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Diss Factsheets

Toxicological information

Immunotoxicity

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Administrative data

Description of key information

The immunotoxicity caused by Dioctyltin is an acute effect

Key value for chemical safety assessment

Effect on immunotoxicity: via oral route

Link to relevant study records
Reference
Endpoint:
immunotoxicity: acute oral
Remarks:
Part of the ongoing study on the read across substance Dioctyltin oxide. This final study will be submitted later based on ECHA decision number CCH-D-2114340406-56-01/F and INC000000190412.
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
JUSTIFICATION OF READ ACROSS
Hydrolysis under stomach condition (pH 1.2) of Diotyltin bis(pentadione) into Dioctyltin oxide and pentadione (cp. Section basic toxicokinetics:)


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:
not specified
Lowest effective dose / conc.:
11.8 mg/kg bw/day (nominal)
System:
immune system
Organ:
thymus
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.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
11.8 ng/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
-

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 demonstrate clearly, the the immunotoxicity of Dioctyltin is a acute effect. The adverese effects related to the immune system takes place hours after administration of the test substance to the animals. A few hours later there is to changes in the thymus, too.


Justification for selection of effect on immunotoxicity via oral route endpoint:
use of an acuty study, to effect, itest type subacute is chosen in due to default selection criteria

Justification for classification or non-classification

In due to mechanism DOT is to classify as STOT Single 2