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EC number: 222-583-2 | CAS number: 3542-36-7
- 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
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Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2002-12-18 to 2003-06-23
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 004
- Report date:
- 2004
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- yes
- Principles of method if other than guideline:
- - Responsible Personnel: D. Jonker M. Sc. and M.V.W. Wijnands DVM should read D. Jonker PhD and M.V.W. Wijnands PhD DVM, respectively;
- M.V.W. Wijnands was responsible for pathology, instead of R.A. Woutersen; Pups were identified by tattoos in paws and tail on PN 1;
On each day of analysis of study samples, QC samples were freshly prepared, in order to check the derivatisation and extraction on that particular day;
- In addition to the protocol, the animals of the satellite groups were weighed once before the start of the study;
The definition used for runts was: pup weight less than mean pup weight of the control group minus 2 standard deviations;
Calculation of the viability index was not mentioned in the protocol;
In addition to the protocol, the intake of test substance per kg body weight per day was calculated;
- Food consumption and food efficiency were statistically analysed by anova followed by L.S.D. tests instead of anova followed by Dunnett's multiple comparison tests; Occasionally, a determination was or could not be conducted in an individual animal.
These deviations were considered not to have influenced the validity of the study. - GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Dichlorodioctylstannane
- EC Number:
- 222-583-2
- EC Name:
- Dichlorodioctylstannane
- Cas Number:
- 3542-36-7
- Molecular formula:
- C16H34Cl2Sn
- IUPAC Name:
- dichlorodioctylstannane
- Details on test material:
- Purity is 92.1%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: (P) 13 - 14 wks;
- Weight at study initiation: Females: 185.5 - 212.8 g
- Fasting period before study: NDA
- Housing: The animals were housed under conventional conditions in one room, in macrolon cages, with sterilized wood shavings (Woody Clean 3/4) as bedding material and environmental enrichment (shreds of paper).
- Use of restrainers for preventing ingestion (if dermal): N/A
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 23rd April 2003 To: 23rd June 2003
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Prepared shortly before the start of the study and every 6 weeks thereafter.
- Mixing appropriate amounts with (Type of food): RM3 diet
- Storage temperature of food: < -18 ºC
VEHICLE
No vehicle used - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: Until copulation had occurred, up until a maximum of 2 weeks
- Proof of pregnancy: sperm in vaginal smear] referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. N/A
- Further matings after two unsuccessful attempts: N/A
- After successful mating each pregnant female was caged (how): Individually
- Any other deviations from standard protocol: No
Females were mated with males from the same dosage group. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- From each diet sample, 2.0 g was transferred into a 50 ml Greiner tube. An aliquot of the internal standard solution (monoheptyltin trichloride, diheptyltin dichloride, tripropyltin chloride and tetrapropyltin in methanol) was added. Subsequently methanol, acetate buffer solution (pH 4.5), 20% aqueous NaBEt4 solution (STEB solution) and hexane (with naphthalene as internal standard) were added to each sample and this mixture will be shaken and heated to 60 °C. During this step, the organotin chlorides were converted into the corresponding ethylated tetraorganotin derivatives, which were extracted into the hexane layer. Prior to GC-MS analysis, the hexane layer was washed with 2 mol/1 HCI in order to remove (most of) the ethylboron compounds that interfere with the GC-MS analysis. The concentration of each test substance in feed was determined by GC-MS analysis of the hexane extracts.
The homogenous distribution, stability and achieved concentration were determined - Duration of treatment / exposure:
- Rats began being fed with dosed feed 2 weeks prior to the mating period. They were fed during gestation and up to euthanasia at or shortly after postnatal day (PN) 4.
- Frequency of treatment:
- ad libitum
- Details on study schedule:
- - Age at mating of the mated animals in the study: 15-16 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg diet
- Remarks:
- Relates to 10 ppm in diet
- Dose / conc.:
- 100 mg/kg diet
- Remarks:
- Relates to 100 ppm in diet
- Dose / conc.:
- 300 mg/kg diet
- Remarks:
- Relates to 300 ppm in diet
- No. of animals per sex per dose:
- 10 females per dose.
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: based on 14 day range finding study
- Rationale for animal assignment (if not random): Computer randomisation
- Other: N/A - Positive control:
- No positive control used
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily in the morning. On weekdays, also checked again in afternoon for dead or moribund animals.
DETAILED CLINICAL OBSERVATIONS: Yes, handled if necessary to detect signs of toxicity
- Time schedule: daily, if necessary.
BODY WEIGHT: Yes
- Time schedule for examinations: The animals were weighed on day -5 (for randomization), gestation day (GD) 0, 7, 14 and 21 and postnatal day (PN) 1 and 4. All animals were weighed on the day of necropsy in order to determine their correct organ to body weight ratios. This was in addition to a weekly measurement being taken throughout the study.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food /kg bw / day and g food / animal / day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): N/A - Oestrous cyclicity (parental animals):
- At the end of the gestation period, females were examined twice daily for signs of parturition. Any difficulties occurring during parturition were recorded.
- Sperm parameters (parental animals):
- NDA
- Litter observations:
- The total litter size and numbers of each sex as well as the number of stillbirths, live and dead pups and grossly malformed pups were evaluated on days 1 and 4 of lactation. The pups were weighed individually and litter weight was calculated for days 1 and 4 of lactation. Mean pup weight was calculated as litter weight / number pups. The number of runts [defined as pup weight less than 2 standard deviations from the litter mean] were noted and reported.
To keep nest disturbance to a minimum the litters were examined only once daily for dead pups. - Postmortem examinations (parental animals):
- SACRIFICE
- The animals were euthanized by decapitation under C02/02-anaesthesia and then examined grossly for pathological changes.
GROSS NECROPSY
At necropsy the following organs were weighed and samples of the organs of all these females were preserved in a neutral aqueous phosphate-buffered 4 per cent solution of formaldehyde:
- ovaries
- uterus (after counting of the implantation sites)
- thymus
- all gross lesions
In addition microscopic examination of the thymus of the control and 300 mg/kg group was performed. After consultation with the sponsor, examination was extended to the thymus of the female rats of the 10 and 100 mg/kg groups because of the effect observed in the 300 mg/kg group for this tissue/organ.
HISTOPATHOLOGY / ORGAN WEIGHTS
The ovaries and uterus of the females of the control and 300 mg/kg were microscopically examined. Furthermore, the reproductive organs of the males of the 10 and 100 mg/kg groups that failed to sire (did not mate or female was not pregnant) and the reproductive organs of females of the 10 and 100 mg/kg groups that were non-mated or non-pregnant were microscopically examined.
Since treatment-related changes were found in the thymus of females of the 300 mg/kg group, histopathology on this organ was extended to females of the intermediate-dose groups. - Postmortem examinations (offspring):
- A necropsy was performed on stillborn pups and pups dying during the study; macroscopic abnormalities were recorded. Pups were examined externally for gross abnormalities and killed by hypothermia at <-18°C.
- Statistics:
- The statistical procedures used in the evaluation of data were as follows:
• Body weight: one way analysis of covariance (covariate: body weight on day 0) followed by Dunnett's multiple comparison tests;
• Food consumption and food efficiency: one way analysis of variance (anova) followed by L.S.D. tests;
• Fisher's exact probability test was used to evaluate the number of mated and pregnant females and females with live pups. Number of implantation sites, live and dead pups were evaluated by Kruskal- Wallis nonparametric analysis of variance followed by the MannWhitney U-test.
• Histopathological changes: Fisher's exact probability test.
All tests were two-sided. Probability values of p<0.05 were considered significant. - Reproductive indices:
- - pre-coital time = time between the start of mating and successful copulation
- duration of gestation = time between gestation day 0 and day of delivery
- mating index = (number of females mated/number of females placed with males) x 100
- male fertility index = (number of males that became sire/number of males placed with females) x 100
- female fertility index = (number of pregnant females/number of females placed with males) x 100
- female fecundity index = (number of pregnant females/number of females mated) x 100
- gestation index = (number of females with live pups/number of females pregnant) x 100 - Offspring viability indices:
- - live birth index = (number of pups born alive/number of pups born) x 100
- pup mortality day n = (number of dead pups on day n/total number of pups on day n) x 100
- viability index day 1-4 = (number of pups surviving 4 days/total number of live pups on day 1) x 100
- number of lost implantations = number of implantations sites - number of pups born alive
- post-implantation loss = [(number of implantation sites - number of pups born alive)/number of implantation sites] x 100
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- effects observed, treatment-related
Details on results (P0)
No clinical signs were observed during the premating period. During the gestation period piloerection was observed in animal A115 (GD 21-24) of the control group and animal D161 (GD 23-24) of the 300 mg/kg group. In addition, blepharospasm was observed in animal D161 (GD 23-24). During lactation piloerection was observed in animal C157 (PN 2-4) of the 100 mg/kg group and D163 (PN 2-4) and D167 (PN 1) of the 300 mg/kg group. Blepharospasm was observed in animal D167 of the 300 mg/kg group. Animals C149 (PN 4-5) and C157 (PN 4) of the 100 mg/kg group and animal D163 (PN 4) of the 300 mg/kg group were considered to be thin. In addition animals C149 and C159 showed a pale appearance. Some animals were sparsely haired during gestation and/or lactation; this finding is normal for this strain.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
During the premating period no significant differences in mean body weight were observed. Mean body weight change was statistically significantly reduced in the 100 and 300 mg/kg groups during the first week of the premating period. During the gestation period, mean body weight was statistically significantly reduced from GD 7-21 in the 300 mg/kg group. Body weight change was statistically significantly reduced during the entire gestation period. During the lactation period, the mean body weight was statistically significantly reduced in the 300 mg/kg group.
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
During the premating period, mean food consumption (expressed as g/animal/day and as g/kg body weight/day) of the female animals of the 100 and 300 mg/kg groups was statistically significantly decreased. During the gestation period, food consumption (g/animal/day) of the females of the 100 mg/kg group was statistically significantly decreased from GD 7-14. Mean food consumption of the 300 mg/kg group (expressed as g/animal/day) was statistically significantly decreased during the entire gestation period and as g/kg body weight/day from GD 0-14. During the lactation period food consumption of the female animals of the 300 mg/kg group was statistically significantly decreased.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No effects
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No effects
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Animal 115 of the control group and animals D161, D171 and D173 of the 300 mg/kg group showed only implantation sites at necropsy. The female fecundity index, female fertility index and male fertility index were comparable among the control and Dichlorodioctylstannane-treated groups. The gestation index was 86, 100, 71 and 50% in the control, 10, 100 and 300 mg/kg groups, respectively. The number of females with liveborn pups was 6, 8, 5 and 4 for the control, 10, 100 and 300 mg/kg groups, respectively. The number of females with stillborn pups amounted to 1, 1, 4 and 3 for the control, 10, 100 and 300 mg/kg groups, respectively. The number of females with all stillborn pups was 0, 0, 2 and 1 in the control, 10, 100 and 300 mg/kg groups, respectively. The live birth index was 99, 95, 53 and 60% in the control, 10, 100 and 300 mg/kg groups, respectively. Post-implantation loss was 22.3, 21.0, 49.2 and 70.0% for the control, 10, 100 and 300 mg/kg groups, respectively.
ORGAN WEIGHTS (PARENTAL ANIMALS)
Absolute and relative uterus and ovary weight were similar in all groups. The absolute and relative thymus weight was statistically significantly decreased in the 100 (62 and 67%) and 300 mg/kg (31 and 38%) groups when compared to the control group.
GROSS PATHOLOGY (PARENTAL ANIMALS)
No effects
HISTOPATHOLOGY (PARENTAL ANIMALS)
Microscopic examination revealed moderate to very severe lymphoid depletion in the thymus, which was considered related to treatment. Lymphoid depletion was characterised by a decrease in the size of the thymic lobules which can be ascribed to extensive loss of cortical en medullary small lymphocytes. Consequently, the distinction between the cortical and medullary areas was blurred. Lymphoid depletion was observed in 5/10 animals of the 10 mg/kg group and in all animals of the 100 and 300 mg/kg groups. Surprisingly, one control animal (A115) also had very severe lymphoid depletion in the thymus. However, this was most probably associated with the fact that this animal was physiologically disturbed, as was demonstrated by 12 resorptions in the uterus and an abnormal kidney (gross changes: flabby and yellow patches). Some 10 mg/kg animals showed thymic involution as a result of pregnancy/lactation. This picture was similar to the thymic pregnancy/lactation involution in control animals and was characterised by a decreased size of thymic lobules exhibiting normal architecture. This phenomenon is a common observation in pregnant or lactating animals. However, the lymphoid depletion in the 10 mg/kg animals was similar to the thymic change in the 100 and 300 mg/kg animals. Therefore, lymphoid depletion in the 10, 100 and 300 mg/kg animals was considered related to treatment with the test substance.
The other histopathological changes observed are common findings in rats of this strain and age or occurred in a single animal only.
Effect levels (P0)
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 0.5 - 0.7 mg/kg bw/day (nominal)
- Sex:
- female
- Basis for effect level:
- other: lymphoid depletion
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, treatment-related
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
The mean number of pups delivered per litter amounted to 11.7, 11.0, 10.3 and 8.6 or the control, 10, 100 and 300 mg/kg (ppm) groups, respectively. Pup mortality on PN 1 was 1.4, 4.5, 47, and 40% in the control, 10, 100 and 300 mg/kg groups, respectively. All pups of the following animals died between PN 1-4: B137 of the 10 mg/kg group, C145 and C159 of the 100 mg/kg group and D165, D175 and D177. Pup mortality on PN 4 was 5.8, 8.3, 26 and 88 %. Viability index (PN 1-4) was 94, 92, 74 and 12% in the control, 10, 100 and 300 mg/kg groups, respectively. The number of live pups per litter on PN 1 amounted to 11.5, 10.5, 7.6, 6.5 for the control, 10, 100 and 300 mg/kg groups, respectively and on PN 4 the number of live pups per litter amounted to 10.8, 11.0, 9.3 and 3.0 for the control, 10, 100 and 300 mg/kg groups, respectively. Both in the 100 and 300 mg/kg groups, 4 litters were entirely stillborn or lost at PN 4.
No difference was observed in the sex ratio between the groups.
CLINICAL SIGNS (OFFSPRING)
On PN 1 and 4, the number of runts was statistically significantly increased in the 100 and 300 mg/kg groups. In addition the number of cold pups was increased in the 300 mg/kg group on PN 1.
BODY WEIGHT (OFFSPRING)
Mean pup weight and pup weight change were similar in the 10 and 100 mg/kg groups when compared to the control group. Pup weight of the 300 mg/kg group (PN 1, 3 litters and PN 4, 1 litter) was reduced.
SEXUAL MATURATION (OFFSPRING)
not examined
ORGAN WEIGHTS (OFFSPRING)
not examined
GROSS PATHOLOGY (OFFSPRING)
No effects
HISTOPATHOLOGY (OFFSPRING)
not examined
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 0.7 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: fertility and developmental observations
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 0.5 - <= 0.7 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: fertility and developmental observations
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Based on reproductive and developmental effects observed after mating of 100 and 300 mg/kg female animals with male animals, the low dose level of 10 mg Dihlorodioctylstannane/kg diet (equivalent to 0.7 mg/ kg body weight/day in males and 0.5-0.7 mg/kg body weight for females) can be considered as a NOAEL for fertility and developmental effects.
Based on the observed histological changes in the thymus (lymphoid depletion) of the 10 mg/kg female animals, 10 mg Dichlorodioctylstannane/ kg diet (equivalent to 0.5-0.7 mg/kg body weight/day) was considered to be a LOAEL for maternal toxicity. - Executive summary:
A screening study to see the reproductive/developmental effects of dioctyltin dichloride was conducted in accordance with OECD test method 421. Female Wistar rats were fed diets containing 10, 100 and 300 mg/kg (ppm) of the test substance. This began two weeks prior to the mating period, and continued through mating, gestation, and up to PN 4 or shortly thereafter. Male rats were mated after a premating period of 10 weeks with female rats of the satellite groups, which were fed the same dose of test diet. Clinical observations, growth, food consumption, food conversion efficiency, neurobehavioural testing, ophthalmoscopy, haematology, clinical chemistry, renal concentration test, urinalysis, organ weights and gross examination at necropsy, microscopic examination of various organs and tissues and assessment of various reproductive and developmental parameters were used as criteria for detecting the effects of treatment.
Based on reproductive and developmental effects observed after mating of 100 and 300 mg/kg female animals with male animals, the low dose level of 10 mg Dihlorodioctylstannane/kg diet (equivalent to 0.7 mg/ kg body weight/day in males and 0.5-0.7 mg/kg body weight for females) can be considered as a NOAEL for fertility and developmental effects. Based on the observed histological changes in the thymus (lymphoid depletion) of the 10 mg/kg female animals, 10 mg Dichlorodioctylstannane/ kg diet (equivalent to 0.5-0.7 mg/kg body weight/day) was considered to be a LOAEL for maternal toxicity.
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