Registration Dossier

Administrative data

Description of key information

Acute toxicity: oral: LD50 > 5000 mg/kg bw (OECD 423 in rats; OECD 423, K, rel.1);
Acute toxicity: dermal: LD50 > 2000 mg/kg bw (E.U. B.3 in rats, read-across, 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:
From 27 July 2012 to 14 November 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study performed according to OECD test guideline No. 423 and in compliance with GLP.
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
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agricultural Chemicals, Acute oral toxicity (2-1-1), 12 Nousan No 8147, Agricultural Production Bureau, November 24, 2000.
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on 2011-08-23/signed on 2011-12-12)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS: Crl:CD'SD' rats
- Source: Charles River (UK) Ltd.
- Age at study initiation: eight to twelve weeks of age
- Weight at study initiation: 188 to 219 g
- Fasting period before study: overnight prior to and approximately four hours after dosing.
- Housing: in groups of three rats of the same sex, in solid bottomed polycarbonate cages with a stainless steel mesh lid
- Diet (e.g. ad libitum): standard rodent diet (Rat and Mouse No. 1 Maintenance Diet) ad libitum. Not contaminated.
- Water (e.g. ad libitum): Potable water taken from the public supply ad libitum. Not contaminated.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23°C
- Humidity (%): 40 to 70%
- Air changes (per hr): not reported (filtered fresh air)
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2012-08-02 To: 2012-08-28
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: LD50 > 5000 mg/kg bw on an analogue substance having the same constituents than the registered substance but at different ratios.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3+3 (females)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality: at least twice daily.
Clinical observation: soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only).
Bodyweight: recorded on Days 1 (prior to dosing), 8 and 15.
- Necropsy of survivors performed: yes, all animals were subject to a macroscopic examination which consisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.
Statistics:
Not required
Preliminary study:
Not applicable
Sex:
female
Dose descriptor:
LD0
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: from the flow chart from OECD Guideline 423 (Appendix 2d)
Mortality:
There were no deaths during the study.
Clinical signs:
Clinical signs of reaction to treatment comprised loose faeces seen in five females, urine staining in the perigenital region in three females and post salivation staining, hunched posture, fast breathing, piloerection and distended abdomen observed in individual females dosed at 2000 mg/kg bw. These signs were seen from approximately one hour after dosing. Recovery of animals, as judged by external appearance and behaviour, was complete by Day 3.
Body weight:
All animals were considered to have achieved satisfactory bodyweight gains throughout the study.
Gross pathology:
Macroscopic examination at study termination on Day 15 revealed enlarged, swollen or thickened kidneys, pallor of the kidneys and clear fluid in the kidneys in one female. These findings are considered unlikely to be test substance related. No abnormalities were revealed in any of the other five animals at the macroscopic examination at this time.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Oral LD50 Female rat > 5000 mg/kg bw. Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP).
Executive summary:

In an acute oral toxicity study performed according to the OECD test guideline No. 423 and in compliance with GLP, a group of three fasted female Sprague-Dawley rats received a single oral gavage dose of the test material, formulated in corn oil, at a dose level of 2000 mg/kg bodyweight. As results at this dose level indicated the acute lethal oral dose of the test substance to be greater than 2000 mg/kg bodyweight, in compliance with the study guidelines, a further group of three fasted females was similarly dosed at 2000 mg/kg bodyweight to complete the study.

Clinical signs of reaction to treatment comprised loose faeces seen in five females, urine staining in the perigenital region in three females and post salivation staining, hunched posture, fast breathing, piloerection and distended abdomen observed in individual females dosed at 2000 mg/kg. These signs were seen from approximately one hour after dosing. Recovery of animals, as judged by external appearance and behaviour, was complete by Day 3.

All animals were considered to have achieved satisfactory bodyweight gains throughout the study.

Macroscopic examination at study termination on Day 15 revealed enlarged, swollen or thickened kidneys, pallor of the kidneys and clear fluid in the kidneys in one female. These findings are considered unlikely to be test substance related. No abnormalities were revealed in any of the other five animals at the macroscopic examination at this time.

The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat can be estimated from the flow chart from OECD Guideline 423 (Appendix 2d) as being greater than 5000 mg/kg bodyweight.

Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP).

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 is GLP-compliant and of high quality (Klimisch score = 1)

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
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 08 April to 06 May 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study performed according to EU Method B.3 and in compliance with GLP.
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on 1990-06-19/signed on 1990-10-05
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Crl:CD(SD)BR (VAF plus)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, England
- Age at study initiation: healthy young animals
- Weight at study initiation: 231-248g (males) 216-225g (females)
- Fasting period before study: no
- Housing: Animals were individually housed in grid bottomed cages suspended over cardboard lined excreta trays. Cardboard tray liners were changed as often as necessary to maintain hygiene.
- Diet (e.g. ad libitum): ad libitum, quality certified
- Water (e.g. ad libitum):ad libitum, quality certified
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22 °C
- Humidity (%): 37-51%
- Air changes (per hr): no data, air conditionned
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: back
- % coverage: no data
- Type of wrap if used: The treated site was covered with a pad of surgical gauze 4 plies thick. This was secured in position by a length of 5.0cm wide 'Elastoplast' elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): gentle swabbing with cotton wool soaked in warm water.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.2 mL/kg bw
- Constant volume or concentration used: yes
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Preliminary range finding study: 1 male + 1 female
Limit test: 5 males + 5 females
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: shortly after dosing, after 30 min, after 1, 2 and 4 hours, daily thereafter for 14 consecutive days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, signs of toxicity, body weight,organ weights, histopathology.
Statistics:
None (limit test at one dose level of at least 2000 mg/kg)
Preliminary study:
A preliminary range finding study was conducted at a dose level of 2000mg/kg bodyweight using one male rat and one female rat.
Following dosing, animals were examined at frequent intervals on the day of dosing and daily thereafter for 7 days. At the end of this period they
were killed and discarded without necropsy. No deaths occurred and both animals appeared throughout the observation period, therefore the main study consisted of a limit test conducted at a dose level of 2000mg/kg bodyweight, using one group of 5 male and 5 female rats.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
no indication of skin irritation up to the relevant limit dose level
Sex:
male/female
Dose descriptor:
LD0
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths
Clinical signs:
There were no signs of systemic toxicity
Body weight:
All animals showed expected gains in bodyweight over the study period
Gross pathology:
The necropsy findings were of low incidence and were considered not to be treatment related.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
Dermal LD50Combined > 2000 mg/kg bw. Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP).
Executive summary:

In a limit acute dermal toxicity study performed according to the EU B.3 test method and in compliance with GLP, young adult Crl:CD(SD)BR (VAF plus) rats were occlusively exposed to undiluted test material for 24 hours at dose of 2000 mg/kg bw. In a preliminary range-finding study, the test material was administered to one male and one female rat. Both of these animals appeared outwardly healthy throughout the 7 day observation period. In the main study, the test material was administered to 5 males and 5 females. After 24 hours, the dressings were removed and the treated sites were washed with warm water. The animals were observed for 14 days and at the end of this period they were killed and necropsied.

No deaths occurred and all animals remained outwardly healthy throughout the study. There was no adverse effect on bodyweight gain in animals of either sex. Necropsy findings were of low incidence and are considered not to be treatment related.

 

Dermal LD50Combined > 2000 mg/kg bw

 

Under the test conditions, the test material is not classified according to the annex VI of the Regulation EC No. 1272/2008 (CLP).

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
2 000 mg/kg bw
Quality of whole database:
The key study is GLP-compliant and of high quality (Klimisch score = 1)

Additional information

Acute toxicity: oral

A key study was identified on the substance (HLS, 2012). This study was performed according to the OECD test guideline No. 423 and in compliance with GLP. A group of three fasted female rats received a single oral gavage dose of the test material, formulated in corn oil, at a dose level of 2000 mg/kg bodyweight. As results at this dose level indicated the acute lethal oral dose of the test substance to be greater than 2000 mg/kg bodyweight, in compliance with the study guidelines, a further group of three fasted females was similarly dosed at 2000 mg/kg bodyweight to complete the study. Clinical signs of reaction to treatment comprised loose faeces seen in five females, urine staining in the perigenital region in three females and post salivation staining, hunched posture, fast breathing, piloerection and distended abdomen observed in individual females dosed at 2000 mg/kg. These signs were seen from approximately one hour after dosing. Recovery of animals, as judged by external appearance and behaviour, was complete by Day 3. All animals were considered to have achieved satisfactory bodyweight gains throughout the study. Macroscopic examination at study termination on Day 15 revealed enlarged, swollen or thickened kidneys, pallor of the kidneys and clear fluid in the kidneys in one female. These findings are considered unlikely to be test substance related. No abnormalities were revealed in any of the other five animals at the macroscopic examination at this time.

The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat was estimated from the flow chart from OECD Guideline 423 (Appendix 2d) as being greater than 5000 mg/kg bodyweight.

Acute toxicity: dermal

No study was available on the substance itself, therefore a read-across approach was used. The source substance is considered adequate for read-across purpose (see Iuclid section 13 for additional justification).

This limit acute dermal toxicity study was performed according to the EU B.3 test method and in compliance with GLP (Toxicol, 1992). No deaths occurred and all rats remained outwardly healthy throughout the study. There was no adverse effect on bodyweight gain in animals of either sex. Necropsy findings were of low incidence and are considered not to be treatment related.

Dermal LD50Combined > 2000 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 less than dermal exposure because the source substance has a low vapour pressure (1.5 Pa at 25°C) and the target substance has a low melting point (< -20°C), so the potential for the generation of inhalable forms is low. Dermal exposure is the more likely route of exposure based on physico-chemical properties (Log Kow = 4.99, WS = 10.3 mg/L, surface-active) and based on skin irritation properties that may enhance penetration.

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 Regulation (EC) No. 1272/2008 as the LD50 is greater than 5000 mg/kg bw.

Acute toxicity via Dermal route:

Based on the available data, the substance is not classified according to the Regulation (EC) No. 1272/2008 as the LD50 is greater than 2000 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 significant health effects were observed immediately or delayed after exposure 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):

No data was available.