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Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010-2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: study according guideline, glp. Only draft report available, discrepance between study summarey and raw data. Study in reevaluation; study not finaliesed

Data source

Reference
Reference Type:
other: Draft Report
Title:
Unnamed
Year:
2012
Report date:
2012

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:
yes
Remarks:
Determination of Sn in plasma
Principles of method if other than guideline:
Additional dtermination of Sn in plasma
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
483-270-6
EC Name:
-
Cas Number:
54068-28-9
Molecular formula:
Hill formula: C26H48O4Sn CAS formula: C26H48O4Sn
IUPAC Name:
(3Z)-4-{[dioctyl({[(2Z)-4-oxopent-2-en-2-yl]oxy})stannyl]oxy}pent-3-en-2-one
Test material form:
solid - liquid: suspension
Remarks:
migrated information: dispersion
Details on test material:
-

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
-

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on mating procedure:
One male was paired with one female of the same treatment group for up to 15 days (actual duration
required for pairing was up to four days). Mating was confirmed by the presence of sperm in a
vaginal smear or a retained vaginal plug. The day in which mating was confirmed was designated as
Day 0 of gestation.
Pairing took place after two weeks of treatment.
Due to the death of animal 68 (Group 2F) on Day 16 of the study, animal 18 was paired with an
untreated female (animal 501).
Mating was confirmed on Day 17 of the study, and the female was sent to necropsy on Day 13 of
gestation.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
-
Duration of treatment / exposure:
6 weeks, additional 2 weecks for recovering group without dosing
Frequency of treatment:
daily by oral gavage
Details on study schedule:
not relevant
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
Doses / Concentrations:
0 mg/kg day/bw
Basis:
analytical conc.
Dose / conc.:
4 mg/kg bw/day
Remarks:
Doses / Concentrations:
4 mg/kg day/bw
Basis:
analytical conc.
Dose / conc.:
20 mg/kg bw/day (nominal)
Remarks:
Doses / Concentrations:
20 mg/kg day/bw
Basis:
analytical conc.
Dose / conc.:
50 mg/kg bw/day
Remarks:
Doses / Concentrations:
50 mg/kg day/bw
Basis:
analytical conc.
No. of animals per sex per dose:
10 female, 10 male
Control animals:
yes, concurrent vehicle
Details on study design:
--
Positive control:
not relevant

Examinations

Parental animals: Observations and examinations:
-
Oestrous cyclicity (parental animals):
-
Sperm parameters (parental animals):
-
Litter observations:
-
Postmortem examinations (parental animals):
-
Postmortem examinations (offspring):
-
Statistics:
--
Reproductive indices:
-
Offspring viability indices:
-

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
-
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
-
Mortality:
mortality observed, treatment-related
Description (incidence):
-
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
-
Food consumption and compound intake (if feeding study):
not specified
Description (incidence and severity):
-
Food efficiency:
not specified
Description (incidence and severity):
-
Water consumption and compound intake (if drinking water study):
not specified
Description (incidence and severity):
-
Ophthalmological findings:
not specified
Description (incidence and severity):
-
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
-
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
-
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
-
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
taste of the test substance causes stress in the test animals-
Immunological findings:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
-
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
-
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
-
Other effects:
not specified
Description (incidence and severity):
-

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, non-treatment-related
Description (incidence and severity):
-
Reproductive function: sperm measures:
effects observed, non-treatment-related
Description (incidence and severity):
-
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
-

Details on results (P0)

-

Effect levels (P0)

Key result
Dose descriptor:
LOAEL
Effect level:
4 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: small thymus - maternal toxicity

Target system / organ toxicity (P0)

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
4 mg/kg bw/day (nominal)
System:
immune system
Organ:
other: thymus
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
no

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
not relevant according to OECD 422
Mortality:
not examined
Description (incidence):
not relevant according to OECD 422
Body weight and weight changes:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
not relevant according to OECD 422
Food efficiency:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
not relevant according to OECD 422
Ophthalmological findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Haematological findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Clinical biochemistry findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Urinalysis findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Behaviour (functional findings):
not examined
Description (incidence and severity):
not relevant according to OECD 422
Immunological findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Gross pathological findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Neuropathological findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Histopathological findings: non-neoplastic:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Other effects:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Details on results:
not relevant according to OECD 422

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
not relevant according to OECD 422
Mortality / viability:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Body weight and weight changes:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
not relevant according to OECD 422
Food efficiency:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
not relevant according to OECD 422
Ophthalmological findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Haematological findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Clinical biochemistry findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Urinalysis findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Sexual maturation:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Gross pathological findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Histopathological findings:
not examined
Description (incidence and severity):
not relevant according to OECD 422
Other effects:
not examined
Description (incidence and severity):
not relevant according to OECD 422

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined
Description (incidence and severity):
not relevant according to OECD 422

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined
Description (incidence and severity):
not relevant according to OECD 422

Details on results (F1)

not relevant according to OECD 422

Effect levels (F1)

Key result
Dose descriptor:
other: not relevant according to OECD 422
Generation:
other: not relevant according to OECD 422
Effect level:
0 other: not relevant according to OECD 422
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: not relevant according to OECD 422

Target system / organ toxicity (F1)

Key result
Critical effects observed:
not specified
Lowest effective dose / conc.:
0 other: not relevant according to OECD 422
System:
other: not relevant according to OECD 422
Organ:
other: not relevant according to OECD 422
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Key result
Reproductive effects observed:
not specified
Lowest effective dose / conc.:
4 mg/kg bw/day (nominal)
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
no

Any other information on results incl. tables

no maleformations found.

Problems in the lactation phase, see ovarall remarks.

Applicant's summary and conclusion

Conclusions:
The LOEAL for maternal toxicty was determined to be 4 mg/kg bw /day, for unschuedled deads and decrease in bw at 20 mg/kg bw/day. There were no adverse effects belonging to reproduction according to the FDA guidelines.
Many litters in the dose groups found dead without milk in the stomach. The data from necropsy show no evidence for adverse effects relating to teats of the dams including no or a decreased milk volume, or the litters could not drink. An analysis of the milk was not performed in due it is not part of the guideline OECD 422. So it is not possible to bevaluate the study in the lactation periode
Executive summary:

-