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Administrative data

Description of key information

Acute oral toxicity: 
Key study: Experimental results: OECD guideline 420 and EU method B.1 bis. GLP study.
The oral LD50 is greater than 2000 mg/kg (rats)
Key study: Experimental results: OECD guideline 401 and EU method B.1. GLP study.
The oral LD50 is greater than 2000 mg/kg (rats)
Key study: Experimental results: OECD guideline 401. GLP study.
The oral LD50 is greater than 5000 mg/kg bw (rats)
Acute inhalation toxicity:
In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since exposure of humans via inhalation is not 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.
Acute dermal toxicity:
Key study: Experimental results: OECD guideline 402 and EU method B.3. GLP study.
The dermal LD50 is greater than 2000 mg/kg bw (rats)

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 23rd December 1998 to 24th March 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: The animals bred by Charles River, were supplied by CRIFFA, S.A.
- Age at study initiation: Approximately 5 weeks
- Weight at study initiation: 108-124 g
- Housing: The animals were housed in Makrolon cages (55 x 32.7 x 19 cm) with sawdust bedding, each cage containing up to 5 rats of the same sex.
- Diet (e.g. ad libitum): standard rat diet UAR A04C (Batch 80609), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 30-45%
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

IN-LIFE DATES: From: 13th January 1999 To: 5th February 1999
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
The test substance was diluted in bidistilled water. The solutions were prepared immediately before the administration.
A single dose was given at a volume of 10 mL/kg.

Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Preliminary study: one group consisting of one female.
Main study: one group consisting of 5 animals/sex.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: On the day the test substance was administered, the rats were frequently observed so as to record the clinical signs. Afterwards, the rats were observed at least twice a day for a 14-day period. All rats were weighed before administration, daily for the first three days and then weekly. At the end of the observation period the animals were weighed before being sacrificed.
- Necropsy of survivors performed: yes
- Other examinations performed: The necropsy included a revision of the intact animal and all its superficial tissues, followed by an observation of the cranial, thoracic and abdominal cavities both in situ and after evisceration.
Preliminary study:
No mortality was recorded in the Preliminary Study animal, a single female treated at 2000 mg/kg.
This female, treated at 2000 mg/kg, did not present any clinical signs during the observation period.
The female showed a normal evolution of growth.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
None of the animals treated at the dose of 2000 mg/kg died.
Clinical signs:
No clinical signs were observed in the animals administered at 2000 mg/kg.
Body weight:
All the animals treated at the dose of 2000 mg/kg presented a normal evolution of growth.
Gross pathology:
In the necropsies carried out, the animals administered with the test substance at the dose of 2000 mg/kg did not show any visible macroscopic lesions related to the treatment.
Interpretation of results:
GHS criteria not met
Conclusions:
It can be concluded that the substance is free of any significant toxicity. The oral LD50 is greater than 2000 mg/kg.
Executive summary:

The acute toxicity of the test substance was assessed following oral administration, in Sprague Dawley rats, by the fixed dose method. The method employed in this study adheres to the EU method B.1 bis and the OECD guideline 420.

The above-mentioned substance was administered at the dose of 2000 mg/kg.

None of the animals treated at the dose of 2000 mg/kg died in the course of the Study.

No clinical signs were observed in the animals administered at 2000 mg/kg.

In the necropsies carried out at the dose 2000 mg/kg no appreciable macroscopic alterations related to the treatment were observed.

It can be concluded that the substance is free of any significant toxicity. The LD50 is greater than 2000 mg/kg.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2 September 1996 to 25 September 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate, Kent, UK
- Age at study initiation: 5 to 8 weeks of age
- Weight at study initiation: males: 161 to 188 g; females: 142 to 153 g
- Fasting period before study: Overnight fast inmmediately before dosing
- Housing: The animals were housed in groups of up to five by sex in solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): Rat and Mouse Expanded Diet No. 1, Special Diets Services Limited, Witham, Essex, UK, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23ºC
- Humidity (%): 49-53 %
- Air changes (per hr): Fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 1.86 ml/kg

Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Range-finding study: one animal/sex
Main study: five animals/sex
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days. Individual bodyweights were recorded prior to dosing on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: The gross pathological examination consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. 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.
Clinical signs:
No signs of systemic toxicity were noted during the study.
Body weight:
All animals showed expected gain in bodyweight during the study.
Gross pathology:
No abnormalities were noted at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.
Executive summary:

A study was performed to assess the acute oral toxicity of the test material in the Sprague-Dawley CD strain rat. The method followed that in the OECD Cuidelines for Testing of Chemicals No. 401 "Acute Oral Toxicity" and Method B1 of Commission Directive 92/69/EEC.

Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of undiluted test material at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of dosing and were then killed and subjected to gross pathological examination.

There were no deaths. No signs of systemic toxicity were noted during the study.

All animals showed expected gain in bodyweight during the study.

No abnormalities were noted at necropsy.

The acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 14th October 1992 to 17th December 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River España (Mejía Lequerica 34, 08028 Barcelona)
- Age at study initiation: Approximately 5 weeks
- Weight at study initiation: 108-136 g
- Fasting period before study: Food was removed approximately 18 hours before treatment was given.
- Housing: The rats were placed in MakrolonR cages (55 x 32.7 x 19 cm) with sawdust bedding, in groups of up to 5.
- Diet (e.g. ad libitum): standard UAR A.04C rat diet (Villemoisson sur Orge, France), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24 ºC
- Humidity (%): 40-70%

IN-LIFE DATES: From: 20th October 1992 To: 12th November 1992
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

Doses:
5000 mg/kg bw
No. of animals per sex per dose:
Preliminary study: 2 animals/sex
Main study: 5 animals/sex
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed at least twice daily for 14 days. The observations included changes in respiratory, circulatory, central and autonomous nervous systems, somatomotor activity and behaviour. All rats were weighed before administration, halfway through the observation period and before being sacrificed.
- Necropsy of survivors performed: yes
- Other examinations performed: The necropsy included an examination of the intact animal and all its superficial tissues, followed by an observation of the craneal, thoracic and abdominal cavities both in situ and after evisceration.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths among the animals treated in both the preliminary study and the main study.
Clinical signs:
None of the animals showed any clinical signs.
Body weight:
Bodyweight gain was normal.
Gross pathology:
No macroscopic changes related to treatment were observed at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 is greater than 5000 mg/kg bw.
Executive summary:

The method used in this study is based on OECD Guideline 401. Following oral administration (by gavage) to rats, the above mentioned substance showed an LD50 of over 5000 mg/kg. None of the rats treated at that dose died. No clinical signs related to treatment were observed. All the animals showed normal bodyweight gain. No macroscopic alterations related to treatment were observed at necropsy.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
Klimisch 1 and the studies were carried out in accordance with internationally valid GLP principles.

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:
From 15th November 2011 to 8th May 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 11 weeks old) were selected.
- Weight at study initiation: Males: 301-321 g; Females: 196-217 g
- Housing: Individually housed in labeled Makrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: at least 5 days before start of treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0ºC (actual range: 19.9 – 21.7ºC)
- Humidity (%): 40-70% (actual range: 44 - 53%)
- Air changes (per hr): approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day.

IN-LIFE DATES: From: 08 December 2011 To: 22 December 2011
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: approx. 25 cm² for males and 18 cm² for females.
- % coverage: approx. 10% of the total body surface
- Type of wrap if used: The test substance was held in contact with the skin with a dressing, consisting of a surgical gauze patch, successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24 hours, after which dressings were removed and the skin cleaned of residual test substance using tap water.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg (1.845 mL/kg) body weight.

Duration of exposure:
24 hours
Doses:
2000 mg/kg (1.845 mL/kg) body weight.
No. of animals per sex per dose:
Five animals per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily.
Body weights: Days 1 (pre-administration), 8 and 15.
Clinical signs At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The time of onset, degree and duration were
recorded and the symptoms graded according to fixed scales:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
- Necropsy of survivors performed: yes. At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Piloerection and/or chromodacryorrhoea were noted in two males and four females on Days 1 and/or 2.
Scales and scabs were seen in the treated skin-area of one male and one female between Days 4 and 15.
Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
Several reddish foci were noted in the lungs of one male. No further abnormalities were found at macroscopic post mortem examination of the other animals.
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 value of the test substance in Wistar rats was established to exceed 2000 mg/kg body weight.
Executive summary:

The test substance was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). No mortality occurred. Piloerection and/or chromodacryorrhoea were noted in two males and four females on Days 1 and/or 2. Scales and scabs were seen in the treated skin-area of one male and one female between Days 4

and 15. The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity. Several reddish foci were noted in the lungs of one male. No further abnormalities were found at macroscopic post mortem examination of the other animals. The dermal LD50 value of the test substance in Wistar rats was established to exceed 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
Klimisch 1 and the study was carried out in accordance with internationally valid GLP principles.

Additional information

Acute oral toxicity:

Key study: Experimental results: OECD guideline 420 and EU method B.1 bis. GLP study.

The oral LD50 is greater than 2000 mg/kg (rats)

Key study: Experimental results: OECD guideline 401 and EU method B.1. GLP study.

The oral LD50 is greater than 2000 mg/kg (rats)

Key study: Experimental results: OECD guideline 401. GLP study.

The oral LD50 is greater than 5000 mg/kg bw (rats)

Acute inhalation toxicity:

In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since exposure of humans via inhalation is not 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.

Acute dermal toxicity:

Key study: Experimental results: OECD guideline 402 and EU method B.3. GLP study.

The dermal LD50 is greater than 2000 mg/kg bw (rats)


Justification for selection of acute toxicity – oral endpoint
Three studies are available. All of them GLP compliant and of high quality (Klimisch 1).

Justification for selection of acute toxicity – inhalation endpoint
In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted since exposure of humans via inhalation is not 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.

Justification for selection of acute toxicity – dermal endpoint
Only one study available.

Justification for classification or non-classification

Based on the available information on acute toxicity, the substance is not classified:

Oral LD50 > 2000 mg/kg bw

Dermal LD50 > 2000 mg/kg bw