Registration Dossier

Administrative data

Description of key information

Acute toxicity: oral: LD50 = 2600 mg/kg bw (similar to OECD 401 in rats, K, rel.2);
Acute toxicity: dermal: LD50 > 2000 mg/kg bw (OECD 402, K, rel. 1);
Acute toxicity: inhalation: waiver.

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:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Pre-guideline and pre-GLP study. Only basic data given but the study is comparable to OECD TG 401.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
(no details on test substance, test animals, environmental conditions of animal room and body weight. )
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
no data
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
no data
Doses:
1220, 1730, 2470 and 5000 mg/kg bw
No. of animals per sex per dose:
10 animals/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for toxicity and clinical signs daily for 14 days.
- Necropsy of survivors performed: Yes
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
not specified
Dose descriptor:
LD50
Effect level:
2 600 mg/kg bw
Based on:
test mat.
95% CL:
>= 1 900 - <= 3 600
Mortality:
Mortality was observed in 1/10 (Day 1), 4/10 (3 animals died on Day 1; one animal died on Day 2) and 10/10 animals (Day 1) at 1730, 2470 and 5000 mg/kg bw, respectively. No mortality was observed at 1220 mg/kg bw.
Clinical signs:
Lethargy was observed in all dose groups. Also, chromodacryorrhea, ptosis and ataxia were observed at 1220, 1730 and 2470 mg/kg bw, respectively.
Body weight:
No data
Gross pathology:
- No macroscopic abnormalities were observed in 8/10, 8/10, 6/10 and 0/10 animals at 1220, 1730, 2470 and 5000 mg/kg bw, respectively.
- Necropsy of remaining animals revealed red/yellow/bloated intestines; red/bloated stomach; dark/mottled liver; kidneys - dark at 1730, 2470 and 5000 mg/kg bw; lungs dark at 2470 and 5000 mg/kg bw; yellow anogenital exudate at 2470 mg/kg bw and red nose/mouth exudate at 2470 and 5000 mg/kg bw.
Other findings:
None

Table 7.2.1.1 – Distribution of mortality

 

Observation day

Dose (mg/kg bw)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1220

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1730

1

0

0

0

0

0

0

0

0

0

0

0

0

0

2470

3

1

0

0

0

0

0

0

0

0

0

0

0

0

5000

10

0

0

0

0

0

0

0

0

0

0

0

0

0

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
Under the test conditions, test material is:
- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw
- classified as category 5 according to the GHS since rat Oral LD50 is lower than 5000 mg/kg bw (2600 mg/kg bw)
Executive summary:

In an acute oral toxicity study, performed similarly to OECD Guideline No. 401, groups of rats (10 animals/dose) were administered a single oral dose of test material at 1220, 1730, 2470 and 5000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

 

All ten animals died at 5000 mg/kg bw. 1/10 and 4/10 animals died at 1730 and 2470 mg/kg bw. No mortality was observed at 1220 mg/kg bw. Lethargy was observed in all dose groups. Also chromodacryorrhea, ptosis and ataxia were observed at 1220, 1730 and 2470 mg/kg bw, respectively. No macroscopic abnormalities were observed in 8/10, 8/10, 6/10 and 0/10 animals at 1220, 1730, 2470 and 5000 mg/kg bw, respectively. Necropsy of remaining animals revealed red/yellow/bloated intestines; red/bloated stomach; dark/mottled liver; kidneys dark at 1730, 2470 and 5000 mg/kg bw; lungs dark at 2470 and 5000 mg/kg bw; yellow anogenital exudate at 2470 mg/kg bw and red nose/mouth exudate at 2470 and 5000 mg/kg bw.

Rat Oral LD50 = 2600 mg/kg bw (95% Cl: 1900-3600 mg/kg bw).

 

Under the test conditions, test material is:

- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- classified as category 5 according to the GHS since rat Oral LD50 is lower than 5000 mg/kg bw (2600 mg/kg bw)

This study is considered as acceptable and satisfies the requirement for acute oral toxicity

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 600 mg/kg bw
Quality of whole database:
The key study performed on the registered substance in rats was pre-GLP, but was similar to OECD Test guideline No 401. This study was considered sufficiently robust to cover this endpoint.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. In the present case, inhalation exposure will be lower than dermal exposure because the registered substance has a low vapour pressure (3 Pa at 25°C) and a low freezing point (-6°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the most likely route of exposure based on physico-chemical properties (Log Kow = 2.8 at 20°C, WS = 1.1 g/L at 20°C).
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:
From June 10 to July 08, 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crl:CD(SD)BR strain (VAF plus)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent
- Weight at study initiation: 200-300 g
- Housing: Animals were individually housed in grid bottomed cages suspended over cardboard lined excreta trays.
- Diet: Pelleted rodent diet (SQC Rat and Mouse Maintenance Diet No. 1 Expanded, produced by Special Diets Services, Witham, Essex), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-24 °C
- Humidity: 47-66 %
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: From: June 10, 1992 To: July 08, 1992
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: Back area
- Type of wrap if used: A pad of surgical gauze 4 plies thick was placed on treated area and semi-occluded with an 'Elastoplast' elastic adhesive bandage (0.5 cm wide).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Dressings were removed and treated skin was washed by gentle swabbing with cotton wool soaked in warm water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Animals were observed for mortality and clinical signs shortly after dosing and approximately 30 minutes, 1, 2 and 4 h after dosing and daily thereafter for 14 days. Individual body weights were recorded on Days 1, 8 and 15.
- Necropsy of survivors performed: Yes; after the 14 days observation period, all animals were killed by carbon dioxide asphyxiation and subjected to gross necropsy.
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
- No mortality was observed.
Clinical signs:
- 2/5 females showed urogenital staining 4 h after dosing. No other clinical signs were observed.
Body weight:
- Body weights were increased in males. Body weight changes in females were normal.
Gross pathology:
- One male showed minimal dilation of right kidney pelvis and one female showed moderate dilation of both kidney pelvises. No significant abnormalities were noted at necropsy.
Other findings:
None

Range-finding study:

- No mortality or clinical signs were observed at any dose level over 7 days study period.

Table 7.2.3/1: Individual bodyweights and bodyweight changes

Dose level

(mg/kg bw)

Animal number

and sex

Body weight (g)

at Day

Change in body weight

Day 1-15

1

8

15

2000

61 Male

253

297

351

98

62 Male

255

311

390

135

63 Male

259

299

362

103

64 Male

260

308

366

106

65 Male

246

291

353

107

Mean ± S.D

255 ± 5.6

301 ± 8.2

364 ± 15.6

110 ± 14.5

66 Female

221

230

247

26

67 Female

232

234

255

23

68 Female

234

247

269

35

69 Female

220

227

249

29

70 Female

212

226

238

26

Mean ± S.D

224 ± 9.1

233 ± 8.5

252 ± 11.5

28 ± 4.5

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the available information, the substance is:
- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw
- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).
Executive summary:

In an acute dermal toxicity study (limit test) performed similarly to OECD Guideline No. 402 and in compliance with GLP, a group of Crl:CD(SD)BR strain (VAF plus) rats (5/sex) was given a single dermal application of the undiluted test material at 2000 mg/kg bw to the clipped back area. Test sites were covered with a semi-occlusive dressing for 24 h. Animals were observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study all animals were sacrificed for macroscopic examination. Range finding study was conducted at the dose levels of 400, 1000 and 2000 mg/kg bw (1 rat/sex/dose) to determine the dose levels for the main study.

In the range-finding study, no mortality or clinical signs were observed at any dose level. In the main study, no mortality or clinical signs were observed except 2/5 females showed urogenital staining 4 h after dosing. No significant abnormalities were noted at necropsy.

Dermal LD50 Combined > 2000 mg/kg bw

Based on the available information, the substance is:

- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).

This study is considered as acceptable and satisfies the requirement for acute dermal toxicity endpoint.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The key study performed on the registered substance in rats was GLP and was compliant with OECD Test guideline No 402 (Klimisch 1). This study was considered sufficiently robust to cover this endpoint.

Additional information

Acute toxicity: oral

A key study was identified (MB Research laboratories, 1978, rel.2). This study was non-GLP, but was similar to OECD Test guideline No 401. Groups of rats (10/dose) were administered a single oral dose of test material at 1220, 1730, 2470 and 5000 mg/kg bw. Animals were then observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study the surviving animals were sacrificed for macroscopic examination.

 

1/10, 4/10 and 10/10 animals died at 1730, 2470 and 5000 mg/kg bw, respectively. No mortality was observed at 1220 mg/kg bw. Lethargy was observed in all dose groups. Also chromodacryorrhea, ptosis and ataxia were observed at 1220, 1730 and 2470 mg/kg bw, respectively. Necropsy revealed red/yellow/bloated intestines; red/bloated stomach; dark/mottled liver; kidneys dark at 1730, 2470 and 5000 mg/kg bw; lungs dark at 2470 and 5000 mg/kg bw; yellow anogenital exudate at 2470 mg/kg bw and red nose/mouth exudate at 2470 and 5000 mg/kg bw.

Rat Oral LD50 = 2600 mg/kg bw (95% Cl: 1900-3600 mg/kg bw).

Acute toxicity: inhalation
In accordance with Column 2 of REACH Annex VIII, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 (acute toxicity by inhalation) and 8.5.3 (acute toxicity by the dermal route) shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. In the present case, inhalation exposure will be lower than dermal exposure because the registered substance has a low vapour pressure (3 Pa at 25°C) and a low freezing point (-6°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the most likely route of exposure based on physico-chemical properties (Log Kow = 2.8 at 20°C, WS = 1.1 g/L at 20°C).

Acute toxicity: dermal

A key study was identified (Toxicol, 1992, rel.1). In an acute dermal toxicity study (limit test) performed similarly to OECD Guideline No. 402 and in compliance with GLP, a group of Crl:CD(SD)BR strain (VAF plus) rats (5/sex) was given a single dermal application of the undiluted test material at 2000 mg/kg bw to the clipped back area. Test sites were covered with a semi-occlusive dressing for 24 h. Animals were observed for mortality, clinical signs and bodyweights for 14 days and at the end of the study all animals were sacrificed for macroscopic examination. Range finding study was conducted at the dose levels of 400, 1000 and 2000 mg/kg bw (1 rat/sex/dose) to determine the dose levels for the main study.

In the range-finding study, no mortality or clinical signs were observed at any dose level. In the main study, no mortality or clinical signs were observed except 2/5 females showed urogenital staining 4 h after dosing. No significant abnormalities were noted at necropsy.

Dermal LD50 Combined > 2000 mg/kg bw

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Acute toxicity via Oral route:

Based on the available data, the substance is:

- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- classified as category 5 according to the GHS since rat Oral LD50 is lower than 5000 mg/kg bw (2600 mg/kg bw)

Acute toxicity via Dermal route:

Based on the available data, the substance is:

- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- not classified according to the GHS since there is no reliable evidence that indicates the LD50 to be in the range of Category 5 values (GHS criteria not met).

Acute toxicity (Inhalation):

No data was available.

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral) for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value (oral) for a Category 2 classification (2000 mg/kg bw≥C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Dermal):

The classification criteria according to the Annex VI of the Regulation (EC) No 1272/2008 as specific target organ toxicant (STOT) – single exposure, dermal are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (dermal) for a Category 1 classification (C≤ 1000 mg/kg bw) and at the guidance value (dermal) for a Category 2 classification (2000 mg/kg bw≥C > 1000 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects were not observed in the acute dermal toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

Based on the classification for skin and eye irritation, the substance should be classified by default and as a worst-case as STOT-SE Category 3 (H335: May cause respiratory irritation) according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP).