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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
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Endpoint summary
Administrative data
Description of key information
ORAL
Waalkens-Berendsen (2004), OECD 422, NOAEL 5 mg/kg diet (based on the effects noted in the thymus) equivalent to 0.3-0.4 mg/kg bw/day for male animals and 0.3-0.5 mg/kg bw/day for female animals, performed on the read across substance dioctyltin oxide (DOTO).
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Remarks:
- combined repeated dose and reproduction / developmental screening
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 05 November 2003 to 08 March 2004
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- 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. The study report was conclusive, done to valid guidelines and the study was conducted under GLP conditions. Since the study was conducted with the read across substance, dioctyltin oxide (DOTO), it has been assigned a reliability score of 2.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 10 - 11 weeks.
- Weight at study initiation: The weight variation of the animals for each sex did not exceed 20 %.
- Diet: ad libitum.
- Water: tap water ad libitum in polypropylene bottles.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark.
DOSE-RANGE FINDING TEST IN-LIFE DATES: From: 12 November 2003 To: 26 November 2003
MAIN TEST IN-LIFE DATES: From: 14 January 2004 To: 08 March 2004 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): The experimental diets were prepared once shortly before the study.
- Mixing appropriate amounts with (Type of food): The test material was weighed and placed in a small grinder. The tray was rinsed with food which was then also added to the grinder and mixed for 2 x 30 seconds. This mixture was moved to a Stephan cutter and the grinder was rinsed with food and moved to the cutter. Approximately 3 kg weighed food was mixed into the cutter for 2 x 2 minutes and moved. This was then moved to the Lödige cutter. The Stephan cutter was rinsed with approximately 3 kg of food and that was also moved to the Lödige cutter. Mixing was continued in the Lödige cutter for 2 minutes with the total amount of food.
- Storage temperature of food: <-18 °C. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The feed was checked for homogenous distribution, stability and concentration of the test material for all the doses in the dose-range finding study. The same dose preparation for the dose-range finding study was also used for the main test. The homogenous distribution and achieved concentration of the low dose in the main test was also analysed.
Directly after preparation of the diet for the dose-range finding study, samples for homogeneity and stability were taken. Five samples were taken (approximately 50 g each) to examine the homogeneity of the dose from the top centre, middle centre, bottom centre, left centre and right centre of the mixer. Secondly samples (around 50 g) were taken from the top centre part of the mixer to measure the stability. The samples taken for measurement of the homogeneity were also used for dose confirmation. In addition the content (achieved concentration) of the test material in the batch of diet used in the main study. Diet samples were taken for analysis immediately after preparation and stored at – 18 °C.
Samples of the 0, 25, 75, 200 and 500 mg/kg diets from the dose-range finding study and doses of 0, 25 and 250 mg/kg from the main study as well as all related calibration samples were derivatised.
A calculated amount of internal standard solution (MHT, DHT and TTPT in methanol) was added to 2.0 g of diet in a 50 mL Corning tube. 10 mL of 100 % acetic acid was then added and the Corning tube was closed and shaken for 60 minutes (250 rpm). 10 mL of acetate buffer solution (pH 4.5) was added along with 10 mL methanol. 2.0 mL of 20 % (m/V) aqueous STEB solutions was added, followed by 10 mL hexane (containing naphthalene, approximately 0.1 mg/L). The tube was shaken for 15 minutes (250 rpm) then placed in an oven at 60 °C for 15 minutes. After phase separation, the hexane layer (approximately 3 mL) was removed and washed with 3 mL of 2 mol/L HCl (30 minutes shaking at 250 rpm). The hexane top layer was diluted with hexane: hexane extracts from sample with dose levels of 0, 25 and 75 mg/kg were diluted five times, the higher doses were diluted fifty times. The resulting solutions were transferred into an amber coloured glass vial and anaylysed using GC-MS.
The procedure for the samples from the main study at doses of 0 and 5 mg/kg followed the same derivatisation procedure, except the initial quantity of the diet was 5.0 g not 2.0 g.
The concentration of organotin compounds in the extracts was determined using GC-MS. For calculation of the amount of DOTO in the samples, the peak area of DHT was used as an internal standard. Quantitiation was achieved using the calibration graphs constructed from the calibration solutions.
The following conditions were used:
- Column: Fused silica HP5 MS, 30 m, 0.25 mm ID, 0.25 µm film
- Precolumn: fused silica HP5 MS, 2.5 m, 0.25 mm ID, 0.25 µm film
- Column temperature: after 3 minutes at 45 °C at a rate of 5 °C/min to 80 °C; then at a rate of 15 °C/min to 260 °C; 15 min at 260 °C.
- Carrier: helium; 1.5 mL/min constant flow
- Injection volume: 1 µL
- Injection temperature: start at 60 °C, then at a rate of 14.5 °C/s to 300 °C; 5 min at 300 °C
- Injection method: splitless
- Ionisation: electron impact 70 eV
- Mass range: 60-600 amu
- Mass fragments used: DOT m/z = 375*; 263; 151, DHT 347*; 249; 179
Mass fragments marked with an asterisk were used for quantitation. - Duration of treatment / exposure:
- 28 days (treated food was available ad libitum).
- Frequency of treatment:
- Daily.
- Remarks:
- Doses / Concentrations:
Range finding study: 0, 25, 75, 200 and 500 mg/kg diet
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
Main study: 0, 5, 25 and 250 mg/kg diet
Basis:
nominal in diet - No. of animals per sex per dose:
- 22 males and 22 females in the dose range finding study (5 groups of 4 male and 4 female rats).
52 males and 52 females in the 14-day main study (4 groups of 12 male and 12 female rats). - Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Doses were selected on the results of the range finding test.
- Rationale for animal assignment: Randomised. - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Every morning throughout the study, and a second observation in the afternoon of working days.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Prior to the first exposure and then once weekly.
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights of male and female rats were taken on day -2 (randomisation) and on days 0 (first day of dosing), 7 and 13 of the premating period.
Males were weighed weekly during the mating period until sacrifice. Females were weighed during mating (day 0, 7 and 13) and mated females were weighed on day 0, 7, 14 and 21 during presumed gestation and on day 1 and 4 of lactation. All animals were weighed at sacrifice.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, also calculated as g/animal/day.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the premating period.
- Anaesthetic used for blood collection: Yes, CO2/02 anaesthesia.
- Anti-coagulant: K2-EDTA.
- Animals fasted: Yes, overnight.
- How many animals: 5 rats/sex/group.
- Parameters checked:
Haemoglobin
Packed cell volume
red blood cell count
reticulocytes
Total white blood cell count
Prothrombin time
Thrombocyte count
Mean corpuscular volume (MCV)
Mean corpuscular haemoglobin (MCH)
Mean corpuscular haemoglobin concentration (MCHC)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the premating period.
- Anaesthetic used for blood collection: Yes, CO2/02 anaesthesia.
- Animals fasted: Yes, overnight.
- How many animals: 5 rats/sex/group.
- Parameters checked:
Fasting glucose
Alkaline phosphatase activity (ALP)
Aspartate aminotransferace activity (ASAT)
Alanine aminotransferace activity (ALAT)
Gamma glutamyl transferase activity (GGT)
Total protein
Albumin
Ratio albumin to globulin
Urea
Creatinine
Bilirubin (total)
Cholesterol (total)
Triglycerides
Phospholipids
Calcium (Ca)
Sodium (Na)
Potassium (K)
Chloride (Cl)
Inorganic phosphate
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Arena testing was performed prior to the first exposure and then once weekly until the end of dosing and in females until the end of lactation. Males and females selected for the functional observation battery test (FOB) and spontaneous activity measurements were excluded from the final arena testing.
At the end of the study, FOB test and spontaneous motor activity measurements were performed on day 27 for males and on post natal day for for females.
- Dose groups that were examined: All animals were subject to the arena testing. For the other two tests, 5 animals per sex were randomly selected from each dose group.
- Battery of functions tested:
Autonomic: lacrimation, salivation, pupil response to light, palpebral closure, piloerection, defecation and urination
Neuromuscular: gait, mobility, forelimb and hindlimb gripstrength, landing foot splay, righting reflex
Sensorimotor: response to tail pinch, click, tough and approach of a visual object
Convulsive: clonic and tonic movements
Excitability: ease of removal, handling reactivity, arousal and vocalisations
Activity: rearing and motor activity
Physiological: body temperature
OTHER: Reproductive and developmental indices were also examined as part of the test. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
The following were taken from all animals:
Ovaries
Uterus
Testes
Epididymides
Seminal vesicles
Prostate
Organs and tissues showing macroscopic abnormalities
The following were taken from 5 animals/sex/group:
Adrenals
Axillary lymph node
Bone marrow (femur)
Brain
Caecum
Coagulation glands
Colon
Duodenum
Eyes
Heart
Jejunum
Lungs
Kidneys
Liver
Mammary gland (females only)
Mesentric lymph node
Parathyroids
Peyer's patches
Pituitary
Rectum
Sciatic nerve
Spinal cord
Spleen
Stomach
Thymus
Thyroids
Trachea
Urinary bladder
The following organs were weighed:
Adrenals
Brain
Heart
Kidneys
Liver
Spleen
Thymus
HISTOPATHOLOGY: Yes
Microscopic examination was performed on the collected organs of all rats in the control and high-dose group.
The liver and ovaries of females and the thymus of the male and female rats in the low and mid-dose groups were also evaluated
The following tissues, though collected were not subject to histopathological examination:
Coagulation glands
Mammary gland (females only)
In addition, reproductive organs of males that failed to sire (mated female which was not pregnant) and females that were non-mated or non-pregnant of the mid and low dose groups were microscopically examined. - Other examinations:
- As part of the developmental screening, gross observations were performed on the pups.
- Statistics:
- Clinical findings were evaluated using Fisher’s exact probability test.
Bodyweight, bodyweight gain, organ weights and food consumption was assessed by one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison tests.
Red blood cell and coagulation variables, total white blood cell counts, absolute differential white blood cell counts, clinical chemistry values and organ weights were assessed by one-way ANOVA followed by Dunnett’s multiple comparison tests (treatment period).
Reticulocytes and relative differential white blood cell counts were assessed using Kriskal-Wallis non-parametric ANOVA followed by Mann-Whitney U-tests.
Histopathological changes were evaluated using Fisher’s exact probability test.
The results of the functional observations were measured on different scales. Continuous measurements were analysed by one-way analysis of variance at each time point, if found to be statistically significant, a post-hoc group comparison was performed. Rank order data were analysed by Kruskal-Wallis analysis of variance at each test time point, followed by planned multiple comparisons between dose groups were a significant results occurred. Categorical data were assessed using Pearson chi-square analysis.
Motor activity data were assessed by one-way analysis of variance at each time point with a post-hoc group comparison performed on significant results.
All tests were two sided and the level of probability p<0.05 was considered to be significant. Effects of treatment on habituation were analysed using repeated measures of analysis variance on time blocks. Each session consisted of 5 time blocks of 6 minutes each. - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- See "Details on results" for information
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- See "Details on results" for information
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- See "Details on results" for information
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- See "Details on results" for information
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See "Details on results" for information
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- See "Details on results" for information
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See "Details on results" for information
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- See "Details on results" for information
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
One female in the high dose group was found dead on gestation day 24.
One male animal in the high dose group showed exopthalmus from week 2 and complete degeneration of the eye from week 3 onwards. This was observed after orbital punction. No other clinical signs were noted in the males.
The only finding during the gestation period (gestation day 21) was a sparsely haired animal in the 250 mg/kg group. During the lactation period, sparsely haired animals were noted in the control (n = 1), 5 mg/kg (n = 1) and in the 250 mg/kg group (n = 1). No other findings were noted in the female animals.
BODY WEIGHT AND WEIGHT GAIN
Mean bodyweights of the treated male animals was comparable to the controls. The bodyweight change of the male animals of the high-dose group was significantly decreased from days 13-21. Mean bodyweights of the dams of the high-dose group was statistically significantly decreased on gestation day 21 and post-natal day 1. Mean bodyweight changes of the dams of the high-dose group were statistically significantly decreased from gestation day 14 to 21. Bodyweights and bodyweight change of the dams of all the treated groups were comparable to the controls group at all other times of the study.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Mean food consumption (g/kg/day) of male animals of the 250 mg/kg diet group was found to be statistically significantly decreased from day 7-13. No other treatment related effects were observed in the male animals.
During the gestation period and lactation period (gestation days 7-14 and 14-21 and post-natal days 1-4), food consumption (expressed as g/animal/day and g/kg bodyweight/day) of the dams in the high-dose group was significantly decreased. No other treatment-related effects were observed.
Test substance intake was as follows:
- Males (listed as low, mid and high dose groups; 5, 25 and 250 mg/kg diet respectively)
premating days 0-7: 0.4, 1.7 and 17.4 mg/kg bodyweight/day
premating days 7-13: 0.3, 1.6 and 15.4 mg/kg bodyweight/day
post-mating days 21-28: 0.3, 1.5 and 14.5 mg/kg bodyweight/day
- Females (listed as low, mid and high dose groups; 5, 25 and 250 mg/kg diet respectively)
premating days 0-7: 0.4, 1.7 and 17.4 mg/kg bodyweight/day
premating days 7-13: 0.3, 1.6 and 15.4 mg/kg bodyweight/day
gestation days 0-7: 0.4, 2.0 and 17.4 mg/kg bodyweight/day
gestation days 7-14: 0.4, 1.9 and 16.7 mg/kg bodyweight/day
gestation days 14-21: 0.3, 1.4 and 11.2 mg/kg bodyweight/day
Post-natal days 1-4: 0.5, 2.4 and 17.4 mg/kg bodyweight/day
HAEMATOLOGY
All treated groups were found to be comparable to controls
CLINICAL CHEMISTRY
Statistically significantly increased alkaline phosphatase levels (U/L) were found in the high-dose males. Bilirubin (µmol/L) was found to be statistically significantly increased in the high-dose females. These findings were considered to be treatment related. Other effects such as the statistically significant increase in chloride in the 25 mg/kg male rats and the significant decrease in calcium in the 5 mg/kg females were not considered to be related to treatment. No other changes were observed.
NEUROBEHAVIOUR
No treatment-related effects were observed.
ORGAN WEIGHTS
The absolute thymus weight in the males of the 250 and 25 mg/kg groups were found to be significantly decreased. Relative thymus weight was found to be significantly decreased in the high dose male rats.
The absolute and relative weight of the female animals of the high dose group was significantly decreased. In the mid-dose group the relative thymus weight was also statistically significantly decreased.
In the female animals of the high-dose group, the relative kidney and liver weights were statistically significantly decreased.
No other effects were observed in either male or female animals.
GROSS PATHOLOGY
At necropsy, a decrease in thymic size was seen in all animals in the 250 mg/kg diet groups, 11 females in the 25 mg/kg diet group, 7 females in the 5 mg/kg group and 5 animals in the control group.
Examination of the female that was found dead revealed hydrothorax, haemorrhagic lungs, dilation of the vena cava and haemorrhagic discharge in the vagina, these were considered to be indicative of problems during parturition.
HISTOPATHOLOGY
Microscopic evaluation of the thymus revealed moderate to very severe lymphoid depletion in all animals (both sexes) of the 250 mg/kg group and in all females of the 25 mg/kg group. Lymphoid depletion was characterised by a decrease in the thymic lobules due to an extensive loss of cortical and medullary small lymphocytes. The distinction between the cortical and medullary areas was unclear. In the more extreme effects observed, the cortex was very small, or absent. The remaining lymphoid cells visible in the cortical areas were mainly lymphoblasts. Lymphoblastic cells and reticuloepithelial cells had increased, and/or higher numbers of these cells were visible due to the disappearance of small lymphocytes and the collapse of the thymic stroma. In 3 high-dose females, lymphoid depletion was accompanied by lymphoid depletion in the PALS (periateriolar lymphocyte sheath areas) in the spleen. The macroscopically observed thymi in 5 control and 7 low dose females exhibited no microscopic abnormalities. In the thymi of the 2 control and 2 low dose females pregnancy/lactation involution was observed. The thymic lobules were decreased in size but exhibited normal structure with the histological appearance of age-involution. Increased glycomeric vacuolation, viz moderate versus very slight was seen in the liver of 4 high dose females and was considered to be a potential cause of the increased weight.
Examination of the reproductive organs revealed a statistically significant increased in the incidence of cysts in the ovaries of 8 high-dose females.
OTHER FINDINGS
In the reproductive and developmental screening observations of this study, increased duration of gestation, increased implantation loss, an increased number of still born pups and pup mortality at postnatal day 4, decreased pup weight at postnatal day and an increased number of runts and postnatal day 1 were all observed in the high dose group. - Dose descriptor:
- NOAEL
- Effect level:
- 0.3 - 0.4 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Decreased thymus weight
- Dose descriptor:
- NOAEL
- Effect level:
- 0.3 - 0.5 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: Decreased thymus weight and microscopic and macroscopic changes in the thymus
- Dose descriptor:
- NOAEL
- Effect level:
- 5 mg/kg diet
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Reduced thymus weights (male and female animals), microscopic and macroscopic changes in the thymus (females only)
- Critical effects observed:
- not specified
- Conclusions:
- Based on the effects noted in the thymus in both male and female rats in the 25 mg/kg diet groups, the NOAEL was concluded to be the lowest group tested, 5 mg/kg diet which was equivalent to 0.3-0.4 mg/kg bw/day for male animals and 0.3-0.5 mg/kg bw/day for female animals.
- Executive summary:
The repeated dose toxicity of the test material was assessed in a repeated dose toxicity and reproductive and developmental screening study in rats. The study was performed in accordance with GLP and to the standardised guideline OECD 422. Only one death was noted during the study, and this was not attributed to toxicity of the test substance. Based on the effects noted in the thymus in both male and female rats in the 25 mg/kg diet groups, the NOAEL was concluded to be the lowest group tested, 5 mg/kg diet which was equivalent to 0.3-0.4 mg/kg bw/day for male animals and 0.3-0.5 mg/kg bw/day for female animals.
Reference
Table 3: Test material concentration in experimental diets
Nominal concentration (mg/kg) |
Mean Nominal Measured Concentration (mg/kg) |
Percent of Nominal |
0 (#1) |
<0.05 |
NA |
0 (#2) |
<0.05 |
NA |
0 (#3) |
<0.05 |
NA |
5 (#1) |
4.52 |
90 |
5 (#2) |
4.93 |
99 |
5 (#3) |
4.40 |
88 |
25 (#1) |
24.9 |
100 |
25 (#2) |
26.5 |
106 |
25 (#3) |
26.3 |
105 |
250 (#1) |
247 |
99 |
250 (#2) |
240 |
96 |
250 (#3) |
244 |
98 |
#3: repeated analysis of batch no. 2
Table 4: Summary of relevant treatment related findings
Parameter |
Dose levels |
||
5 mg/kg diet |
25 mg/kg diet |
250 mg/kg diet |
|
Bodyweight: GD 21, PN 1 (females only) |
Decreased |
||
Bodyweight change: GD 14-21 (females only) |
Decreased |
||
Food consumption: PM 7-13 (males) GD 7-14, 14-21 and PN 1-4 (females only) |
Decreased |
||
Bilirubin (females only) |
Increased |
||
Alkaline phosphatase (males only) |
Increased |
||
Relative liver weight (females only) |
Increased |
||
Relative kidney weight (females only) |
Increased |
||
Absolute and/or relative thymus weight |
Decreased |
Decreased |
|
Thymus: lymphoid depletion (males only) |
Increased |
||
Thymus: lymphoid depletion (females only) |
Increased |
Increased |
|
Ovary: cysts (females only) |
Increased |
||
Liver: glycogenic vacuolation (females only) |
Increased |
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 0.3 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- A reliable study has been provided to address this endpoint, therefore the overall quality of the dataset is considered to be high.
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Oral
In the key study (Waalkens-Berendsen, 2004) the repeated dose toxicity of the test material was assessed in a repeated dose toxicity and reproductive and developmental screening study in rats. The study was performed in accordance with GLP and to the standardised guideline OECD 422. Only one death was noted during the study, and this was not attributed to toxicity of the test material. Based on the effects noted in the thymus in both male and female rats in the 25 mg/kg diet groups, the NOAEL was concluded to be the lowest group tested, 5 mg/kg diet which was equivalent to 0.3-0.4 mg/kg bw/day for male animals and 0.3-0.5 mg/kg bw/day for female animals. As the study was performed on a read-across substance (dioctyltin oxide, DOTO), the study was assigned a reliability score of 2 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and considered suitable for assessment as an accurate reflection of the test material.
The sub-acute (28 day) repeated dose and reproductive and developmental screening study provides an NOAEL sufficient for classification, which can be extrapolated to represent a 90-day NOAEL for the same route. Further testing for this endpoint is considered to be inappropriate and is therefore omitted.
Inhalation
In accordance with Column 2 (specific rules for adaptation from Column 1), points 8.6.1 of Annex VIII and point 8.6.2 of Annex XI of the Regulation (EC) No. 1907/2006 (REACH), the test for repeated dose toxicity should be performed on the most appropriate route. Testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. The vapour pressure of the substance is low (less than 2.2 x 10^-3 Pa at 25 ºC) and so exposure via the inhalation route is unlikely. A test was submitted addressing the repeated dose toxicity of the substance via the oral route; this was considered the most appropriate route of exposure based on the physical properties of the substance.
Dermal
In accordance with Column 2 (specific rules for adaptation from Column 1), points 8.6.1 of Annex VIII and point 8.6.2 of Annex XI of the Regulation (EC) No. 1907/2006 (REACH), the test for repeated dose toxicity should be performed on the most appropriate route. A test was submitted addressing the repeated dose toxicity of the substance via the oral route. This was considered the most appropriate route of exposure based on the physical and toxicological properties of the substance.
Justification for selection of repeated dose toxicity via oral
route - systemic effects endpoint:
Only one study was available, which was performed on a structural
analogue (dioctyltin oxide) of the substance to be registered,
dioctyltin dilaurate. The study was performed in line with standardised
guidelines and under GLP conditions. The study was assigned a
reliability score on 2 in accordance with the principles for assessing
data quality, defined in Klimisch (1997).
Justification for selection of repeated dose toxicity inhalation -
systemic effects endpoint:
A data waiver has been submitted to address this endpoint.
Justification for selection of repeated dose toxicity inhalation -
local effects endpoint:
A data waiver has been submitted to address this endpoint.
Justification for selection of repeated dose toxicity dermal -
systemic effects endpoint:
A data waiver has been submitted to address this endpoint.
Justification for selection of repeated dose toxicity dermal - local
effects endpoint:
A data waiver has been submitted to address this endpoint.
Repeated dose toxicity: via oral route - systemic effects (target
organ) cardiovascular / hematological: thymus
Justification for classification or non-classification
Diotyltin dilaurate causes an acute adverse effect in the immune system. In general subacute, subchronic and chronic suties only the thymus effect is registered. The "late" detection of the sdverse effect releation to the immune system is based on the study protrocl.
It was shown in several sttudies after a one time exposure, that dioctyltin compunds cause an acute efffect (see section immunotoxicity).
Therefor the substance is to classify as STOT SE
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