Registration Dossier

Administrative data

Description of key information

ACUTE ORAL TOXICITY
LD50 = 3793 mg/kg, male/female rat, OECD 401, Sarasin 1982
ACUTE DERMAL TOXICITY
LD50 = >2000 mg/kg bw, male/female rat, OECD 402, EU Method B.3, Sanders 2012

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:
07 July 1982 to 04 August 1982
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP 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.
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: Tif:RAIF(SPF), F3-crosses of RII 1/Tif x RII2/Tif
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: 180 - 196 g
- Housing: Groups of 5, in cages with standardised soft wood bedding
- Diet (e.g. ad libitum): Rat food, ad libitum
- Water (e.g. ad libitum): ad libitum
- Fasting period before study: Animals were fasted overnight before dosing.

ENVIRONMENTAL CONDITIONS
- Kept under conventional laboratory conditions.
- Air conditioned.
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 15 %
- Air changes (per hr): Approximately 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark
Route of administration:
oral: gavage
Vehicle:
other: Distilled water containing 0.5 % carboxymethylcellulose and 0.1 % polysorbate 80
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bodyweight
Doses:
1000, 2500 and 5000 mg/kg
No. of animals per sex per dose:
5 males and 5 females per dose
Control animals:
no
Details on study design:
OBSERVATIONS
- Period: 14 days or until all symptoms have disappeared.
- Mortality: daily am and pm on working days.
- Clinical Signs: daily.
- Bodyweight: on days 1, 7, 14 and at death.
- Necropsies: spontaneously dying animals were subjected to gross necropsy as soon as possible and survivors at the termination of the study.
Statistics:
- Bodyweights: Group means and standard deviations were calculated.
- The LD50 including the 95 % confidence limit was calculated by the logit method (Berkson, 1944).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 793 mg/kg bw
Based on:
test mat.
95% CL:
2 648 - 6 646
Sex:
male
Dose descriptor:
LD50
Effect level:
3 821 mg/kg bw
Based on:
test mat.
95% CL:
2 178 - 25 811
Sex:
female
Dose descriptor:
LD50
Effect level:
3 821 mg/kg bw
Based on:
test mat.
95% CL:
2 178 - 25 811
Mortality:
4 males and 4 females died at the 5000 mg/kg dose level. All deaths occurred within 5 days post exposure. See Table 1 for details.
Clinical signs:
The following clinical signs were observed: sedation, dyspnoea, exophthalmus, ruffled fur and curved body position.
Surviving animals recovered within 14 days. See Table 2 for details.
Body weight:
At the higher doses, bodyweight development was highly erratic during the first week following treatment, but normalised thereafter. See Table 3 for details.
Gross pathology:
No treatment-related gross organ changes were observed.

Table 1 Mortality Data

Dose (mg/kg)

Totals

Time of Death

In the Group

Deaths

Hours After Treatment

Days After Treatment

Number

%

1

3

5

24

2

3

4

5

Males

 

1000

5

0

 

 

 

 

 

 

 

 

 

2500

5

0

 

 

 

 

 

 

 

 

 

5000

5

4

80

 

 

 

 

 

1

1

2

Females

 

1000

5

0

 

 

 

 

 

 

 

 

 

2500

5

0

 

 

 

 

 

 

 

 

 

5000

5

4

80

 

 

 

1

 

2

1

 

Table 2 Clinical Signs

Observations

Hours After Treatment

Days After Treatment

1

3

5

24

2

3

4

5

6

7

8

9

10

11

12

13

1000 mg/kg

 

Sedation

 

 

X

X

 

 

 

 

 

 

 

 

 

 

 

 

Dyspnoea

XX

XX

XX

XX

X

X

X

X

X

X

X

X

X

X

X

 

Exophthalmus

 

 

 

X

X

X

X

X

X

X

X

 

 

 

 

 

Ruffled fur

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

X

X

X

X

X

Curved body

X

X

X

X

X

X

X

X

X

X

 

 

 

 

 

 

2500 mg/kg

 

Sedation

 

X

X

X

 

 

 

 

 

 

 

 

 

 

 

 

Dyspnoea

XX

XX

XX

XX

X

X

X

X

X

X

X

X

X

X

X

 

Exophthalmus

 

 

 

X

X

X

X

X

X

X

X

X

 

 

 

 

Ruffled fur

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

X

X

X

X

X

Curved body

X

X

X

X

X

X

X

X

X

X

 

 

 

 

 

 

5000 mg/kg

 

Sedation

X

XX

XX

XX

XX

XX

XX

X

X

 

 

 

 

 

 

 

Dyspnoea

XX

XX

XX

XX

XX

XX

XX

X

X

X

X

X

X

X

X

 

Exophthalmus

 

 

 

 

 

 

 

X

X

X

X

X

X

X

 

 

Ruffled fur

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

XX

X

Curved body

X

X

X

X

X

X

X

X

X

X

X

X

X

X

 

 

 

Table 3 Bodyweights (g)

Dose (mg/kg)

Males

Females

Day 1

Day 7

Day 14

Day 1

Day 7

Day 14

1000

183 (4.1)

237 (6.3)

272 (6.0)

184 (3.0)

211 (7.1)

226 (12.6)

2500

185 (5.0)

199 (18.9)

246 (7.9)

188 (5.4)

196 (24.3)

222 (11.1)

5000

185 (6.5)

-

-

184 (4.1)

-

-

( ) = Standard deviation

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 of the test material was determined to be 3793 mg/kg in the male and female rat. The test material requires no classification in accordance with EU criteria.
Executive summary:

The acute oral toxicity of the test material was evaluated in a study conducted in accordance with the standardised guideline OECD 401.

Albino rats were administered a single oral dose of the test material by gavage at dose levels of 1000, 2500 and 5000 mg/kg bodyweight. Five animals per sex were dosed at each concentration and the animals observed for 14 days.

Four male and 4 female animals died within 5 days at the 5000 mg/kg bodyweight dose level. No further mortality was seen. Clinical signs included sedation, dyspnoea, exophthalmus, ruffled fur and exhibiting a curved body position. All survivors had recovered by the end of the observation period and no gross abnormalities were observed at necropsy.

Under the conditions of this study, the LD50 was determined to be 3793 mg/kg bodyweight and the test material requires no classification in accordance with EU criteria.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
3 793 mg/kg bw
Quality of whole database:
The supporting study was performed on a read-across substance, the study was assigned a reliability score of 2 (reliable with acceptable restrictions) in accordance with the criteria for assessing data quality as outlined in Klimisch (1997). The overall quality of the dataset is considered to be high.

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:
13 June 2012 to 04 July 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP 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.
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
see below
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
see below
Principles of method if other than guideline:
Due to a technical error, the day 3 clinical observations for two females were not recorded. This deviation was considered not to affect the integrity of the study.
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: RccHan:WIST
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: at least 200 g
- Housing: animals were housed individually during the 24 hour exposure period and in groups of up to 4, by sex, for the remainder of the study in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet: Rodent diet, ad libitum
- Water: mains water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): at least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

IN-LIFE DATES: From: 13 June 2012 To: 4 July 2012
Type of coverage:
semiocclusive
Vehicle:
arachis oil
Details on dermal exposure:
TEST SITE
- Area of exposure: on the day before treatment the back and flanks of each animal were clipped free of hair
- % coverage: approximately 10 % of the total body surface area
- Type of wrap if used: a piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage

REMOVAL OF TEST SUBSTANCE
- After the 24 hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test material

TEST MATERIAL
- The appropriate amount of test material was moistened with arachis oil BP and applied as evenly as possible to the area of shorn skin
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 males and 5 females.
Control animals:
no
Details on study design:
In the absence of data suggesting the test material was toxic, one male and one female rat were initially treated with the test material at a dose level of 2000 mg/kg bodyweight. As no mortalities were noted, a further group of 4 male and 4 female animals were similarly treated at a dose level of 2000 mg/kg bodyweight to bring the total of each sex to 5.

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for deaths and overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and once daily thereafter. The test site was observed daily for evidence of primary irritation and scored according to Draize (1977). Individual bodyweights were recorded prior to application of the test material on day 0 and on days 7 and 14.
- Necropsy of survivors performed: Yes. Animals were killed by cervical dislocation. All animals were subjected to gross necropsy, consisting of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths during the study.
Clinical signs:
No signs of systemic toxicity were noted during the study.
Body weight:
One female showed bodyweight loss during the first week but expected gain in bodyweight during the second week and one female showed expected gain in bodyweight during the first week but bodyweight loss during the second week. Remaining animals showed expected gains in bodyweight over the study period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
Signs of dermal irritation noted were very slight erythema, crust formation and desquamation. There were no signs of dermal irritation noted at the test site of one male.

Table 1: Individual Dermal Reactions

Animal no. and sex

Observation

Effects noted after initiation of exposure (days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1 -0 M

Erythema

1

1

1

1

1

1

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

D

D

D

Cf

Cf

Cf

Cf

D

D

0

3 -0 M

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3 -1 M

Erythema

1

0

1

1

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

D

D

0

0

0

0

0

0

0

0

3 -2 M

Erythema

1

0

0

0

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3 -3 M

Erythema

1

0

0

0

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

D

D

0

0

0

0

0

0

0

0

2 -0 F

Erythema

1

1

0

0

0

0

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

4 -0 F

Erythema

1

0

0

0

1

1

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

D

D

D

0

0

0

0

0

0

0

4 -1 F

Erythema

1

0

1

1

1

1

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

D

D

0

0

0

0

0

0

0

0

4 -2 F

Erythema

1

0

1

1

1

1

0

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

D

D

0

0

0

0

0

0

0

0

4 -3 F

Erythema

1

1

1

1

1

1

1

0

0

0

0

0

0

0

Oedema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

D

D

D

D

0

0

0

0

0

0

0 = no reactions

D = desquamation

Cf = crust formation

Table 2: Individual Bodyweights and Weekly Bodyweight Changes

Animal no. and sex

Bodyweight (g) at day

Bodyweight change (g) during week

0

7

14

1

2

1 -0 M

350

361

376

11

15

3 -0 M

260

285

299

25

14

3 -1 M

255

276

299

21

23

3 -2 M

244

275

308

31

33

3 -3 M

234

256

289

22

33

2 -0 F

230

227

237

-3

10

4 -0 F

217

220

224

3

4

4 -1 F

200

210

218

10

8

4 -2 F

214

223

221

9

-2

4 -3 F

206

213

218

7

5

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, the LD50 of the test material in the Wistar strain rat was determined to be greater than 2000 mg/kg bw and the test material requires no classification in accordance with EU criteria.
Executive summary:

The acute dermal toxicity of the test material was investigated in accordance with the standardised guidelines OECD 402 and EU Method B.3. During the study, a group of ten animals (five males and five females) was given a single 24 hour, semi-occluded dermal application of the test material to intact skin clipped free of hair at a dose level of 2000 mg/kg bw. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

During the study there were no deaths and no signs of systemic toxicity were observed. One female showed bodyweight loss during the first week but expected gain in bodyweight during the second week and one female showed expected gain in bodyweight during the first week but bodyweight loss during the second week. Remaining animals showed expected gains in bodyweight over the study period. Signs of dermal irritation noted were very slight erythema, crust formation and desquamation. There were no signs of dermal irritation noted at the test site of one male. No abnormalities were noted at necropsy. The acute dermal median lethal dose (LD50) of the test material in the Wistar strain rat was therefore determined to be greater than 2000 mg/kg bw and the test material requires no classification in accordance with EU criteria.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The overall quality of the dataset is considered to be high.

Additional information

Acute Oral Toxicity

In the key study, the acute oral toxicity of the test material was evaluated in accordance with the standardised guideline OECD 401.

Albino rats were administered a single oral dose of the test material by gavage at dose levels of 1000, 2500 and 5000 mg/kg bodyweight. Five animals per sex were dosed at each concentration and the animals observed for 14 days.

Four male and 4 female animals died within 5 days at the 5000 mg/kg bodyweight dose level. No further mortality was seen. Clinical signs included sedation, dyspnoea, exophthalmus, ruffled fur and exhibiting a curved body position. All survivors had recovered by the end of the observation period and no gross abnormalities were observed at necropsy.

Under the conditions of this study, the LD50 was determined to be 3793 mg/kg bodyweight

Supporting information is available on the read across substance, dioctyltin (DOTO) which was used for dosing test animals, in polyethylene glycol, at 4640 and 6000 mg/kg bw. The study was conducted to a guideline similar to that of the OECD 401 standardised guideline. During the study no mortalities were observed during the test and all clinical signs observed had alleviated by day 6. Under the conditions of the test, the acute oral LD50 of the test material was found to be greater than 6000 mg/kg bw in male and female rats.

Acute Inhalation Toxicity

In accordance with Column 2 (Specific rules for adaptation from Column 1), point 8.5.2 of Annex VIII, testing by the inhalation route is appropriate if exposure of humans via inhalation is likely, taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.

Based upon the available vapour pressure of 0.13 Pa at 25 °C, exposure to the test material via inhalation is considered unlikely. Acute toxicity data has been submitted on the more appropriate routes (oral and dermal) to fulfil the data requirements for acute toxicity.

Acute Dermal Toxicity

The acute dermal toxicity of the test material was investigated in accordance with the standardised guidelines OECD 402 and EU Method B.3. During the study, a group of ten animals (five males and five females) was given a single 24 hour, semi-occluded dermal application of the test material to intact skin clipped free of hair at a dose level of 2000 mg/kg bw. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

During the study there were no deaths and no signs of systemic toxicity were observed. One female showed bodyweight loss during the first week but expected gain in bodyweight during the second week and one female showed expected gain in bodyweight during the first week but bodyweight loss during the second week. Remaining animals showed expected gains in bodyweight over the study period. Signs of dermal irritation noted were very slight erythema, crust formation and desquamation. There were no signs of dermal irritation noted at the test site of one male. No abnormalities were noted at necropsy. The acute dermal median lethal dose (LD50) of the test material in the Wistar strain rat was therefore determined to be greater than 2000 mg/kg bw.


Justification for selection of acute toxicity – oral endpoint
The key study was conducted in compliance with agreed protocols, with no deviations from standard test guidelines and 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 to a good standard. As such the study was assigned a reliability score of 1 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and considered suitable as an accurate reflection of the test material.

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
Only one study is available which was conducted in compliance with agreed protocols, with no deviations from standard test guidelines and 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. As such the study was assigned a reliability score of 1 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and considered suitable as an accurate reflection of the test material.

Justification for classification or non-classification

The substance was demonstrated to have a high LD50 (>2000 mg/kg bw) in rats. In accordance with the Regulation (EC) No. 1272/2008 and Directive 67/548/EEC, the substance does not meet the criteria for classification for acute toxicity via the oral or dermal routes.