Bis(dodecylthio)dioctylstannane

Endpoint summary

Description of key information

Read-across data: DOTI (CAS 26401 -97 -8)

- Rat 13 week oral study (1970)

Under the conditions of the study the 13 week oral no adverse effect level was found to be 150 ppm in male and female rats, the highest dose tested.

- Dog 14 week oral study (1970)

Under the conditions of the study the sub-chronic repeated dose oral no observed adverse effect level was 150 ppm in male and female beagle dogs, the highest dose level tested.

- Oral 30 days rat and dog (1963)

Under the conditions of the studies the NOAEL of the test material to male rats and dogs was 25 and 75 ppm, respectively.

Read-across data - Rat 13 week oral study (mixture DOTE:MOTE:TOTE, 97: 0.3: 2.7) (CAS No 15571 -58 -1, CAS 27107-89-7, CAS 61912-55-8)

The NOAEL was determined to be 10 ppm (equivalent to 0.5 mg/kg bw/day) and the LOAEL was determined to be 25 ppm (equivalent to 1.3 mg/kg bw/day) based on reduced thymus weight.

Read-across data - Rat 13 week oral study (mixture DOTE: MOTE. 70:30) (CAS No 15571-58-1 and CAS 27107-89-7)

The no effect level for the test material was determined to be 25 ppm (calculated as 1.25 mg/kg/day, based on a food factor of 0.05) based on reduced absolute and relative thymus gland weights.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

other: read-across target

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

no

Remarks:

This study pre-dates the inception of GLP

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: weanlings
- Weight at study initiation: Males: 92 to 100 g, females: 83 to 88 g
- Housing: Animals were housed individually in temperature-controlled quarters
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days

Route of administration:

oral: feed

Vehicle:

acetone

Details on oral exposure:

DIET PREPARATION
- The test material was mixed in the diet by adding (for each level) a 50 mL aliquot of an appropriately prepared acetone solution to six kilograms of basal ration; and mechanically mixing for eight minutes. The acetone evaporated in the process.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Continuous in diet

Dose / conc.:

150 ppm

Dose / conc.:

50 ppm

Dose / conc.:

20 ppm

Dose / conc.:

0 ppm

No. of animals per sex per dose:

15 animals per sex per dose

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

OBSERVATIONS: Yes
- Time schedule: behaviour and appearance were observed daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
- Haemoglobin, haematocrit, coagulation time, thrombocyte count, and total and differential leucocyte counts, were determined on five males and five females each from the control and 150 ppm groups at 4, 8 and 13 weeks.

CLINICAL CHEMISTRY: Yes
- Clinical chemistry determinations, consisting of blood glucose; prothrombin time and serum glutamic-pyruvic transaminase, were made on five males and five females each from the same groups and at the same intervals as were the haemograms.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- At termination all rats were sacrificed by guillotine and a gross autopsy was performed on each.
- Except for eyes; which were fixed in Zenker's solution, the following organs (or portions thereof) were preserved in 10 per cent formalin for histopathological examination; liver, kidneys, heart, spleen, lungs, adrenals, thyroid, pituitary, gonads, uterus or prostate, mesenteric lymph node, stomach, small intestine, pancreas, urinary bladder, brain, bone marrow and skeletal muscle. (Underscored organs were weighed.)
- Of these organs, the following were weighed: liver, kidneys, heart, spleen, lungs, adrenals, thyroid, pituitary, gonads and uterus or prostate.

HISTOPATHOLOGY: Yes
- Histopathological examinations were made on all the tissues listed above from five rats per sex from the control and 150 ppm groups and from eight tissues (liver, kidneys, adrenals, thyroid, pituitary and gonads) from five rats per sex in each of the other two groups.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

-All animals remained in good physical condition with slight exception.
- A few instances of soft stool were observed for both control and compound-treated rats.
-One instance of urine stains was noted at the 150 ppm level and two at the 20 ppm level, at various weeks.
-One female animal at the 50 ppm level had swelling around the throat and neck during week 13.

Mortality:

no mortality observed

Description (incidence):

None of the rats on the study died

Body weight and weight changes:

no effects observed

Description (incidence and severity):

- Treated and control rats had comparable rates of body weight gain.
- At week 13, the means of the compound-treated groups were 98 to 103 % of those of the control rats.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Inspection of the weekly mean food intake values showed control and treated groups to be comparable in this respect.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

- The haemograms for both male and female rats in the high-level group were comparable to those of the controls at 4, 8 and 13 weeks with slight exception.
- There were elevated thrombocyte counts for four males at the 150 ppm level at four weeks (only), and slightly lowered total leucocyte counts for rats of both sexes in the 150 ppm level at 8 and 13 weeks. Neither the pattern nor the degree of these changes appeared to be related to compound administration.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

- Clinical chemistry values were within normal ranges in rats of both the control and 150 ppm groups.
- Some high serum glutamic-pyruvic transaminase figures in the controls at 13 weeks were not substantiated by repetition of the assays. Means at this interval, when computed with regard to the repeat values, were comparable to those of the high-level group.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

- No dose-related differences between groups were seen in the various mean weights, either in actual or relative weights.
- The somewhat lower mean prostate weight for the 150 ppm males was not significantly different from the control figure when tested by the Rank Sum method.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The following observations were made from the gross necropsy:
- Control animals: Kidneys: speckled with white spots (1M), Liver: one lobe attached to diaphragm (1M) and Liver: small, yellowish-white granular mass on one lobe (1M).
- 150 ppm: Testis: one small and non-pliable (1M) and uterus: fluid-filled (1F)
- 50 ppm: Seminal vesicles: small (1M), Colon: hard with red spot (1M), Uterus: fluid-filled (1F), Salivary gland: enlarged (1F) and Ovary: cyst on left ovary (1F).
- 20 ppm: Lung: red spots on lobes (1M and 1F), Kidney: one has granular appearance (1M) and uterus: fluid-filled (1F).

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No distinctions could be made between treated and control groups and no effects of test material administration were detected.

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

> 150 ppm

Based on:

test mat.

Sex:

male/female

Conclusions:

Under the conditions of this study the 13 week oral no adverse effect level was found to be 150 ppm in male and female rats, the highest dose tested.

Executive summary:

The repeated dose toxicity of the test material was investigated in a study similar to OECD 408, where male and female Sprague Dawley rats were fed the test material for 13 weeks.

Fifteen animals per sex per dose were fed the test material in their diets at 0, 20, 50 and 150 ppm for 13 weeks. Following the dosing period animals were sacrificed and gross necropsy was performed.

There were no mortalities in any animals during the study. Treated and control rats had comparable rates of body weight gain at the end of the study. Inspection of the weekly mean food intake values showed control and treated groups to be comparable. All animals remained in good physical condition with slight exceptions of soft stools and urine staining. No observed haematological changes appeared to be related to test material administration and all clinical chemistry values were comparable to control groups. No dose-related differences between groups were seen in the various mean organ weights, either in actual or relative weights. No findings at gross necropsy were shown to be treatment related.

Under the conditions of this study the 13 week oral no adverse effect level was found to be 150 ppm in male and female rats, the highest dose tested.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

other: read-across target

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

GLP compliance:

no

Remarks:

This study pre-dates the inception of GLP

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 7 to 14 months
- Weight at study initiation: Females: 7.6 to 8.8 kg, Males: 8.4 to 9.6 kg
- Housing: animals were housed in individual cages in temperature controlled quarters.
- Diet: Food, consisting of 200 g baked dog meal and 71 g of canned chopped beef, mixed with water fir palatability was offered to each dog seven days per week.
- Water: ad libitum
- Acclimation period: minimum of 4 weeks
- Animals were immunised against distemper, hepatitis, leptospirosis and rabies and treated with appropriate anthelmentics.

Route of administration:

oral: feed

Vehicle:

acetone

Details on oral exposure:

DIET PREPARATION
- Treated diet was prepared by adding a 100 mL aliquot of acetone solution of test material to 6000 g of dry dog meal and mixing in a Hobart-Dayton mixer for 20 minutes. The acetone evaporated in the process.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

14 weeks

Frequency of treatment:

Food containing the test material was offered to the animals every day.

Dose / conc.:

150 ppm

Dose / conc.:

50 ppm

Dose / conc.:

20 ppm

Dose / conc.:

0 ppm

No. of animals per sex per dose:

3 animals per sex per dose

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- General condition, behaviour, physical activity and stool consistency

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the study and on days 2, 4 and during the first week and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Measured daily

OPHTHALMOSCOPIC EXAMINATION: Yes
- Eye examinations, which included direct and indirect ophthalmoscopy, to detect changes in intraocular tension, conjunctivae, eyelids, cornea, pupillary reflex, aqueous humour, iris, lens, vitreous humour, and fundus or sclera, were made on each dog initially and at termination.

HAEMATOLOGY: Yes
- Haemograms consisting of haemoglobin, haematocrit, sedimentation rates, coagulation time, thrombocyte count and total and differential leucocyte counts were determined on all animals twice initially and at 4, 8, and 13 weeks.

CLINICAL CHEMISTRY: Yes
- Clinical chemistry determinations of blood urea nitrogen; serum alkaline phosphatase, blood glucose, prothrombin time, serum glutamic-pyruvic transaminase, and serum glutamic-oxalacetic transaminase were performed initially and at 4, 8, and 13 weeks.

URINALYSIS: Yes
- Qualitative urinalyses, made on cage-collected specimens and that included general appearance, pH, albumin, sugar, specific gravity, and microscopic examination of urinary sediment, were performed initially and at 4, 8, and 13 weeks.

OTHER:
- At 0, 4, 8, and 13 weeks blood pressures were taken using a small cuff and an Infraton condenser microphone taped to the underside of the tail, and connected to a cathode ray oscilloscope.
- Electrocardiograms (lead II) were taken at these same time intervals. Heart rates were measured from the electrocardiogram tracings.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- After 14 weeks on study, all dogs were weighed, sacrificed with sodium pentobarbital intravenously, exsanguinated, and autopsied. Gross pathological observations were recorded.
- The following organs were weighed: heart, lungs, liver, kidneys, spleen, thyroid, adrenals, prostate or uterus, gonads, pituitary and brain.

HISTOPATHOLOGY: Yes
- Except for eyes, which were saved in Zenker's fixative, the following tissues or portions thereof were preserved in 10 per cent formalin for histopathological examinations heart, lungs, liver, kidneys, spleen, thyroid, adrenals, prostate or uterus, gonads, pituitary, brain, peripheral nerve, oesophagus, duodenum, jejunum, ileum, colon, cecum, stomach, pancreas, parotid gland, thymus, trachea, gall bladder, intercostal muscle, urinary bladder, mesenteric lymph node, bone marrow, spinal cord, mammary gland, and skin.
- Microscopic examination of all of these tissues from all control and high-level dogs was carried out. In addition, a selection of tissues (eyes, heart, liver, kidneys, thyroid, adrenals, gonads, pituitary, pancreas, urinary bladder, mesenteric lymph node and bone marrow) were examined for dogs in the middle and low-level groups

Clinical signs:

no effects observed

Description (incidence and severity):

All animals maintained good physical condition throughout the study.

Mortality:

no mortality observed

Description (incidence):

All dogs survived the duration of the experiment.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

- Dogs receiving the test material in their diet could not be distinguished from control dogs on the basis of body weight change with but one exception.
- A decline of 1.0 kilogram from initial body weight was observed for one male treated at 50 ppm, at 14 weeks. This represented a loss of 7.5 % of initial weight.
- Mean body weights can be seen in Table.1.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption of the dogs receiving the test material in their diet was comparable to that of the controls. Except for occasional isolated instances, all dogs ate all of their daily ration throughout the study.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

effects observed, non-treatment-related

Description (incidence and severity):

- Ophthalmic examinations were negative except for one animal. One low-level male exhibited a surface lesion on the cornea of the right eye at week four. This had disappeared by week 8 and was probably due to a cage injury.
- One control male, had bilateral nuclear cataracts that were seen in the 0-interval examination and did not change throughout the study.

Haematological findings:

no effects observed

Description (incidence and severity):

Haemograms showed no meaningful differences between treated and untreated dogs.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

- Biochemical determinations showed no differences between treated and untreated dogs with slight exception.
- 1 male animal treated at 150 ppm had elevated serum alkaline phosphatase values at weeks 4, 8, and 13. One female from the same group also had increased serum levels of this enzyme at 8 and 13 weeks.

Urinalysis findings:

no effects observed

Description (incidence and severity):

Qualitative urinalyses on cage-collected samples showed treated and control animals to be comparable.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

- No clearly dose-related differences between the various mean organ weights were seen.
- A large mean uterus weight of the high-dose group was related to one dog that was noted to be in oestrus at sacrifice, and possibly to a second animal that had been in oestrus four weeks previously.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

- Gross necropsy revealed no changes which could be ascribed to administration of the test material.
- The one juvenile testis (weight 203 g) found in a male treated at 50 ppm was noted in the pre-study physical examination. One male animal at 20 ppm had a bifurcation of the trachea. No other gross changes were recorded.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

- The appearance of the tissues examined were those commonly seen in untreated dogs. No effects of test material administration were detected.

Histopathological findings: neoplastic:

not examined

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

- Blood pressure determinations showed no distinction between treated and control dogs.
- Electrocardiograms (lead II) recorded at the same intervals as the blood pressure determinations showed no recognised changes beyond sinus arrhythmias and inverted T-waves characteristically seen in the dog. Heart rates measured from the electrocardiograms were comparable for treated and control dogs.

Key result

Dose descriptor:

NOAEL

Effect level:

150 ppm

Based on:

test mat.

Sex:

male/female

Table 1: Mean bodyweights during the study

Dose level (ppm)	Mean bodyweights in kg
	Week
	0	4	8	13
Males
Control	8.6	9.0	8.9	8.8
150	8.4	9.2	9.3	9.1
50	9.3	9.5	9.5	9.3
20	9.6	10.4	10.4	10.1
Females
Control	8.8	9.3	9.1	8.9
150	8.5	8.8	8.8	8.3
50	7.6	7.7	8.2	7.9
20	8.3	8.5	8.7	8.2

 

Conclusions:

Under the conditions of the study the sub-chronic repeated dose oral no observed adverse effect level was 150 ppm in male and female beagle dogs, the highest dose level tested.

Executive summary:

The repeated dose oral toxicity of the test material was investigated in a study similar to OECD 409, using male and female beagle dogs.

Three animals per sex per dose were treated with the test material at 0, 20, 50 and 150 ppm in their diet for 14 weeks. Observations and measurements of the following were taken during the dosing period: body weights, general condition, physical activity and behaviour, food consumption, urine analysis, haematology, clinical biochemistry, blood pressure and heart rates. Gross pathological observations were recorded following sacrifice after the dosing period.

All dogs survived the duration of the experiment and maintained good physical condition throughout. Weekly body weights were in-line with the control groups with the exception of one animal. Food consumption of the dogs receiving the test material in their diet was comparable to that of the controls. Haemograms showed no meaningful differences between treated and untreated dogs. Qualitative urinalyses on cage-collected samples showed treated and control animals to be comparable in this respect also. Two dogs in the high-level group (150 ppm) had elevated serum alkaline phosphatase values during the study, although no histopathological changes were seen to correlate with this.

No clearly test material dose-related differences between the various mean organ weights were seen or in the appearance of the tissues examined.

Under the conditions of the study the sub-chronic repeated dose oral no observed adverse effect level was 150 ppm in male and female beagle dogs, the highest dose level tested.

Reference 3

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

other: read-across target

Qualifier:

no guideline followed

Principles of method if other than guideline:

10 male rats per dose were treated with the test material at the following concentrations: 25, 75 and 225 ppm. The test material was administered to the animals in their diet for 30 continuous days. The animals were observed for general behaviour and condition. Animals were weighed twice weekly and gross pathology was performed following the dosing period.

GLP compliance:

no

Remarks:

This study pre-dates the inception of GLP.

Limit test:

no

Species:

rat

Strain:

Long-Evans

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 150 to 300 g
- Housing: animals were housed individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: ‘several days’

Route of administration:

oral: feed

Vehicle:

other: ether

Details on oral exposure:

DIET PREPARATION
- The test material (liquid) was weighed and dissolved in ether. This solution was sprayed over a weighed amount of the animal food which was then mixed together with a rotating mixer.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

30 days

Frequency of treatment:

Continuously available in their diet.

Dose / conc.:

25 ppm

Remarks:

(based on an intake of 20 g diet per rat per day)

Dose / conc.:

75 ppm

Remarks:

(based on an intake of 20 g diet per rat per day)

Dose / conc.:

225 ppm

Remarks:

(based on an intake of 20 g diet per rat per day)

No. of animals per sex per dose:

10 male animals per dose

Control animals:

yes, plain diet

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Organ weights were obtained for organ-body weight ratios

HISTOPATHOLOGY: Yes
- Sections of appropriate tissues were preserved in formalin for later microscopic study were this deemed appropriate

Clinical signs:

no effects observed

Description (incidence and severity):

- Rats at the highest doses refused to eat initially, but they generally accepted their diets after a few days.
- No unusual behaviour patterns were noted.

Mortality:

no mortality observed

Description (incidence):

No animals died during dosing with the test material.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

- None of the experimental groups differed significantly in their weight gain from the controls.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

- Brain to body weight ratio was significantly higher in the middle and high dose groups (75 and 225 ppm).
- Liver to body weight ratio was significantly higher in the middle dose group (75 ppm).
- Kidney ratios were higher in the high dose group (225 ppm)

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

- Kidney effects were seen at the high dose level (225 ppm). Affected kidneys seemed flabby; there were dilated pelvis’ which were sometimes filled with fluid.
- Distended bladders were also seen frequently.
- In addition, a peculiar pigmentation or discolouration was noted in the temporal brain lobe of many of the rats.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

25 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

Conclusions:

Under the conditions of this study the 30 day repeated dose NOAEL of the test material to rats was 25 ppm.

Executive summary:

The short term repeated dose oral toxicity of the test material to male rats was investigated in a 30 day study.

10 male rats per dose were treated with the test material at the following concentrations: 25, 75 and 225 ppm. The test material was administered to the animals in their diet for 30 continuous days. The animals were observed for general behaviour and condition. Animals were weighed twice weekly and gross pathology was performed following the dosing period.

Animals accepted their diets after a few days and no unusual behaviour patterns were noted. None of the experimental groups differed significantly in their weight gain from the controls.

Brain to body weight ratio was significantly higher in the middle and high dose groups (75 and 225 ppm). Liver to body weight ratio was significantly higher in the middle dose group (75 ppm). Kidney effects were seen at the high dose level (225 ppm). Affected kidneys seemed flabby; there were dilated pelvis’ which were sometimes filled with fluid. Distended bladders were also seen frequently. In addition, a peculiar pigmentation or discolouration was noted in the temporal brain lobe of many of the rats.

Under the conditions of this study the NOAEL of the test material to male rats was 25 ppm.

Reference 4

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

other: read-across target

Qualifier:

no guideline followed

Principles of method if other than guideline:

Two male dogs per dose were treated with the test material at the following concentrations: 25, 75, 225 and 675 ppm. The test material was administered to the animals in the form of a capsule, via a balling gun, daily for 30 continuous days. The animals were observed for general behaviour and condition. Animals were weighed weekly, blood collection was carried out for analysis and gross pathology was performed following the dosing period.

GLP compliance:

no

Limit test:

no

Species:

dog

Strain:

other: Mongrels

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 6 to 12 kg
- Housing: Dogs were housed two to a cage in indoor-outdoor runs
- Diet: fed once per day around the time of capsule administration

Route of administration:

oral: capsule

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
- The test material was suspended in corn oil in appropriate proportions so that capsules contained 0.5 or 1.0 mL.
- All capsules were the same size.
- Capsules were administered by a balling gun.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

30 days

Frequency of treatment:

Daily

Dose / conc.:

25 ppm

Dose / conc.:

75 ppm

Dose / conc.:

225 ppm

Dose / conc.:

675 ppm

No. of animals per sex per dose:

2 male animals per dose (4 males in the control group)

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
- Blood was collected from each dog for the purpose of haemoglobin, packed cell volume, white blood cell and differential determinations.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- Animals were sacrificed by exsanguination under pento-barbital anaesthesia, and posted. Organ weights were obtained for organ-body weight ratios, and sample tissues were preserved in formalin.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

- Dogs remained alert and active for the most part except those who became extremely emaciated.
- Some dogs were somewhat irritable and objected to the capsules, but were otherwise friendly.
- Dogs that died were moderately to extremely emaciated and lethargic for several days preceeding death. Some also had eye and nasal secretions.

Mortality:

mortality observed, treatment-related

Description (incidence):

- 1/2 dogs died in the second highest dose group (225 ppm) on day 14.
- 1/2 dogs died in the highest dose group (675 ppm) on day 29.
- Dogs that died were moderately to extremely emaciated and lethargic for several days preceding death. Some also had eye and nasal secretions.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

- Practically all dogs, including controls, either showed no weight gain, or actually lost weight during the month of the experiment. However, there was a wide variation in size and age of the animals.
- Though the animals were deloused and wormed, undoubtedly tape worm re-infestations occurred. This could partly account for the lack of weight gain.
- Weight loss was not found to be significant but this could be due to small numbers in the sample.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

The haemoglobin, packed cell volume, and differential data were not analysed statistically because the values were fairly uniform throughout the various groups.

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

- Many of the organ-body weight ratios were considerably varied but not significantly different, due to the small number in the sample.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

- Post-mortem examination indicated some pathology in three out of four of the controls, including ascites and kidney, liver and bladder conditions. It is therefore difficult to ascribe to the ingestion of the test material the pathology seen among the other groups; with the exception of fat depletion which did not occur in the controls.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

75 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

mortality

Conclusions:

Under the conditions of this study the 30 day repeated dose NOAEL of the test material to male dogs was 75 ppm.

Executive summary:

The short term repeated dose oral toxicity of the test material to male dogs was investigated in a 30 day study.

Two male dogs per dose were treated with the test material at the following concentrations: 25, 75, 225 and 675 ppm. The test material was administered to the animals in the form of a capsule, via a balling gun, daily for 30 continuous days. The animals were observed for general behaviour and condition. Animals were weighed weekly, blood collection was carried out for analysis and gross pathology was performed following the dosing period.

One of two dogs died in the highest and second highest dose groups (675 and 225 ppm) on days 29 and 14, respectively. Dogs that died were moderately to extremely emaciated and lethargic for several days preceding death. Some also had eye and nasal secretions. Practically all dogs, including controls, either showed no weight gain, or actually lost weight during the month of the experiment. However, there was a wide variation in size and age of the animals. Though the animals were deloused and wormed, undoubtedly tape worm re-infestations occurred. This could partly account for the lack of weight gain. The haemoglobin, packed cell volume, and differential data were not analysed statistically because the values were fairly uniform throughout the various groups.

Many of the organ-body weight ratios were considerably varied but not significantly different, due to the small number in the sample. Post-mortem examination indicated some pathology in three out of four of the controls, including ascites and kidney, liver and bladder conditions. It is therefore difficult to ascribe to the ingestion of the test material the pathology seen among the other groups; with the exception of fat depletion which did not occur in the controls.

Under the conditions of this study the NOAEL of the test material to male dogs was 75 ppm.

Reference 5

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Raw data (histopathological, biochemical, hematological, ophthalmologic, body weight gain, and food consumption) not provided.

Reason / purpose for cross-reference:

other: read-across target

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

Some limitations

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 120 - 142 g
- Fasting period before study: no data
- Housing: Animals were caged in groups of five
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2 °C
- Humidity (%): 50 ± 10%.
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Treated diets were prepared weekly.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

continuously

Dose / conc.:

25 ppm

Remarks:

1.6 mg/kg bw/day

Dose / conc.:

50 ppm

Remarks:

3.3 mg/kg bw/day

Dose / conc.:

100 ppm

Remarks:

6.6 mg/kg bw/day

No. of animals per sex per dose:

Four groups of 40 rats (20 male/20 female) 

Control animals:

yes, concurrent no treatment

Details on study design:

Post-exposure period: 30 days

Positive control:

no

Observations and examinations performed and frequency:

Blood and urine samples for hematology and biochemistry were collected during weeks 5, 9, and 13. Clinical symptoms of toxicity were recorded daily, and body weights and food consumption were recorded weekly. An ophthalmic examination was conducted pre-exposure and in rats from the 25 and 100 ppm dose groups, during weeks 5, 9, and 13.

Sacrifice and pathology:

The following organs were weighed at necropsy: adrenals, kidneys, brain, liver, heart, gonads, and thymus.  
The following organs and tissues were collected for histopathological examination: adrenals, brain, gonads, kidneys, lymph nodes, muscle, pituitary, spleen, thymus, aorta, colon, gross lesions, liver, pancreas, prostate, uterus, spinal cord, thyroids, bone marrow, eye, heart, lungs, mammary gland, sciatic nerve, small intestine, stomach, and urinary bladder.

Other examinations:

no

Statistics:

no data

Clinical signs:

no effects observed

Description (incidence and severity):

No deaths occurred and no clinical symptoms of toxicity were recorded.

Mortality:

no mortality observed

Description (incidence):

No deaths occurred and no clinical symptoms of toxicity were recorded.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

There was a significant dose-related reduction in absolute and relative thymus gland weights in the 50 ppm (3.3 mg/kg) and 100 ppm (6.6 mg/kg) dose groups.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

Body weight gains, food consumption, clinical chemistry, and urine analysis for treated rats were comparable to the control group. Ophthalmic examination did not reveal any abnormalities in treated rats.
The no effect level was determined to be 25 ppm (calculated as 1.25 mg/kg/day, based on a food factor of 0.05).

Dose descriptor:

NOAEL

Effect level:

25 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

other: At 50 and 100 ppm : significant dose-related reduction in absolute and relative thymus gland weights. 25 ppm is equivalent to 1.25 mg/kg/day, based on a food factor of 0.05.

Critical effects observed:

not specified

Conclusions:

The no effect level for DOT(2-EHMA) was determined to be 25 ppm (calculated as 1.25 mg/kg/day, based on a food factor of 0.05) based on reduced absolute and relative thymus gland weights.

Executive summary:

A repeated dose oral toxicity test was carried out with a Dioctyltin bis(2-EHMA) [CAS No. 15571-58-1]:Octyltin tris(2-EHMA) [CAS No. 27107-89-7] (70:30% mixture). The test material was dosed via the diet. The test material homogeneity and stability was not determined. Effects on the thymus weight were observed. The no effect level  for DOT(2-EHMA) was determined to be 25 ppm (calculated as 1.25 mg/kg/day, based on a food factor of 0.05) based on reduced absolute and relative thymus gland weights.

Reference 6

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

No information on the homogeneity or stability of the test substance in the diet was provided.

Reason / purpose for cross-reference:

other: read-across target

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

some limitations

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: Test animals were housed in groups of 5
- Diet (e.g. ad libitum): not precised, ad libitum
- Water (e.g. ad libitum): not precised, ad libitum
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24°C
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

In the first experiment, groups of 30 weanling Wistar rats (CIVO-colony) (15 rats/sex/group) were exposed to the test substance, administered in the diet, at dose levels of 0, 100, 500, and 1000 ppm. Due to excessive mortality at 1000 ppm, a second experiment was initiated.
Groups of rats (15 per sex) were exposed to dose levels of 0, 50, and 250 ppm test substance in the diet. In a third experiment, groups of rats were exposed to 10 and 25 ppm of the test substance in the diet.

The test diets were prepared every two weeks and stored at room temperature. The test substance was thoroughly mixed in the stock diet.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

continuously

Remarks:

Doses / Concentrations:
100, 500, and 1000 ppm (experiment 1)
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
50 and 250 ppm (experiment 2)
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
10 and 25 ppm (experiment 3)
Basis:
nominal in diet

No. of animals per sex per dose:

15 rats/sex/group (experiment 1,2 and 3)

Control animals:

yes, concurrent no treatment

Details on study design:

no

Positive control:

no

Observations and examinations performed and frequency:

Body weights were recorded weekly. Food intake (by group) was determined during the exposure period. Food efficiency was calculated over the first four weeks of exposure. Water consumption (by group) was determined during the first week of exposure. Blood samples were collected in weeks 6 and 12.

Hematological data included hemoglobin content, packed cell volume, red blood cell counts, and total and differential white blood cell counts. Biochemical data collected terminally included blood sugar, blood urea nitrogen (BUN), serum glutamic-pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), serum alkaline phosphatase (SAP), and total serum protein (TSP).
Kidney function was examined by determining glutamic oxaloacetic transaminase (UGOT) in the urine and urine protein.
Urine samples were collected, pooled by treatment level, and examined for appearance, pH, glucose, albumin, occult blood, ketones, and microscopy of the sediment.

Sacrifice and pathology:

At the end of the experimental period, animals were sacrificed and examined macroscopically for pathological changes. In the first experiment, the water content of the brain was determined in 10 rats (5 per sex) from each treatment group. In the second experiment, the tin content of pooled samples of the liver, kidneys, and testicles of 10 rats of each treatment group was determined.

Detailed microscopic examination of organs and tissues in the first experiment (control and 500 ppm groups) included: lungs, trachea, pancreas, salivary glands (parotid, submaxillary, and sublingual), prostate, epididymis, uterus, coagulating gland, seminal vesicle, thoracic aorta, stomach, duodenum, ileum, cecum, colon, mesenteric and axillary lymph nodes, urinary bladder, skeletal muscle, spinal cord, femoral nerve, sternum with marrow, exorbital lachrymal glad, preputial gland, and skin. Microscopic examination of rats in the 100 ppm group was limited to the liver, kidneys, spleen, thymus, lymph nodes, heart, and testicles. Animals that died before the end of the exposure period were not examined pathologically.
In the second experiment, microscopic examinations of all groups were limited to the liver, kidney, spleen, thymus, and lymph nodes.

Other examinations:

no

Statistics:

no data

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Description (incidence):

Mortality occurred at 250, 500, and 1000 ppm.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights and food intake were reduced at 250, 500, and 1000 ppm.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Mean body weights and food intake were reduced at 250, 500, and 1000 ppm.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Hemoglobin content and white blood cell counts were slightly decreased at 250 and 500 ppm. There was a considerable increase in the number of neutrophils and leukocytes, and a decrease in the number of lymphocytes at ≥ 100 ppm.

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

There were minimal to moderate changes in the microscopic findings in urine. Specific gravity of the urine was decreased and UGOT levels were increased at 500 ppm. Specific gravity of the urine of females at 100 ppm was decreased. SAP levels were significantly increased at ≥ 100 ppm. Glucose levels were decreased at 500 ppm and BUN levels were increased in males at 500 ppm. SGPT levels for males and females were increased at 500 and 100 ppm, respectively.

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

There was no increase in water content of the brain. Relative liver and kidney weights were slightly increased at ≥ 100 ppm. Relative thymus weights were reduced at >=25 ppm. The relative weights of the heart (females), brain (both sexes), and gonads (males) were significantly increased at 500 ppm. The increase in relative weight of the liver was not dose-dependent. The relative weights of the brain and the testicle showed an inverse relationship with body weights. The relative spleen weight was slightly increased in some dose groups. Treatment-related gross pathological changes observed included a reduction in thymus size at ≥ 100 ppm. The number of lymphocytes in the thymus were depleted at ≥ 100 ppm.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

There was no increase in water content of the brain. Relative liver and kidney weights were slightly increased at ≥ 100 ppm. Relative thymus weights were reduced at ≥ 25 ppm. The relative weights of the heart (females), brain (both sexes), and gonads (males) were significantly increased at 500 ppm. The increase in relative weight of the liver was not dose-dependent. The relative weights of the brain and the testicle showed an inverse relationship with body weights. The relative spleen weight was slightly increased in some dose groups. Treatment-related gross pathological changes observed included a reduction in thymus size at ≥ 100 ppm. The number of lymphocytes in the thymus were depleted at ≥ 100 ppm.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

Other changes observed included signs of chronic respiratory disease, unilateral hydronephrosis, and proteinaceous plugs in the urinary bladder; however, the latter are commonly found in the strain of rats tested and, therefore, may not be related to exposure to the test substance. Treatment-related histological lesions in the liver and kidneys ranged from minimal (250 ppm) to moderate (500 and 1000 ppm).

The no-observable-adverse-effect-level (NOAEL) was determined to be 10 ppm in the diet (equivalent to 0.5 mg/kg/bw/day) of rats exposed for 90 days, on the basis of reduced thymus weight at 25 ppm. Based on these findings, the lowest-observable-adverse-effect level (LOAEL) was determined to be 25 ppm in the diet (calculated as 1.07-1.24 mg/kg bw/day in males and 1.46-1.51 mg/kg bw/day in females). Calculation of dosage was performed using body weights of 0.34 kg (males) and 0.2 kg (females), and average food consumption of 14.6-16.8 g/rat/day (males) and 11.7-12.1 g/rat/day (females).

Key result

Dose descriptor:

NOAEL

Effect level:

10 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

other: reduced thymus weight (10 ppm is equivalent to 0.5 mg/kg/bw/day)

Critical effects observed:

not specified

Conclusions:

The NOAEL for DOT(2-EHMA) was determined to be 10 ppm (equivalent to 0.5 mg/kg bw/day) based on reduced thymus weight.

Executive summary:

A repeated dose oral toxicity study was carried out with rats and a mixture of Dioctyltin bis(2-EHMA) [CAS No. 15571-58-1]:Octyltin tris(2-EHMA) [CAS No. 27107-89-7]: Trioctyltin (2-EHMA) [CAS No. 61912-55-8] (97.0:0.3:2.17% mixture). The study predates GLP, but is well documented and quality assurance is comparable. No information on the homogeneity or stability of the test substance in the diet was provided, due to which the study was considered less reliable. The NOAEL was determined to be 10 ppm (equivalent to 0.5 mg/kg bw/day) and the LOAEL was determined to be 25 ppm (equivalent to 1.3 mg/kg bw/day) based on reduced thymus weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

System:

immune system

Organ:

thymus

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

Read-across data: DOTI (CAS 26401 -97 -8)

- Oral 13 week rat (1970)

The repeated dose toxicity of the read across substance, DOTI, was investigated in a study similar to OECD 408, where male and female Sprague Dawley rats were fed the test material for 13 weeks. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

During the study, fifteen animals per sex per dose were fed the test material in their diets at 0, 20, 50 and 150 ppm for 13 weeks. Following the dosing period animals were sacrificed and gross necropsy was performed.

There were no mortalities in any animals during the study. Treated and control rats had comparable rates of body weight gain at the end of the study. Inspection of the weekly mean food intake values showed control and treated groups to be comparable. All animals remained in good physical condition with slight exceptions of soft stools and urine staining. No observed haematological changes appeared to be related to test material administration and all clinical chemistry values were comparable to control groups. No dose-related differences between groups were seen in the various mean organ weights, either in actual or relative weights. No findings at gross necropsy were shown to be treatment related.

Under the conditions of this study the 13 week oral no adverse effect level was found to be 150 ppm in male and female rats, the highest dose tested.

- Oral 14 week dog (1970)

The repeated dose oral toxicity of the read across substance, DOTI, was investigated in a study similar to OECD 409, using male and female beagle dogs. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

During the study, three animals per sex per dose were treated with the test material at 0, 20, 50 and 150 ppm in their diet for 14 weeks. Observations and measurements of the following were taken during the dosing period: body weights, general condition, physical activity and behaviour, food consumption, urine analysis, haematology, clinical biochemistry, blood pressure and heart rates. Gross pathological observations were recorded following sacrifice after the dosing period.

All dogs survived the duration of the experiment and maintained good physical condition throughout. Weekly body weights were in-line with the control groups with the exception of one animal. Food consumption of the dogs receiving the test material in their diet was comparable to that of the controls. Haemograms showed no meaningful differences between treated and untreated dogs. Qualitative urinalyses on cage-collected samples showed treated and control animals to be comparable in this respect also. Two dogs in the high-level group (150 ppm) had elevated serum alkaline phosphatase values during the study, although no histopathological changes were seen to correlate with this.

No clearly test material dose-related differences between the various mean organ weights were seen or in the appearance of the tissues examined.

Under the conditions of the study the sub-chronic repeated dose oral no observed adverse effect level was 150 ppm in male and female beagle dogs, the highest dose level tested.

- Oral 30 days rat (1963)

The short term repeated dose oral toxicity of the read across substance, DOTI, to male rats was investigated in a 30 day study. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

During the study, 10 male rats per dose were treated with the test material at the following concentrations: 25, 75 and 225 ppm. The test material was administered to the animals in their diet for 30 continuous days. The animals were observed for general behaviour and condition. Animals were weighed twice weekly and gross pathology was performed following the dosing period.

Animals accepted their diets after a few days and no unusual behaviour patterns were noted. None of the experimental groups differed significantly in their weight gain from the controls.

Brain to body weight ratio was significantly higher in the middle and high dose groups (75 and 225 ppm). Liver to body weight ratio was significantly higher in the middle dose group (75 ppm). Kidney effects were seen at the high dose level (225 ppm). Affected kidneys seemed flabby; there were dilated pelvis’ which were sometimes filled with fluid. Distended bladders were also seen frequently. In addition, a peculiar pigmentation or discolouration was noted in the temporal brain lobe of many of the rats.

Under the conditions of this study the NOAEL of the test material to male rats was 25 ppm.

Oral 30 days dog (1963)

The short term repeated dose oral toxicity of the read across substance, DOTI, to male dogs was investigated in a 30 day study. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

During the study, two male dogs per dose were treated with the test material at the following concentrations: 25, 75, 225 and 675 ppm. The test material was administered to the animals in the form of a capsule, via a balling gun, daily for 30 continuous days. The animals were observed for general behaviour and condition. Animals were weighed weekly, blood collection was carried out for analysis and gross pathology was performed following the dosing period.

One of two dogs died in the highest and second highest dose groups (675 and 225 ppm) on days 29 and 14, respectively. Dogs that died were moderately to extremely emaciated and lethargic for several days preceding death. Some also had eye and nasal secretions. Practically all dogs, including controls, either showed no weight gain, or actually lost weight during the month of the experiment. However, there was a wide variation in size and age of the animals. Though the animals were deloused and wormed, undoubtedly tape worm re-infestations occurred. This could partly account for the lack of weight gain. The haemoglobin, packed cell volume, and differential data were not analysed statistically because the values were fairly uniform throughout the various groups.

Many of the organ-body weight ratios were considerably varied but not significantly different, due to the small number in the sample. Post-mortem examination indicated some pathology in three out of four of the controls, including ascites and kidney, liver and bladder conditions. It is therefore difficult to ascribe to the ingestion of the test material the pathology seen among the other groups; with the exception of fat depletion which did not occur in the controls.

Under the conditions of this study the NOAEL of the test material to male dogs was 75 ppm.

Read-across to (DOTE) (CAS No 15571 -58 -1)

- Anon. (1970): A repeated dose oral toxicity study was carried out with rats and a mixture of Dioctyltin bis(2-EHMA) [CAS No. 15571-58-1]:Octyltin tris(2-EHMA) [CAS No. 27107-89-7]: Trioctyltin (2-EHMA) [CAS No. 61912-55-8] (97.0:0.3:2.17% mixture). The study predates GLP, but is well documented and quality assurance is comparable. No information on the homogeneity or stability of the test substance in the diet was provided. The NOAEL was determined to be 10 ppm (equivalent to 0.5 mg/kg bw/day) and the LOAEL was determined to be 25 ppm (equivalent to 1.3 mg/kg bw/day) based on reduced thymus weight.

- Anon (1974): A repeated dose oral toxicity test was carried out with a Dioctyltin bis(2-EHMA) [CAS No. 15571-58-1]:Octyltin tris(2-EHMA) [CAS No. 27107-89-7] (70:30% mixture). The test material was dosed via the diet. The test material homogeneity and stability was not determined. Effects on the thymus weight were observed. The no effect level  for DOT(2-EHMA) was determined to be 25 ppm (calculated as 1.25 mg/kg/day, based on a food factor of 0.05) based on reduced absolute and relative thymus gland weights.

Justification for classification or non-classification

STOT RE category 1 for specific target organ toxicity, specifically for effects on the thymus (H372). Justification: A NOAEL of 0.5 mg/kg bw/d and a LOAEL is 1.3 mg/kg bw/d. These values are smaller than 10, therefore a classification 'STOT RE 1' is required according to the regulation EC no.1272/2008 (CLP).