Dioctyltin dilaurate

Endpoint summary

Description of key information

Oral
LD50 > 2000 mg/kg bw, rat (female), OECD 423, EU Method B.1 tris. Dreher (2013)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 March 2013 to 11 April 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

(On one occasion the relative humidity was recorded below the protocol range with a recording of 44 %. This study deviation neither affected the overall interpretation of study findings nor compromised the integrity of the study.)

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

(On one occasion the relative humidity was recorded below the protocol range with a recording of 44 %. This study deviation neither affected the overall interpretation of study findings nor compromised the integrity of the study.)

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: HsdHan™:WIST

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Limited, Bicester, UK
- Age at study initiation: 8 - 9 weeks
- Weight at study initiation: 179 - 196 g
- Fasting period before study: animals were fasted from the evening of the day prior to dosing (Day -1) until approximately 3 hours after dosing
- Housing: animals were housed in groups of up to five during the acclimatisation period in cages that conform to the 'Code of Practice for the Housing and Care of Animals Used in Scientific Procedures' (Home Office, London, 1989). From the day prior to dosing (Day –1), the rats were housed in groups of three in similar cages.
- Diet: SQC(E) Rat and Mouse Maintenance Diet No 1, from Special Diets Services Ltd, Witham, UK, ad libitum
- Water: mains water, ad libitum
- Acclimation period: 7 - 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 45 - 65 %
- Air changes (per hr): 15 - 20 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

In order to enrich both the environment and the welfare of the animals, they were provided with wooden Aspen chew blocks, nesting materials and rodent retreats. Environmental enrichment materials were removed during the period of fasting from the evening of the day prior to dosing (Day -1) until approximately 3 hours after dosing.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

- Individual doses
Individual doses (mL) were calculated using the fasted body weights of the rats on the morning of dosing (Day 1) and the specific gravity for the neat material.

- Dose volume
The test material was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.
During the study, the animals were treated with a dose volume of 1.87 mL/kg

Doses:

2000 mg/kg

No. of animals per sex per dose:

3 animals initially then a further 3 animals once the survival of the previously treated animals was confirmed.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: All animals were examined at the beginning and end of the working day throughout the acclimatisation and study periods to ensure they were in good health. Treated rats were observed closely for clinical signs of reaction to treatment. Clinical signs were recorded immediately post dose, at approximately 15 and 30 minutes post dose, hourly between 1 and 4 hours post dose (inclusive), twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period.
- Frequency of weighing: Individual body weights were recorded on Day 1 (day before dosing) and on Days 1, 4, 8 and 15.
- Necropsy of survivors performed: yes. A full macroscopic necropsy was performed and all lesions were recorded. The necropsy procedure included inspection of external surfaces and orifices, all viscera and tissue within the abdominal, thoracic and cranial cavities, free hand sectioning of the liver and kidneys and examination of representative sections of mucosal surfaces of the stomach, small and large intestines. No tissue preservation or histopathological assessment of tissues was undertaken.

- Other examinations performed: yes (gene analysis)
Blood samples for gene analysis (0.5 mL nominal) were taken from all animals on Day -1 and Day 1 (24 hours after dosing).
Samples were taken from jugular vein into into trisodium citrate anticoagulant. Samples were mixed gently by hand then continuously for at least 2 minutes on automatic mixer. Once mixed the 3 samples from each group, at each timepoint, were pooled together and placed in a cooled Kryorack. The resultant plasma was separated, transferred to uniquely labelled clear polypropylene tubes and frozen immediately at <–50 °C.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

None of the animals died during the study.

Clinical signs:

other: No clinical signs were seen during the study.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

Gene analysis findings were not reported.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the study, the acute median dose level of the test material was found to exceed 2000 mg/kg.

Executive summary:

The acute oral toxicity of the test material was investigated in a GLP study which was conducted in accordance with the standardised guidelines OECD 423 and EU Method B.1 tris, following the Acute Toxic Class method.

During the study two groups of 3 female rats were sequentially treated with test material at dose level of 2000 mg/kg bw. The test material was administered orally, by gavage, without dilution. All animals were killed on Day 15 and subsequently underwent a full necropsy.

There were no deaths and no signs of toxicity. All rats achieved body weight gains during the first and second weeks of the study. No abnormalities were noted at necropsy. Therefore, under the conditions of the study, the acute median dose level of the test material was found to exceed 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The key study was assigned a reliability score of 1 according to the criteria of Klimisch. Supporting data were assigned a reliability score of 4. Overall, the quality of the database is good.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

tudy conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

additional blood sampling for determination of absorption

Principles of method if other than guideline:

Blood samples for toxicokinetics (0.5 mL nominal) were taken from all animals on Day 1 at 3 and 24 hours after dosing.

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Sex:

male/female

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24 h

Doses:

2000 mg / kg bw

No. of animals per sex per dose:

5 male and female

Control animals:

not required

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Clinical signs following treatment

Dose level: 2000 mg/kg

Clinical sign	Animal number and sex
	29M	30M	31M	32M	33M
No observations	ü	ü	ü	ü	ü

 

Clinical sign	Animal number and sex
	34F	35F	36F	37F	38F
No observations	ü	ü	ü	ü	ü

 

Dermal reactions

Dose level: 2000 mg/kg

Day	Dermal reaction	Animal number and sex
		29M	30M	31M	32M	33M
2 to 15	Erythema Oedema Other	0 0 -	0 0 -	0 0 -	0 0 -	0 0 -

 

Day	Dermal reaction	Animal number and sex
		34F	35F	36F	37F	38F
2 to 15	Erythema Oedema Other	0 0 -	0 0 -	0 0 -	0 0 -	0 0 -

Individual body weights and weekly increments

Dose level (mg/kg)	Animal number and sex	Body weight (g) at:					Increment (g)
		Day -1	Day 1	Day 4	Day 8	Day 15	Day 1 to 8	Day 8 to 15
2000	29M	257	266	273	279	308	13	29
	30M	260	269	269	279	294	10	15
	31M	279	286	284	289	307	3	18
	32M	268	271	272	281	294	10	13
	33M	269	281	283	293	306	12	13
2000	34F	181	188	195	189	203	1	14
	35F	201	207	203	213	216	6	3
	36F	180	183	179	190	202	7	12
	37F	178	186	178	191	200	5	9
	38F	195	202	202	210	222	8	12

Necropsy findings

Dose level:2000 mg/kg

Animal number and sex	Time and manner of death (Day)	Necropsy comments
29M	15T	No macroscopic changes
30M	15T	No macroscopic changes
31M	15T	No macroscopic changes
32M	15T	No macroscopic changes
33M	15T	No macroscopic changes
34F	15T	No macroscopic changes
35F	15T	No macroscopic changes
36F	15T	Liver: raised area, right median lobe - 9 mm diameter           raised area protruding into thoracic cavity - moderate #
37F	15T	No macroscopic changes
38F	15T	No macroscopic changes

 

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute median lethal dermal dose of TIB KAT 216 to rats was found to exceed 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The key study was assigned a reliability score of 1 according to the criteria of Klimisch. Supporting data were assigned a reliability score of 4. Overall, the quality of the database is good.

Additional information

Oral

In the key study (Dreher, 2013), the acute oral toxicity of the test material was investigated under GLP conditions, and in accordance with the standardised guidelines OECD 423 and EU Method B.1 tris, following the Acute Toxic Class method. During the study two groups of 3 female rats were sequentially treated with test material at dose level of 2000 mg/kg bw. The test material was administered orally, by gavage, without dilution. All animals were killed on Day 15 and subsequently underwent a full necropsy. There were no deaths and no signs of toxicity. All rats achieved body weight gains during the first and second weeks of the study. No abnormalities were noted at necropsy. Therefore, under the conditions of the study, the acute median dose level of the test material was found to exceed 2000 mg/kg.

 

Supporting information is available in the form of an abstract of an internet source with no reported methodology which reported the LD50 of the test material to be 6450 mg/kg (WHO, 1980). Data from an abstract of a journal with limited information regarding the methodology (Klimmer, 1969) reported the LD50 of the test material to be 6450 mg/kg. Furthermore, Smith (1978) cited LD50 values from secondary sources; in the first (cited from Barth et al, 1964), the LD50 value was reported to be 600 – 6450 mg/kg, and in the second (cited from Schering) the LD50 value was reported to be in excess of 4000 mg/kg. The supporting data all support the findings of the key study.

Inhalation

In accordance with point 8.5.2, Column 2 (Specific rules for adaptation from Column 1), Annex VIII of Regulation (EC) No. 1907/2006, an acute inhalation study does not need to be performed as the substance has a low vapour pressure (less than 2.2 x 10^-3 Pa at 25 ºC) and the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur. The acute toxicity endpoint has been addressed by assessing the toxicity via the oral route, which is more appropriate when considering the properties of this substance.

Justification for selection of acute toxicity – oral endpoint
Dreher (2013) was selected as the key study since it was performed under GLP conditions and in accordance with standardised guidelines. Supporting data are taken from publications with limited detail on experimental materials and methods.

Justification for selection of acute toxicity – inhalation endpoint
A data waiver has been submitted to address this endpoint.

Justification for selection of acute toxicity – dermal endpoint
Dreher (2013) was selected as the key study since it was performed under GLP conditions and in accordance with standardised guidelines. Supporting data are taken from publications with limited detail on experimental materials and methods.

Justification for classification or non-classification

Oral

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008, the test material does not require classification for acute oral toxicity as no signs of toxicity were noted during the course of the key study.