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Administrative data

Description of key information

Acute toxicity: oral: LD50 > 5000 mg/kg bw (OECD 423 in rats, GLP, rel.1, K)

Acute toxicity: dermal: LD50 expected to be > 5000 mg/kg bw (non-OECD, non-GLP, rel.4, S)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From July 18 to August 08, 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on August 30, 2005/ signed on November 21, 2005)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: Sprague Dawley CD rats
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, Kent, UK.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 193-236 g
- Fasting period before study: Animals were fasted for overnight period before test item administration and for approximately 3-4 h after dosing.
- Housing: Animals were housed in groups of three in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet: Food (Certified Rat and Mouse Diet (Code 5LF2) supplied by BCM IPS Limited, London, U.K.), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25 °C
- Humidity: 30-70 %
- Air changes: At least 15 changes/h
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: From July 18 to August 08, 2006
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Test material was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level. Specific gravity of test material is 0.965.

DOSE VOLUME APPLIED: 2.08 mL/kg bw

CLASS METHOD
- Rationale for the selection of the starting dose: In the absence of data suggesting the test material was toxic, 2000 mg/kg bw was chosen as the starting dose.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 h after dosing and subsequently once daily for fourteen days. Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment.
- Necropsy of survivors performed: Yes; At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross pathological examination.
- Other examinations performed: clinical signs, body weight
Statistics:
None
Preliminary study:
Not applicable
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality was observed at 2000 mg/kg bw
Mortality:
No mortality was observed.
Clinical signs:
Signs of systemic toxicity noted during the study were hunched posture, lethargy, ataxia, increased salivation, decreased respiratory rate and noisy respiration. Animals appeared normal two, three or four days after dosing.
Body weight:
All animals showed expected gains in bodyweight over the study period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
None

See the attached document for information on Tables of results 423 - Acute oral toxicity

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the substance is not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS as the estimated oral LD50 is higher than 5000 mg/kg bw.
Executive summary:

In an acute oral toxicity study performed according to OECD Guideline No. 423 and in compliance with GLP, a group of three fasted female Sprague Dawley CD rats was treated with the test material at a dose level of 2000 mg/kg bw. This was followed by a further group of three fasted females at the same dose level. 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.

No mortality was observed. Signs of systemic toxicity noted during the study were hunched posture, lethargy, ataxia, increased salivation, decreased respiratory rate and noisy respiration. Animals appeared normal two, three or four days after dosing. All animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy.

 

Estimated Oral LD50 (female) > 5000 mg/kg bw.

Under the test conditions, the substance is not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS as the estimated oral LD50 is higher than 5000 mg/kg bw.

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

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Basic data given; no details on environmental conditions of animal room; 2 animals/sex/dose used.
Principles of method if other than guideline:
Acute gavage administration to rats.
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Charles River strain (COBS)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., North Wilmington, Massachusetts.
- Weight at study initiation: Males: 163-198 g; females: 163-213 g
- Fasting period before study: Animals were fasted for 16 h before dosing.
- Housing: Animals were housed individually in suspended, wire-mesh cages.
- Diet: Standard laboratory diet, ad libitum
- Water: Water, ad libitum
- Acclimation period: 5 days
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
DOSAGE PREPARATION: Test material was administered as a 50 % (w/v) solution in corn oil.
Doses:
6834, 10250, 15380 and 23070 mg/kg bw
No. of animals per sex per dose:
2
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 daily for 14 days. Initial and final bodyweights of animals were recorded.
- Necropsy of survivors performed: Yes; necropsy was conducted on any animal which died during the study and on all animals sacrificed at the end of the 14-day observation period.
Statistics:
Acute oral median lethal dose (LD50) of the test material was calculated using the techniques of Weil CS (1952); Thompson WR (1947); Thompson WR and Weil CS (1952).
Preliminary study:
Not applicable
Sex:
male/female
Dose descriptor:
other: LD50 (50%)
Effect level:
>= 18 830 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Test material is at 50% in corn oil
Sex:
male/female
Dose descriptor:
approximate LD50
Effect level:
>= 9 415 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Calculated for 100% test material
Mortality:
One female died at 15380 mg/kg bw.
One male and two females died at 23070 mg/kg bw.
No mortality was observed at 6834 and 10250 mg/kg bw.
Clinical signs:
- Hypoactivity, ruffed fur and labored breathing were observed at 6834 mg/kg bw.
- Hypoactivity, ruffed fur, labored breathing and muscular weakness were observed at 10250 mg/kg bw.
- Hypoactivity, ruffed fur, labored breathing, muscular weakness and salivation were observed at 15380 mg/kg bw.
- Hypoactivity, ruffed fur, labored breathing, muscular weakness, salivation and convulsions were observed at 23070 mg/kg bw.
Body weight:
- All animals showed expected gains in bodyweight over the 14 day study period.
Gross pathology:
- Necropsy examinations of the animals that died revealed gastroenteritis.
- No gross pathologic alterations were noted among the animals sacrificed at 14 days.
Other findings:
None

Table 7.2.1/1: Mortality and Body Weight Data

Dose (mg/kg bw)

Animal number and sex

Individual Body Weights (grams)

 

Number Dead / Number Tested

Percent Dead

Day 0

Day 14

6834

1-M

198

316

0/4

0

2-M

189

303

3-F

213

238

4-F

210

230

10250

5-M

179

280

0/4

0

6-M

188

300

7-F

213

231

8-F

163

219

15380

9-M

195

308

1/4

25

10-M

194

302

11-F

210

(6 days)

12-F

201

226

23070

13-M

174

302

3/4

75

14-M

163

(6-22 h)

15-F

201

(6-22 h)

16-F

210

(3 days)

 

Note: Figures in parentheses indicate time of death

Interpretation of results:
GHS criteria not met
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, test material is not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS as the oral LD50 is higher than 5000 mg/kg bw.
Executive summary:

In an acute oral toxicity study, groups of Charles River strain (COBS) rats (2/sex/dose) were administered a single oral dose of test material at 50% in corn oil at doses of 6834, 10250, 15380 and 23070 mg/kg bw by gavage. 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.

One female died at 15380 mg/kg bw of test item 50%. One male and two females died at 23070 mg/kg bw of test item 50%. No mortality was observed at 6834 and 10250 mg/kg bw. Hypoactivity, ruffed fur and labored breathing were observed in all treated groups. Muscular weakness was observed at 10250 mg/kg bw, 15380 mg/kg bw and 23070 mg/kg bw of test item 50%. Salivation was observed at 15380 mg/kg bw and at 23070 mg/kg bw of test item 50%. Convulsions were observed at 23070 mg/kg bw of test item 50%. All animals showed expected bodyweight gains over the 14 day study period. Necropsy examinations of the animals that died revealed gastroenteritis. No gross pathologic alterations were noted among the animals sacrificed at 14 days.

 

Oral LD50 Combined (50%) ≥ 18830 mg/kg bw

Corresponding to Oral LD50 Combined (100%) ≥ 9415 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) and to the GHS as the oral LD50 is higher than 5000 mg/kg bw.

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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 000 mg/kg bw
Quality of whole database:
The key study was a GLP study conducted in compliance with OECD Guideline No. 423 without any deviation. This study was considered sufficiently robust to cover this endpoint. The other study performed on the registered substance in rats was non-GLP and was of poor quality (Klimish score = 4) but supports the results of the key study.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1973
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
Only 2 animals/sex used, diluted substance (50%), Occlusive patch instead of semi-acclusive. The study was not considered sufficient in its own for acute dermal toxicity endpoint and was therefore used in a weight of evidence assessment.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
basic data given; no details on environmental conditions of animal room; occlusive dressing and 2 animals/sex/dose used
Principles of method if other than guideline:
The test substance was applied to skin of albino rabbits with occlusive patch for 24 h at dose of 2000 mg/kg bw. The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations.
GLP compliance:
no
Remarks:
pre-GLP
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Housing: Animals were housed individually in suspended wire-bottomed cages.
- Diet: Food (standard laboratory ration), ad libitum
- Water, ad libitum
- Acclimation period: 7 days
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
PRETREATMENT
- Twenty-four hours prior to the dermal applications, the backs of the rabbits were shaved free of hair with electric clippers. The shaved area on each animal constituted about 30% of the total body surface area. The animals were then returned to their cages to await testing on the following day. The 24 h waiting period allowed recovery of the stratum corneum from the disturbance which accompanied the close- clipping procedure and permitted healing of any microscopic abrasions possibly produced during the process.

TEST SITE
- Area of exposure: Backs of rabbits
- % coverage: 30% of the total body surface area
- Type of wrap if used: Test site was covered by wrapping the trunk of the animal with impervious plastic sheeting which was securely taped in place. This plastic wrap insured close contact of the epidermis and test material. To prevent oral ingestion of the test material, each animal was fitted with a light-weight, flexible plastic collar which was worn throughout the observation period.

REMOVAL OF TEST SUBSTANCE
- Washing: At the end of exposure (24 h), the plastic sheeting and all residual test material were removed.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration: Test material was applied undiluted
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
2
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Test sites were examined for local skin reactions and the animals were returned to their cages. Observations for mortality, local skin reactions, and behavioural abnormalities were continued for a total of 14 days following the skin applications. Initial and final body weights were recorded.
- Necropsy of survivors performed: Yes, at the end of observation, necropsy was conducted on all animals.
Statistics:
None
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks:
50%
Remarks on result:
other: 100% test substance: > 1000 mg/kg bw
Mortality:
No mortality was observed during the study.
Clinical signs:
No untoward behavioral reactions were noted.
Body weight:
Two animals (1 male and 1 female) showed weight gain, but weight loss was observed in remaining two animals (1 male and 1 female).
Gross pathology:
Necropsy of all animals did not reveal any gross pathologic alterations other than the dermal alterations.
Other findings:
Skin reactions observed at 24 h were pale red to red, well-defined erythema and barely perceptible edema. Severe desquamation was observed at 7and 14 days.

None

Interpretation of results:
study cannot be used for classification
Conclusions:
This study cannot be used for classification since the test substance was not tested up to limit doses which are relevant for classification according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In an acute dermal toxicity study (limit test), a group of New Zealand Albino rabbits (2/sex) were given a single dermal application of test substance at 2000 mg/kg bw. The test substance ( 50% N-1505 573507 GEL) was applied topically to the shaved skin area of the animals and covered with occlusive binding for 24 h. Animals were observed for toxicity, clinical signs and body weight for 14 days and then necropsied for macroscopic observations.

 

No mortality or clinical signs were observed. Skin reactions observed at 24 h were pale red to red, well-defined erythema and barely perceptible edema. Severe desquamation was observed at 7and 14 days. No other gross pathologic alterations were observed.

 

Dermal median LD50 rabbit (50%) > 2000 mg/kg bw, thus dermal median LD50 rabbit (100%) > 1000 mg/kg bw

                                                                     

This study cannot be used for classification since the test substance was not tested up to limit doses which are relevant for classification according to the annex VI of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

The study was not considered sufficient in its own for acute dermal toxicity endpoint.

Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to ECHA R7a guidance (2016), the study need not to be conducted because the substance does not meet the criteria for classification for acute toxicity or STOT-SE by the oral route and no systemic toxicity was observed in the existing acute dermal toxicity study up to 1000 mg/kg bw, nor in the in the GPMT study. Moreover, the substance being highly lipophilic (log Kow = 5.05), the rate of uptake into the stratum corneum is expected to be high while the rate of penetration is likely to be limited by the rate of transfer between the stratum corneum and the epidermis. Moreover, it is assumed that the dermal uptake is also limited by the slight water solubility of the target substance.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
5 000 mg/kg bw
Quality of whole database:
The available study was not conducted according to accepted test guideline and it is of poor quality (Klimisch score = 4). It is not considered sufficient in its own for acute dermal toxicity endpoint but was used together with the acute oral toxicity study (Klimisch score = 1) to conclude on the dermal hazard potential.

Additional information

Acute toxicity: oral

A key study was identified (Safepharm, 2006, rel.1). In this limit acute oral toxicity study, which was performed according to OECD Guideline No. 423 and in compliance with GLP, female Sprague Dawley CD rats was treated with the test material at a dose level of 2000 mg/kg bw.The animals were observed for mortality, clinical signs and body weight for 14 days and then necropsied for macroscopic observations. No mortality was observed. Signs of systemic toxicity noted during the study were hunched posture, lethargy, ataxia, increased salivation, decreased respiratory rate and noisy respiration. Animals appeared normal two, three or four days after dosing. All animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy.

This study gave an estimated oral LD50 (rats) > 5000 mg/kg bw.

In an other acute oral toxicity study (Industrial Bio-Test Laboratories, 1973, rel.4), groups of Charles River strain (COBS) rats (2/sex/dose) were administered a single oral dose of test material at 50% in corn oil at doses of 6834, 10250, 15380 and 23070 mg/kg bw by gavage. 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.

One female died at 15380 mg/kg bw of test item 50%. One male and two females died at 23070 mg/kg bw of test item 50%. Hypoactivity, ruffed fur and labored breathing were observed in all treated groups. Muscular weakness was observed at 10250 mg/kg bw, 15380 mg/kg bw and 23070 mg/kg bw of test item 50%. Salivation was observed at 15380 mg/kg bw and at 23070 mg/kg bw of test item 50%. Convulsions were observed at 23070 mg/kg bw of test item 50%. All animals showed expected bodyweight gains over the 14 day study period. Necropsy examinations of the animals that died revealed gastroenteritis. No gross pathologic alterations were noted among the animals sacrificed at 14 days.

This study gave a combined oral LD50 (rats) > 9415 mg/kg bw.

Acute toxicity: dermal

In an acute dermal toxicity study (Industrial Bio-Test Laboratories, 1973, rem.4), a group of rabbits (2/sex) were given a single dermal application of test substance at 50% at the dose of 2000 mg/kg bw under occlusive dressing for 24 hours. Animals were observed for toxicity, clinical signs and body weight for 14 days and then necropsied for macroscopic observations.No mortality or clinical signs were observed. Skin reactions observed at 24 h were pale red to red, well-defined erythema and barely perceptible edema. Severe desquamation was observed at 7and 14 days. No other gross pathologic alterations were observed.

This study gave a dermal median LD50 rabbit (50%) > 2000 mg/kg bw, thus dermal median LD50 rabbit (100%) > 1000 mg/kg bw. This study cannot be used alone for classification since the substance was tested diluted and not up to the limit dose relevant for classification.

However, according to ECHA R7a guidance (2016), further study need not to be conducted because the substance does not meet the criteria for classification for acute toxicity or STOT-SE by the oral route and no systemic toxicity was observed in the existing acute dermal toxicity study up to 1000 mg/kg bw, nor in the in the GPMT study. Thus, the dermal LD50 is expected to be higher than 5000 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:

Under the test conditions, the substance is not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS as the estimated oral LD50 is higher than 5000 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) and to the GHS as the oral LD50 is expected to be greater than 5000 mg/kg bw.

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. The effects observed in the acute oral toxicity studies are considered to be linked to the stress produced by gavage administration at high doses.

Specific target organ toxicity: single exposure (Dermal):

Based on available data via both the oral and dermal route, the classification criteria according to the Annex VI of the Regulation (EC) No 1272/2008 as specific target organ toxicant (STOT) – single dermal exposure Category 1 or 2 are not considered to be met. 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, nor in the acute oral toxicity study.

Specific target organ toxicity: single exposure (Inhalation):

No data was available.