Registration Dossier

Administrative data

Description of key information

In a guideline 90-day subchronic dietary study in rats, based on the changes in neurobehavioral parameters and associated brain histopathology that occurred at the high dose of 750 ppm (equivalent to 49.7 mg/kg bw/day in males and 53.6 mg/kg bw/day in females), as well as changes in haematology, clinical chemistry, urinalysis, organ weights, and pathology of the thymus at the same dose, the NOAEL was the next lower dose of 150 ppm (equivalent to 9.8 mg/kg bw/day in males and 10.2 mg/kg bw/day in females).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: guideline study conducted on read across material
Justification for type of information:
Read-across test result from source substance MMTC to target substance MMT(EHTG).
This data requirement is fulfilled by read-across. Justification for the read-across of this test result is provided in Section 7.1 Toxicokinetics. The simulated gastric hydrolysis study shows rapid and complete conversion of MMT(EHTG) to MMTC. Based on this result, MMTC fulfills the requirements of being a source compound for studies required for MMT(EHTG) where the endpoint is based on oral exposure. The study on MMTC can be applied both quantitatively and qualitatively for the end point for MMT(EHTG).
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
On each day of the analysis of study samples, QC samples were freshly prepared; Validation of the anlaytical method for test material in the diet at the low dose of the main study was performed, because the dose wasn't covered by the pilot study.
Principles of method if other than guideline:
The method of analysis involved derivatisation. This method only measures the amount of the alkyltin moiety, MMT, present and does not identify the other ligands attached to the tin. Currently there is no analytical method available that can quantify the actual named substance, i.e., the entire organotin compound with its associated chloride ligand. All measured MMT was fully attributed to the named substance, MMTC.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 7 weeks old; satellite group- 13-14 weeks old
- Weight at study initiation: 134.9-178.5 g in males and 113.9 -138.8 in females; 178.8 - 213.5 g in females satellite group
- Fasting period before study: no
- Housing: under conventional conditions in one room in macrolon cages with sterilized wood shavings and environmental enrichment 2 (dose-range finder) or 5 rats per cage (13-week study) separated by sex. During the premating period females of the satellite groups were housed 3 or 4 per group per cage. During the gestation and lacation period the females were housed individually.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8, 13 and 13 days for the dose-range finder, 13-week and satellite groups

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 degrees C
- Humidity (%): at least 30% and not exceeding 70%, other than during room cleaning
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

IN-LIFE DATES: dose range finder From: January 30, 2003 To: February 13, 2003
13-week study From: April 1, 2003 To: July 1, 2003- males; July 2, 2003- males; June 26 to July 14, 2003 for satellite groups
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): at the start of the study and every six weeks thereafter
- Mixing appropriate amounts with (Type of food): commercial rodent diet (rat and mouse No 3 Breeding Diet Services, Witham, England)
- Storage temperature of food: stored in a freezer

VEHICLE- not applicable
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), 2% 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 wa washed with 2 mol/L HCl 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.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Dose / conc.:
30 mg/kg diet
Dose / conc.:
150 mg/kg diet
Dose / conc.:
750 mg/kg diet
No. of animals per sex per dose:
10 plus 10 females for the satellite groups
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: no
- Dose selection rationale: Based on dose-range finder. Dietary doses of 50, 250, 750, and 1500 mg trichloromethylstannane/kg feed (ppm) were administered for 14 days. No treatment-related clinical signs were observed. The body weights were sporadically decreased in males of the 750 mg/kg group and throughout at 1500 mg/kg. Body weights were not significantly different among females. Food consumption was significantly decreased in males of the 750 and 1500 mg/kg groups on day 7 and 14. Food consumption was significantly increased in females of the 50 and 250 mg/kg groups (day 7) and significantly decreased in females of the 750 mg/kg group (days 7 and 14) and the 1500 mg/kg group (day 7). Food conversion efficiency was significantly decreased in males of the 1500 mg/kg group (days 7 and 14). Food conversion efficiency was not significantly different among females. The absolute weights of the testes were significantly decreased in the males of the 50 and 1500 mg/kg groups. Absolute spleen weights, relative kidney weights and absolute and relative liver weights were significantly decreased in the males of the 1500 mg/kg group. Absolute weights of the ovaries were significantly increased in the females of the 250 mg/kg group and decreased in the females of the 1500 mg/kg group. Absolute and relative spleen weights were significantly decreased in females of the 750 and 1500 mg/kg groups. Macroscopic examination at necropsy did not reveal any treatment related changes. Dietary exposure of trichloromethylstannane up to 1500 mg/kg for 14 days was tolerated; however, the body weight and food consumption decreases were deemed palatability effects at 750 and 1500 mg/kg. The low food intake, low food efficiency, and organ weight effects at these doses were suggestive of a toxic response threshold. Doses for the main and satellite studies were chosen as 30, 150, and 750 mg/kg in the diet.
- Rationale for animal assignment (if not random): computer randomisation
- Rationale for selecting satellite groups: to provide additional data on possible reproductive and developmental effects of the test substance
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): allowed to give birth
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily (in the morning) and on working days also once in the afternoon.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily (in the morning) and on working days also once in the afternoon.

BODY WEIGHT: Yes
- Time schedule for examinations: once during the acclimatization period, once at initiation  of the study prior to introduction of feed.  Thereafter body weights were  recorded once weekly.  Furthermore, all animals were weighed on the day  of necropsy in order to determine their correct organ to body weight  ratios.

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 - Food consumption: measured per cage over weekly periods by weighing the  feeders (in g/animal/day).  Data of male rats was not  measured in weeks 10 (all animals) and 11 (some animals), because this  was hampered by the mating procedure (male rats of the 13-week study were  used to mate with female rats from the satellite group).
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes the intake of substance per kg/bw/day was  calculated from the nominal dietary concentration of the substance, the  food consumption and the mean body weight in the period for which the  intake of the substance is calculated.

FOOD EFFICIENCY:
- Yes the efficiency of food utilisation was calculated and expressed in g weight gain per g food consumed.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations: provided ad libitum, the amount consumed was not  measured

OPHTHALMOSCOPIC EXAMINATION: Yes   Eye examinations were carried out using an ophthalmoscope after  induction of mydriasis by a solution of atropine sulphate
- Time schedule for examinations: observations made prior to the start of  the treatment in all animals and towards the end of the treatment period  in all surviving animals of the control and high dose (750 mg/kg) groups. 
- Dose groups that were examined: prior to the start of  the treatment in all animals and towards the end of the treatment period  in all surviving animals of the control and high dose (750 mg/kg) groups. 

HAEMATOLOGY: Yes  
- Time schedule for collection of blood: at necropsy at the end of treatment, after overnight  fasting, blood samples were taken from the abdominal aorta of all  surviving animals. 
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes overnight
- How many animals: all surviving animals
-Determinations carried out included: haemoglobin  (Hb), packed cell volume (PCV), red blood cell count (RBC),  reticulocytes, total white blood cell count, differential white blood  cell count, prothrombine time, thrombocyte count.  The mean corpuscular  volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular  haemoglobin concentration (MCHC) were calculated.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:at necropsy at the end of treatment, after overnight  fasting, blood samples were taken from the abdominal aorta of all  surviving animals
- Animals fasted: Yes overnight
- How many animals: all surviving animals
- Measurements made included alkaline phosphatase  activity (ALP), aspartate aminotransferase activity (ASAT), alanine  aminotransferase activity (ALAT), gamma glutamyl transferase activity  (GGT), total protein, albumin, albumin to globulin ratio (A/G), urea,  creatinine, total bile acid, bilirubin (total and direct), cholesterol  (total), triglycerides, phospholipids, Ca, Na, K, Cl, inorganic  phosphate, fasting glucose


URINALYSIS: Yes  all animals were deprived of water for 24 hours  and of food during the last 16 hours of this period.  During the last 16  hours of deprivation, the rats were kept in metabolism cages and urine  was collected.  The concentrating ability of the kidneys was investigated  by measuring the volume and density of the individual samples.  
- Time schedule for collection of urine: Shortly before the end of the  treatment (days 86-87)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes 24 hours
- The  determinations carried out with the urine collected in the renal  concentration test included appearance, glucose, pH, occult blood,  ketones, protein, bilirubin, urobilinogen, microscopy of the sediment.


NEUROBEHAVIOURAL EXAMINATION: Yes .
- Time schedule for examinations: prior to the first exposure and then once weekly up to and including week 12.
- Dose groups that were examined: all surviving animals
- Battery of functions tested: arena testing, functional observational  battery (FOB) and motor activity assessment


Sacrifice and pathology:
GROSS PATHOLOGY: Yes All animals of the 13-week study and all adult animals of the satellite group were subjected to a complete gross necropsy. organs weighed included adrenals, brain, epididymides, heart, kidneys, liver, ovaries, spleen, testes, thymus, thyroid (with  parathyroids), uterus. 
HISTOPATHOLOGY: Yes performed on  tissues and organs of all animals of the control and high dose group and  included adrenals, aorta, brain (brain stem, cerebrum, cerebellum),  caecum, colon, epididymides, eyes, GALT (gut associated lymphoid tissue,  including Peyer's patches), heart, kidneys, liver, lungs, mammary gland  (females), mesenteric lymph nodes, nerve-peripheral (sciatic),  oesophagus, ovaries, pancreas, parathyroid, pituitary, prostate, rectum,  skin (flank), small intestine (duodenum, ileum, jejunum), spinal cord (at  3 levels), spleen, sternum with bone marrow, stomach (glandular and non-glandular), sublingual salivary glands, submaxillary salivary glands,  testes, thymus, thyroid, trachea/bronchi, urinary bladder, uterus (with cervix) and all gross lesions. Lungs, liver, kidneys and gross lesions were examined microscopically in all intermediate dose groups.  Since treatment related  changes were found in the thymus and brain of males and females of the  high dose group, histopathology on these organs was extended to the animals  of the intermediate dose groups.
Statistics:
STATISTICAL METHODS: - See other information on material and methods section
Clinical signs:
no effects observed
Description (incidence and severity):
No treatment related findings were observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Similar among the groups in males and females throughout the study.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Similar among the groups in males throughout the study. Food consumption was slightly higher (ca. 8 %) in females of the 750 mg/kg group. This difference was statistically significant during the last three weeks of the study.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Similar among the groups in males and females throughout the study. An occasional significant difference was seen.
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No treatment related ocular changes were observed.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
RBC, Hb and PVC were statistically significantly increased in females and MCV and MCH were statistically significantly increased in males of the 750 mg/kg group. Thrombocytes (females) and prothrombin time (males and females) were statistically significantly decreased in the 750 mg/kg group. Absolute and relative numbers of eosinophils were significantly decreased in females of the 750 mg/kg group. Haematology parameters were similar among the control, 30 and 150 mg/kg groups, with the exception of a statistically significantly lower number of neutrophils in males of the 30 mg/kg groups, which was considered a chance finding.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the treatment period the following statistically significant differences (relative to the control group) were observed:
ALP: increased in males of the 750 mg/kg group and decreased in females of the 30 mg/kg group;
ASAT: increased in males and females of the 750 mg/kg group;
Albumin: increased in males of the 750 mg/kg group;
Albumin/globulin ratio: decreased in females of the 750 mg/kg group;
Urea: increased in males of the 750 mg/kg group;
Creatinine: increased in males of the 750 mg/kg group;
Total bilirubin: decreased in females of the 750 mg/kg group;
Cholesterol: increased in males of the 750 mg/kg group;
Phospholipids: increased in males of the 750 mg/kg group;
Chloride: increased in males of the 750 mg/kg group;
Potassium: decreased in males of the 750 mg/kg group.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Urinary pH and urinary crystals were statistically significantly increased in males and females of the 750 mg/kg group. Other semi-quantitative and microscopic urinary observations were similar among the groups. Urinary volume was statistically significantly increased and urinary density was statistically significantly decreased in males and females of the 750 mg/kg group.
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
In animals of the 750 mg/kg group, some statistically significant effects were observed during neurobehavioural testing at the end of the study in week 13. In males, increases in forelimb grip strength, landing footsplay and body temperature were measured, and a marginal effect was shown on click response. Hyperactivity was clearly observed in both males and females. The changes were considered related to treatment and toxicologically relevant.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The following organ weights were statistically significantly increased in the 750 mg/kg group:
Absolute (males and females) and relative (males) adrenal weights;
Absolute and relative kidney weights (males and females).

The following organ weights were statistically significantly decreased in the 750 mg/kg group:
Absolute and relative thymus weights (males and females);
Absolute and relative brain weights (females);
Absolute and relative spleen weight (males);
Absolute and relative epidydimidal weights.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment related changes were observed.
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
At microscopic examination, treatment related histopathological changes were observed in the brain. The treatment related histopathological changes in the brain consisted of loss of perikarya of neuronal cells in specific areas of the brain. All females and all but one male showed loss of perikarya in the pyramidal layer of the Hippocampus CA1/2. In addition, four males of the 750 mg/kg group demonstrated loss of perikarya in the piriform cortex, which was also considered related to treatment. The histopathological changes observed in the brain were not observed in any of the animals of the control, 30 or 150 mg/kg groups.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
At microscopic examination, treatment related histopathological changes were observed in the thymus. Six males of the 750 mg/kg group showed a decreased cortex/medulla ratio in the thymus. This change was also present in three females. Although the incidence in the females of the 750 mg/kg group was not statistically significantly higher than that in the controls, it was considered related to treatment because the thymic change was similar to that in the males. The decreased cortex/medulla ratio was characterised by a smaller cortex while the general architecture of the thymus was not changed. Decreased cortex/medulla ratio was not observed in any of the animals of the control, 30 or 150 mg/kg groups.
Histopathological findings: neoplastic:
no effects observed
Details on results:
NOAEL: Based on the changes in neurobehavioural parameters, haematology, clinical chemistry, urinalysis and organ weights and the associated histopathological findings in thymus and brain in animals of the 750 mg/kg group, the NOAEL in the sub-chronic toxicity study was placed at 150 mg trichloromethylstannane/kg diet (equivalent to 9.8 mg trichloromethylstannane/kg bw/day in males and 10.2 mg trichloromethylstannane/kg bw/day in females).
Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg diet
Sex:
male/female
Basis for effect level:
haematology
clinical biochemistry
urinalysis
behaviour (functional findings)
organ weights and organ / body weight ratios
neuropathology
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
750 mg/kg diet
System:
nervous system
Organ:
brain
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
The NOAEL for general sub-chronic toxicity and maternal toxicity, fertility and developmental effects was placed at 150 mg trichloromethylstannane per kg diet.
Executive summary:

The toxicity of trichloromethylstannane in Wistar rats was examined using continuous administration via the diet for 13 consecutive weeks (OECD Test Guideline 408). In satellite groups of female rats a reproduction/developmental screening test (OECD Test Guideline 421) was performed to provide initial data on possible reproductive and developmental effects of trichloromethylstannane. The main study used four groups of 10 rats/sex (13-week study) and the satellite study used four groups of 10 female rats (reproduction/developmental screening study). For both studies, the control group was kept on control diet and three test groups received experimental diets containing 30,150 and 750 mg/kg [ppm] of the test substance. The dose levels used in both studies were based on the results of a preceding dose range finding study.

 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.

The calculated doses for the groups receiving 30, 150, or 750 mg/kg trichloromethylstannane in the diet were 1.9, 9.8, and 49.7 mg/kg body weight/day in males and 2.1, 10.2, and 53.6 mg/kg body weight/day in females.

No treatment-related changes were observed in clinical signs, body weight, food conversion efficiency and ophthalmoscopy.

A number of haematological changes (statistically significant increases in RBC, Hb, PCV, MCV and MCH and decreases in thrombocytes, prothrombin time and eosinophilic leucocytes) observed in the 750 mg/kg group, were considered treatment-related and toxicologically relevant.

A number of clinical chemistry parameters (statistically significant increases in ALP, ASAT, albumin, urea, creatinin, cholesterol, phospholipids and chloride and a decreases in potassium) observed in the 750 mg/kg group, were considered treatment-related and toxicologically relevant.

The changes in urinary volume and density and in urinary pH and crystals observed in the 750 mg/kg group, were considered treatment-related and toxicologically relevant.

The changes in organ weights (increases in adrenal and kidney weights and decreases in thymus, brain, spleen and epidydimidal weights) observed in the 750 mg/kg group were considered treatment-related and toxicologically relevant.

The decrease in thymus weights was accompanied by a decrease in cortex/medulla ratio in the thymus of males and females, which was considered treatment-related and toxicologically relevant.

The treatment-related changes in neurobehavioural parameters (increased forelimb gripstrength, increased landing footsplay, increased body temperature and increased hyperactivity) are indicative of a neurotoxic potential of trichloromethylstannane. The neurobehavioural changes were corroborated by the treatment-related histopathological changes in the brain of most animals of the 750 mg/kg group. The observed histopathological lesion (loss of perikarya in the pyramidal layer of the Hippocampus CA1/2) was located in a functional domain that is generally consistent with the observed neurobehavioural changes and provides further evidence of the neurotoxic potential of the test substance at the 750 mg/kg level.

 Based on the changes in neurobehavioural parameters, haematology, clinical chemistry, urinalysis, organ weights and the associated histopathological findings in thymus and the brain in animals of the 750 mg/kg group, the No Observed Adverse Effect Level (NOAEL) in the sub-chronic toxicity study was placed at 150 mg Trichloromethylstannane/kg diet. This level was equivalent to 9.8 mg/ kg body weight/day in males and 10.2 mg/kg body weight/day for females. 

Based on the effects on body weight and food consumption in the 750 mg/kg group, 150 mg Trichloromethylstannanel kg diet (equivalent to 6.2-11.7 mg/kg body weight/day) can be considered as a NOAEL for maternal toxicity.

The NOAEL for general sub-chronic toxicity and maternal toxicity, fertility and developmental effects was placed at 150 mg trichloromethylstannane per kg diet.

Endpoint:
short-term repeated dose toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with Column 2 of REACH Annex VIII, information requirement 8.6.1, the short term toxicity study (28 days) does not need to be conducted if a reliable sub-chronic (90 days) or chronic study is available. A reliable sub-chronic toxicity study is available.
Critical effects observed:
not specified
Endpoint:
chronic toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
9.8 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
A subchronic guideline and GLP compliant key study is available on a suitable read across material, with supporting information in the form of a further 90 day guideline study on the same substance. The quality of the database is therefore considered to be good.
System:
nervous system
Organ:
brain

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Remarks:
Doses / Concentrations:

Basis:

Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Remarks:
Doses / Concentrations:

Basis:

Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Remarks:
Doses / Concentrations:

Basis:

Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Remarks:
Doses / Concentrations:

Basis:

Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The toxicity of trichloromethylstannane in Wistar rats was examined using continuous administration via the diet for 13 consecutive weeks (OECD Test Guideline 408). In satellite groups of female rats a reproduction/developmental screening test (OECD Test Guideline 421) was performed to provide initial data on possible reproductive and developmental effects of trichloromethylstannane. The main study used four groups of 10 rats/sex (13-week study) and the satellite study used four groups of 10 female rats (reproduction/developmental screening study). For both studies, the control group was kept on control diet and three test groups received experimental diets containing 30,150 and 750 mg/kg [ppm] of the test substance. The dose levels used in both studies were based on the results of a preceding dose range finding study.

 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.

The calculated doses for the groups receiving 30, 150, or 750 mg/kg trichloromethylstannane in the diet were 1.9, 9.8, and 49.7 mg/kg body weight/day in males and 2.1, 10.2, and 53.6 mg/kg body weight/day in females.

No treatment-related changes were observed in clinical signs, body weight, food conversion efficiency and ophthalmoscopy.

A number of haematological changes (statistically significant increases in RBC, Hb, PCV, MCV and MCH and decreases in thrombocytes, prothrombin time and eosinophilic leucocytes) observed in the 750 mg/kg group, were considered treatment-related and toxicologically relevant.

A number of clinical chemistry parameters (statistically significant increases in ALP, ASAT, albumin, urea, creatinin, cholesterol, phospholipids and chloride and a decreases in potassium) observed in the 750 mg/kg group, were considered treatment-related and toxicologically relevant.

The changes in urinary volume and density and in urinary pH and crystals observed in the 750 mg/kg group, were considered treatment-related and toxicologically relevant.

The changes in organ weights (increases in adrenal and kidney weights and decreases in thymus, brain, spleen and epidydimidal weights) observed in the 750 mg/kg group were considered treatment-related and toxicologically relevant.

The decrease in thymus weights was accompanied by a decrease in cortex/medulla ratio in the thymus of males and females, which was considered treatment-related and toxicologically relevant.

The treatment-related changes in neurobehavioural parameters (increased forelimb gripstrength, increased landing footsplay, increased body temperature and increased hyperactivity) are indicative of a neurotoxic potential of trichloromethylstannane. The neurobehavioural changes were corroborated by the treatment-related histopathological changes in the brain of most animals of the 750 mg/kg group. The observed histopathological lesion (loss of perikarya in the pyramidal layer of the Hippocampus CA1/2) was located in a functional domain that is generally consistent with the observed neurobehavioural changes and provides further evidence of the neurotoxic potential of the test substance at the 750 mg/kg level.

 Based on the changes in neurobehavioural parameters, haematology, clinical chemistry, urinalysis, organ weights and the associated histopathological findings in thymus and the brain in animals of the 750 mg/kg group, the No Observed Adverse Effect Level (NOAEL) in the sub-chronic toxicity study was placed at 150 mg Trichloromethylstannane/kg diet. This level was equivalent to 9.8 mg/ kg body weight/day in males and 10.2 mg/kg body weight/day for females. 

Based on the effects on body weight and food consumption in the 750 mg/kg group, 150 mg Trichloromethylstannanel kg diet (equivalent to 6.2-11.7 mg/kg body weight/day) can be considered as a NOAEL for maternal toxicity.

The NOAEL for general sub-chronic toxicity and maternal toxicity, fertility and developmental effects was placed at 150 mg trichloromethylstannane per kg diet.

14 -Day Range Finder Study, Swathi (2018)

A recent 14 -day repeated oral (dietary) toxicity study was performed, this study can aid the selection of doses for subsequent toxicity studies but is not sufficient alone to use for classification purposes:

The objective of this repeated oral (dietary) toxicity study was to generate information on health hazards likely to arise from repeated exposures to the test material for a period of two weeks to aid selecting doses for subsequent toxicity studies.

A total of 30 (15 males + 15 females) Sprague Dawley rats were distributed to five groups viz., Vehicle control (G1), Low dose (G2), Low-Mid dose (G3), High-Mid dose (G4) and High dose (G5). Each group consisted of 3 males and 3 females. The test material was admixture with powder diet and fed to rats at the doses of 250, 500, 750 and 1500 ppm. Control group rats were fed with basal diet throughout the treatment period without any test material.

All animals were observed once daily for clinical signs and twice daily for mortality. Body weight and feed consumption was measured at weekly intervals. At the end of the treatment period, blood and urine samples were collected and analysed. Subsequently, the animals were sacrificed and subjected to gross pathological examination and the organs were collected and preserved.

No mortality and clinical signs was observed throughout the experimental period. No treatment related changes in body weight, percent change in body weight with respect to day 1, feed consumption, haematology, clinical chemistry, urinalysis and organ weights (both absolute and relative) were observed.

There were no treatment related gross pathological changes observed at any of the tested doses in either sex during gross pathological examination.

Based on the results observed, it is concluded that the test material was well tolerated up to 1500 ppm in diet (males: 134.33 mg/kg/day and females: 132.36 mg/kg/day) and did not reveal any adverse changes when administered for a period of 15 consecutive days by oral (diet) route to Sprague Dawley rats under the experimental conditions employed. Hence, for the subsequent toxicity studies, dose levels up to 1500 ppm in diet (134.33 mg/kg/day for males/132.36 mg/kg/day for females) or above will be considered.

The sub-chronic toxicity study (90-day), oral route (EU B.26./OECD 408) as required by Decision number: CCH-D-2114373450-54-01/F has not been completed in time to allow the registration to be updated by the stipulated deadline of the 20th November 2018. As soon as the study is completed the dossier will be updated and this section amended as necessary.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance requires classification with respect to repeated dose toxicity as STOT rep. Category 2 (H373: May cause damage to organs through prolonged or repeated exposure).