Registration Dossier

Administrative data

Description of key information

data on acute oral and dermal toxicity are available for the components.

Amine: LD50 oral > 2000 mg/kg bw (BASF 1993); LD50 dermal 8000 mg/kg bw (UC1973)

Acid: LD50 oral 775 mg/kg bw (SPL1988); LD50 dermal >2000 mg/kg bw (Sodium salt of acid 1986)

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
Remarks:
the tested substance is the acid part of the compound
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.
Qualifier:
according to
Guideline:
other: Safepharm Standard Test Method Number 513.01
Principles of method if other than guideline:
A group of three fasted males and three fasted females were treated with the starting dose (2000 mg/kg bw). As the females dosed with 2000 mg/kg bw died, a further three fasted males and three fasted females were treated with the dose level 300 mg/kg bw. The test material was administered orally as a solution in distilled water. The animals were observed 1/2, 1, 2, and 4 hours after dosing and then once daily for up to 14 days. Bodyweights were recorded on Day 0 (day of dosing) and on Days 7 and 14 or at death. At the end of the observation period the surviving animals were killed by cervical dislocation and all animals were subject to gross necropsy.
GLP compliance:
not specified
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distilled
Details on oral exposure:
The test material was administered orally as a solution in distilled water. The animals were observed 1/2, 1, 2, and 4 hours after dosing and then once daily for up to 14 days.
Doses:
300,2000
No. of animals per sex per dose:
9
Control animals:
yes
Details on study design:
A group of three fasted males and three fasted females were treated with the starting dose (2000 mg/kg bw). As the females dosed with 2000 mg/kg bw died, a further three fasted males and three fasted females were treated with the dose level 300 mg/kg bw. The test material was administered orally as a solution in distilled water. The animals were observed 1/2, 1, 2, and 4 hours after dosing and then once daily for up to 14 days. Bodyweights were recorded on Day 0 (day of dosing) and on Days 7 and 14 or at death. At the end of the observation period the surviving animals were killed by cervical dislocation and all animals were subject to gross necropsy
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
775 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 value is geometric mean between 300 and 2000 mg/kg bw.
Mortality:
Three females were found dead one day after dosing at the 2000 mg/kg bw dose level. There were no deaths at the 300 mg/kg bw dose level.
Clinical signs:
No clinical signs of toxicity were noted in animals treated with 300 mg/kg bw.
Body weight:
The surviving animals showed expected gains in body weight over the study period.
Gross pathology:
Abnormalities noted at necropsy of animals that died duringthe study were abnormally red lungs, dark liver, and dark kidneys.
Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The acute oral LD50 in male/female rats is 775 mg/kg bw. LD50 value is geometric mean between 300 and 2000 mg/kg.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Remarks:
the tested substance is the amine part of the compound
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (OECD 401), GLP compliant
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
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: DR. K. THOMAE GMBH- Age at study initiation: young adult animals- Weight at study initiation: 150 - 300 g- Fasting period before study: 16 h before administration- Housing: single housing- Diet: Kliba-Labordiaet 343, Klingenthalmuehle AG, CH-4303 Kaiseraugust, ad libitum- Water: tap water ad libitum- Acclimation period: at least 1 weekENVIRONMENTAL CONDITIONS- Temperature (°C): 20-24°C- Humidity (%): 30-70 %- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
VEHICLE- Justification for choice of vehicle: The test substance is insoluble in aqua bidest- Concentration in vehicle: 20 or 40 g/100 ml for the 1000 or 2000 mg/kg bw dose, respectively - Amount of vehicle: 5 ml/kg bw
Doses:
1000 and 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: Twice each workday and once on weekends- Frequency of weighing: Individual body weights shortly before application (day 0), weekly thereafter and at the end of the study.- Necropsy of survivors performed: yes- Other examinations performed: clinical signs, body weight
Statistics:
No statistics needed
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality occured.
Clinical signs:
No symptoms were observed.
Body weight:
The expected body weight gain has been observed in the course of the study.
Gross pathology:
No abnormalities were noted at necropsy of animals sacrificed at the end of the study.

Mean body weights.

   male     female     
 Dose  1000 mg/kg  2000 mg/kg  1000 mg/kg  2000 mg/kg  
 day 0 (before application)  181  200  189  188  
 day 7  248  264  220  215  
 day 12  273  -  224  
 day 13  -  301  -  226  
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
775 mg/kg bw
Quality of whole database:
data from representatives of both parts of the salt are used in a worst case approach

Acute toxicity: via inhalation route

Endpoint conclusion
Quality of whole database:
no reliable studies available, waiver based on exposure considerations

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
other: the tested substance is the acid part of the compound
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: CFY (remote Sprague Dawley origin)
Sex:
male/female
Details on test animals and environmental conditions:
Rats were in a weight range of 210 to 239 g prior to dosing on day 1 and approximately six to eight weeks of age. All the rats were acclimated to the experimental environment for a period of 15 days prior to study initiation. Animals were housed in individual metal cages with wire mesh floors. Standard diet and water were provided ad libitum. Each animal was identified by cage number and ear punching.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Test material was a yellow viscous liquid and was applied to an area clipped with electric clippers (approximately 10% of the area) on the backs of 10 rats (five male, five female) at a dose of 2000 mg/kg. The areas were covered with gauze held in place with an impermeable plastic dressing. At the end of 24 hours the dressings were carefully removed and the treated area of skin washed in warm water and blotted dry with absorbent paper.
Duration of exposure:
24 hr
Doses:
2000 mg/kg (undiluted)
No. of animals per sex per dose:
5 male and 5 female
Control animals:
not specified
Details on study design:
Animals were observed soon after dosing and then at frequent intervals for the remainder of day 1. On subsequent days the animals were observed once in the morning and again at the end of the experimental day. The treated areas were examined daily for signs of dermal irritation and assessed according to the standard scoring system for erythema, eschar and oedema. All animals were observed for 14 days after dosing. On day 15 all animals were sacrificed and given a macroscopic post-mortem examination of internal organs.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: undiluted
Mortality:
No mortality was observed exposure to 2000 mg/kg of the undiluted test material.
Clinical signs:
There were no signs of systemic reaction. Well defined or slight erythema and slight oedema were observed at all test sites after removal of the occlusive dressings. These reactions were unresolved before progressive hardening of the skin was first detected on day 4. All test sites were entirely covered by scab formation from day 7. Sloughing from the scabbed skin began at various times between day 7 and day 12 and was completed before test termination.
Body weight:
Low bodyweight gains or loss of bodyweight were recorded for one male and three female rats on day 8. Two of the same females and a third female rat also showed low bodyweight gains between days 8 and 15.
Gross pathology:
All terminal autopsy findings were normal.

There were no deaths or signs of a systemic reaction following a single dermal application at 2000 mg/kg bw. Well defined or slight erythema and slight oedema were observed at all test sites after removal of the occlusive dressing on Day 2. All test sites were entirely covered by scab formation from Day 7. Sloughing from the scabbed skin began at various timesbetween Day 7 and Day 12 and was completed before termination. Lowbodyweight gains or loss of body weight were recorded for one male andthree females in Day 8. Two of the same females and a third female alsoshowed low bodyweight gain between Days 8 and 15.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute lethal dermal dose was found to be greater than 2000 mg/kg.
Executive summary:

The clipped skin on the backs of five male and five female rats were exposed to the test material under an occlusive dressing for 24 hours and observed for another 14 days. Results indicate slight erythema and slight oedema but no acute mortality. The dermal LD50 is > 2000 mg/kg.

Endpoint:
acute toxicity: dermal
Type of information:
other: the tested substance is the amine part of the compound
Adequacy of study:
key study
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was not conducted according to guidelines or GLP but the report contains sufficient data for interpretation of study results.
Reason / purpose:
reference to same study
Reason / purpose:
read-across source
Principles of method if other than guideline:
24 hr dosing period followed by a 14 hour observation period
GLP compliance:
no
Test type:
other: 24 hr dermal dosing period followed by a 14 our observation period
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
Albino rabbits, 3 to 5 months of age.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Male albino rabbits, 3 to 5 months of age, are immobilized during the 24-hour contact period with the compound retained unter impervious sheeting on the clipped intact skin of the trunk. Thereafter, excess fluid is removed to prevent ingestion.
Duration of exposure:
24-hours
Doses:
16000, 8000 or 4000 mg/kg
No. of animals per sex per dose:
4 male rabbits/dose level
Control animals:
not specified
Details on study design:
Non-fasted animals are maintained on appropriate Rockland diets and water ad lib except during period of manipulation or confinement. Dosage intervals differ by a factor of 2 in a geometric series.
Statistics:
LD50 was calculated by the moving average method based on a 14-day observation period.
Preliminary study:
not applicable
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
8 000 mg/kg bw
Mortality:
Rabbits given 16000, 8000 or 4000 mg/kg resulted in 4/4, 2/4 and 0/4 (dead/dosed),
Clinical signs:
Skin irritation consisting of erythema and necrosis where pressure of stocks was present, was observed at all dose levels.
Body weight:
8000 mg/kg in survivors:one rabbit gained 318 g while other rabbit lost 143 g over 14 day observation period4000 mg/kg:all rabbits gained weight during 14 day observation period. Weight gain ranged from 140 to 313 g.
Gross pathology:
Gross pathology consisted of congestion of lungs, livers, spleens and kidneys, mottled livers and opaque stomachs.
Other findings:
no data

Rabbits given 16000, 8000 or 4000 mg/kg resulted in 4/4, 2/4 and 0/4 (dead/dosed), respectively. Skin irritation consisting of erythema and necrosis where pressure of stocks was present, was observed at all dose levels. Gross pathology consisted of congestion of lungs, livers, spleens and kidneys, mottled livers and opaque stomachs.

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The test substance was slightly toxic following acute, covered dermal application
Executive summary:

The amine was applied dermally for 24 hours at doses of 4000, 8000 or 16,000 mg/kg to the intact skin of groups of 4 male rabbits. All rabbits from the 16,000 mg/kg group died while 2 of 4 rabbits from the 8000 mg/kg group died within the 14-day observation period. The dermal LD50 was determined to be 8000 mg/kg using the moving average method of statistical analysis.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
data from representatives of both parts of the salt are used in a worst case approach

Additional information

The acute toxicity testing with the amine and the acid shows that the amine is of lower toxicity than the acid. Therefore in a worst case approach the toxicity data from acid are used to assess the toxicity of the salt.

Justification for classification or non-classification

For oral toxicity the substance needs to be classified in accordance with Regulation (EC) No 1272/2008 (CLP) as acute toxic cat 3 (H302). No classification is necessary for dermal toxicity based on the outcome of the studies.