment and Ethics Committee of National
Cheng Kung University Hospital of Taiwan since 02/25/2008. The
certification number is ER-96-157. Briefly, thymus tissue was
minced and filtered, and then digested by collagenase and deoxyribonuclease
(DNase). After they had been centrifuged several
times and then washed with phosphate-buffered saline (PBS), thymus
cell pellets (7.5 107) were resuspended in a T-75 plastic
flask containing 2 mL of RPMI medium 1640 with 10% fetal bovine
serum, 1 mmol/L of L-glutamine (25030081; Invitrogen, Carlsbad,
CA, USA), 10 IU/mL of penicillin (15140122; Invitrogen), and
10 lg/mL of streptomycin (15140122; Invitrogen) and then cultured
in a humidified atmosphere of 5% CO2 and 95% air at 37 C.
The culture medium was changed every 2–3 days, and fibroblast
inhibitor (H1637; Sigma–Aldrich) was added. The cells were collected
for further study when 80–90% of the flash was occupied
by cells in a confluent monolayer, usually after 2–3 weeks of incubation.
The supernatant was collected before every change of medium
and before the cells were harvested for a cytokine antibody
array. Some of the collected cells were for flow cytometric analysis,
and others were subsequently cultured with or without serum for
further study. For morphological observation, the cells were visualized
under a microscope (IX71; Olympus, Tokyo, Japan).
Flow cytometric analysis
The cells were detached using 1000 U/mL of trypsin and 0.5 mM
of ethylene diamine tetra acetate (EDTA). Suspended cells were
fixed and permeabilized using a kit (BD PharMingen Cytofix/Cytoperm;
BD Biosciences, San Jose, CA). Antibodies specific for cytokeratin
(Dako) or isotype IgG were added to the cells and
incubated at 4 C for 1 h. After they had been washed with PBS,
the cells were incubated with Alexa Fluor 488-conjugated secondary
antibodies at 4 C for 1 h. The incubated cells were then
washed again with PBS and analyzed using flow cytometry with
excitation set at 488 nm (FACSCalibur; BD Biosciences).
Cytokine antibody array analysis
The cytokine production profile was determined using a cytokine
antibody array (Human Cytokine Antibody Array III AAHCYT-
3-8; RayBiotech, Inc., Norcross, GA) according to the manufacturer’s
instructions. Briefly, 100 lg/mL of protein from cell-conditioned
culture medium was incubated with the array membrane
at 4 C for 1 h. After they had been washed with PBS-T (PBS plus
0.05% Tween-20), the cell membranes were incubated with primary
biotin-conjugated antibodies and HRP-conjugated streptavidin.
Signals were detected using enhanced chemiluminescence
(ECL) (Pierce Biotechnology Inc., Rockford, IL), and the relative signal
intensity was quantified using densitometry with bio-imaging
software (LabWorks; UVP, Inc., Upland, CA) with reference to the
positive controls on the membrane
ELISA
Cells were seeded in 96-well plates at a density of 1 104 cells/
well. After the treatment, we used commercial ELISA kits (88-
7066-77; eBioscience, San Diego, CA) and (DY275; R&D Systems,
Minneapolis, MN), according to the manufacturer’s instructions,
to detect the concentrations of mouse IL-6 and GRO-a, respectively,
in cell-conditioned culture medium. Cell-conditioned culture
medium was regularly diluted, and the concentrations were
calculated so that they did not exceed detection limits. IL-6 and
GRO-a concentrations were measured using spectrophotometry
(Spectra MAX 340PC; Molecular Devices Corporation, Sunnyvale,
CA) at 540 nm, and the concentration was calculated using a standard
curve with ELISA software (Softmax Pro; Molecular Devices).
Viability assay
Cell viability was assayed using a colorimetric assay (Cell
Counting kit-8 (CK04); Dojindo Laboratories, Gaithersburg, MD)
according to the manufacturer’s instructions. Aliquots of the culture
media were transferred to 96-well microplates. A microplate
reader (Spectra MAX 340PC; Molecular Devices) was used to
measure the absorbance at 620 nm with a reference wavelength
of 450 nm, and the data were analyzed with ELISA software (Softmax
Pro; Molecular Devices). The relative optical density was
calculated.
Statistical analysis
Data were analyzed using Student’s t test with commercially
available statistical software (SigmaPlot 8.0 for Windows; Systat
Software, Inc., San Jose, CA). Statistical significance was set at Pvalues
< 0.05. - Limit test:
- no
- Species:
- mouse
- Strain:
- other: not relevant
- Sex:
- not specified
- Route of administration:
- other: not relevant
- Vehicle:
- other: not relevant
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- see priciples of methode if other tahn guideline
- Frequency of treatment:
- see priciples of methode if other tahn guideline
- No. of animals per sex per dose:
- see priciples of methode if other tahn guideline
- Conclusions:
- IL-6 is a critical cytokine in the
thymus and is of paramount importance for the differentiation,
proliferation, and survival of both thymic epithelial cells and thymocytes.
IL-6 is an immunosuppressive cytokine that induces
acute thymus atrophy - Endpoint:
- immunotoxicity: acute oral
- Remarks:
- Part of the OECD 414 study on the read across substance Dioctyltin oxide.
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2017-2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Justification for type of information:
- READ ACROSS
Hydrolysis under stomach condition (pH 1.2) of Diotyltin dilaurate into Dioctyltin oxide and lauric acid (cp. Section basic toxicokinetics: Nasshan, In vitro metabolism study)
Study for justification of read across is link via cross reference.
DIOCTYLTIN DILAURATE
Furthermore another study with dioctyltin dilaurate shows additional information regarding the immune toxicity. - Reason / purpose for cross-reference:
- reference to other study
- Reason / purpose for cross-reference:
- other: Hydrolysis under stomach condition (pH 1.2)
- Reason / purpose for cross-reference:
- other: Main study (OECD 414, rat)
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EPA OPP 85-7 (Immunotoxicity)
- Deviations:
- not applicable
- Principles of method if other than guideline:
- see attached report: study performed as port of an OECD 414 study
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- female
- Route of administration:
- oral: feed
- Vehicle:
- other: in diet
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 72 h
- Frequency of treatment:
- in diet
- Dose / conc.:
- 0 mg/kg diet
- Remarks:
- 0 mg/kg bw/day
- Dose / conc.:
- 5 mg/kg diet
- Remarks:
- 0-4 mg/kg bw/day
- Dose / conc.:
- 25 mg/kg diet
- Remarks:
- 1.8 mg/kg bw/day
- Dose / conc.:
- 200 mg/kg diet
- Remarks:
- 11.8 mg/kg bw/day
- No. of animals per sex per dose:
- 5 in control, low and mid dise, 4 in high dose group
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale:
Subpart of OECD 414 study in rat, test substance Dioctyltin oxide. So rationale for dose selection is the main study. Dose selection form outcome of former studies with Dioctyltin oxide ((Waalkens-Berendsen, OECD 422, DOTO)
- Rationale for selecting satellite groups:
Determination of immunotoxicity as maternal toxicity
- Post-exposure recovery period in satellite groups:
Not planed, but time of last exposure to necropsy showed recovery of the immune system of test animals
- Rationale for animal assignment (if not random):
Subpart of OECD 414 study in rat, test substance Dioctyltin oxide
- Other:
Immunophenotyping:
Immunophenotyping was performed on Immunotoxicity animals from blood samples (0.5mL in EDTA) during the predose phase and on Gestation Days 7 (24 hours after first dose), 8 (48 hours after first dose), 9 (72 hours after first dose) and 10 (prior to necropsy)
Cytokine Measurement:
Blood samples (0.5 mL in serum separator tubes) were collected from Immunotoxicity cohort animals during the predose phase and on Gestation Days 7 (24 hours after first dose), 8 (48 hours after first dose), 9 (72 hours after first dose) and 10 (prior to necropsy) - Observations and clinical examinations performed and frequency:
- Immunophenotyping:
Immunophenotyping was performed on Immunotoxicity animals from blood samples (0.5mL in EDTA) during the predose phase and on Gestation Days 7 (24 hours after first dose), 8 (48 hours after first dose), 9 (72 hours after first dose) and 10 (prior to necropsy)
Cytokine Measurement:
Blood samples (0.5 mL in serum separator tubes) were collected from Immunotoxicity cohort animals during the predose phase and on Gestation Days 7 (24 hours after first dose), 8 (48 hours after first dose), 9 (72 hours after first dose) and 10 (prior to necropsy) - Positive control:
- not required
- Clinical signs:
- not specified
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- In the moin OECD 414 study no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- In the moin OECD 414 study no effects observed
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- In the moin OECD 414 study no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Description (incidence and severity):
- not reported at the moment, if findings, report in endpoint of main OECD study
- Clinical biochemistry findings:
- not examined
- Description (incidence and severity):
- not reported at the moment, if findings, report in endpoint of main OECD study
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- see section specific immunotoxic examinations
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- 4ß percent of thymus decrease in high dose group
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Description (incidence and severity):
- not reported at the moment, if findings, report in endpoint of main OECD study
- Histopathological findings: neoplastic:
- not examined
- Description (incidence and severity):
- not reported at the moment, if findings, report in endpoint of main OECD study
- Other effects:
- not examined
- Description (incidence and severity):
- not reported at the moment, if findings, report in endpoint of main OECD study
- Details on results:
- not reported at the moment, if findings, report in endpoint of main OECD study
- Cell viabilities:
- effects observed, treatment-related
- Description (incidence and severity):
- Blood
At gestation Day 9, activated B lymphocyte numbers (CD3-/CD45RA+/CD25+) were markedly higher than the control group animals (approximately 3 to 4 times for the majority of the animals) at the 11.8mg/kg/day dose level.
Other observed differences, were limited to several lymphocyte sub-populations and tended to be slight to moderate in nature. On gestation Day 9, moderate increases were noted for CD3+/CD8+/CD25+, CD3+/CD25+ and CD3+/CD4+/CD25+ cell counts in animals dosed 11.8mg/kg/day. When compared to the control group results, the aforementioned populations were +85%, +60% and +50% greater, respectively.
At gestation Days 8 and 10, all groups administered Dioctyltin Oxide, displayed slightly lower numbers and relative percentages of NK cells (CD3-/CD161a+) when compared to the control group, although results within the treated groups were relatively unchanged when compared to other sampling days. No other changes of note were observed on Days 8 and 10.
Cytokines
Results for serum concentrations of IL-2 varied from day to day, with almost all animals, across all groups including controls, displaying quantifiable results on Days 8 and 10, but no animals recording results above the lower limit of quantitation (LLOQ) on Day 10. No test article-related effect could be determined, as the frequency and magnitude of quantifiable IL-2 were similar across all groups, and comparable to the results observed during the pre-dose phase. Quantifiable results, where observed were either slightly above the LLOQ value, or at least within 3 times the LLOQ value. - Humoral immunity examinations:
- not examined
- Specific cell-mediated immunity:
- not specified
- Non-specific cell-mediated immunity:
- not specified
- Other functional activity assays:
- not examined
- Other findings:
- not specified
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 11.8 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- immunology
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 1.8 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- immunology
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 11.8 mg/kg bw/day (nominal)
- System:
- immune system
- Organ:
- thymus
- other: immune system
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
- Conclusions:
- The LOAEL for acute immune toxicity for Dioctyltin oxide was determined to be 11.8 mg / kg bw7day thus a NOAEL of 1.8 mg/kg bw7day results.
Referenceopen allclose all
Publication describes the mechanism of apoptosi of thymocytes after activation of NR3C1.
It is shwon, that adverse effects beloning to immune suppressive substance are an acute effect , beginning after a few hours
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEL
- 25.46 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- REMARK: Study duration: acute !; fIn the fiield study duration the value "subacute" was chosen, in due the filed has ti be filled in for TCC. Value "acute" in the choice box not included.
Effect on immunotoxicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Effect on immunotoxicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
Additional information
Several studies demonstrate clearly the immunotoxicity of Dioctyltin is an acute effect. These adverse effects related to the immune system take place hours after administration of the test substance to the animals. A few hours later there are changes in the thymus, too.
Justification for selection of effect on immunotoxicity via oral route endpoint:
use of an acute study, to effect, test type subacute is chosen due to default selection criteria.
Justification for classification or non-classification
In due to mechanism DOT is to classify as STOT Single 2
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.