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Administrative data

Description of key information

There are Klimisch 2 studies available on the 1-methyl piperazine available for acute oral and inhalation toxicity allowing for classification for inhalation acute toxicity.  Dermal acute toxicity tests are not available and due to the corrosive properties of 1-methyl piperazine it is not considered scientifically justified to carry out a study

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:
07. Nov 1967 - 15. Nov 1967
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented report which meets basic scientific principles.
Principles of method if other than guideline:
BASF-Test: The study was conducted according to an internal BASF method which in principle is comparable to the OECD Guideline 401.
A test group consisting of 5 animals/sex was treated by single gavage application with an aqueous solution of the test substance. The animals were observed for mortality and for clinical symptoms of toxicity. At the end of the observation period of 7 days, the surviving animals were sacrificed for the purpose of necropsy; animals that died during the observations period also were subjected to necropsy.
GLP compliance:
not specified
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 118 - 236 g
Route of administration:
oral: gavage
Vehicle:
water
Doses:
800, 1600, 2000, 2500, 3200, 4000 cmm/kg bw (722, 1444, 1806, 2258, 2890, 3612 mg/kg bw - conversation in mg/kg is based on the density: d= 0.903 g/cm3).
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 2 258 mg/kg bw
Remarks on result:
other: conversation in mg/kg is based on the density: d=0.903 g/cm3.
Mortality:
3612 mg/kg: all animals die within 24 h.
2890 mg/kg: 1 male and 5 females died within 24 h.
2258 mg/kg: 1 male and 5 females died within 24 h.
Lower dose levels: no mortalities.
Clinical signs:
3612 mg/kg: 3 h post application abdominal and lateral position, closed eyes, irregular respiration. 24 h post application ruffled fur, apathy, closed eyes, shallow respiration.
2890 mg/kg: After 30 min abdominal position, intermittent respiration, closed eyes. 24 h post application squatting posture, irregular respiration, rufled fur.
1806 mg/kg: After 10 min high stepping gait, accelerated respiration. 24 h post application accelerated respiration, ruffled fur and high stepping gait.
Body weight:
no data
Gross pathology:
Animals that died:
All animals showed stomach ectasia with liquid-mucous, partially bloody content. 10 x blood filled secretion vesicles in the nose.

Mortality:

 Dose (mg/kg)  Gender  Conc.(%)  dead within 1h  dead within 24 h  dead within 48 h  dead within 7 days  
3612  male  30 0/5 5/5 5/5 5/5  
3612  female  30 0/5 5/5 5/5 5/5  
2890  male  30 0/5 1/5 1/5 1/5  
2890  female  30 0/5 5/5 5/5 5/5  
2258  male  20 0/5 1/5 1/5 1/5  
2258  female  20 0/5 5/5 5/5 5/5    
1806  male  20 0/5  0/5 0/5 0/5    
1806   female  20 0/5 0/5  0/5 0/5    
1444  male  20 0/5 0/5  0/5 0/5    
1444  female  20 0/5 0/5  0/5 0/5     
722  male 0/5 0/5  0/5 0/5     
722  female 8 0/5 0/5  0/5 0/5    

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 258 mg/kg bw
Quality of whole database:
The study is considered to be adequate for classification and labeling purposes, the test substance was clearly specified as mono methyl piperazine of 99% purity.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06. Nov 1967 - 13. Nov 1967
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented report which meets basic scientific principles.
Principles of method if other than guideline:
Method: BASF-Test: Test was performed in principle as described in OECD Guideline 403.
The test demonstrates the toxicity of an atmosphere saturated with vapours of the volatile components of a test substance at the temperature chosen for vapour generation (room temperature). 3 rats per sex were exposed sequentially to the vapours, generated by bubbling 200 l/h air through a substance column of about 5 cm above a fritted glassdisc in a glass cylinder for 1, 3 and 8 h. The documentation of clinical signs was performed over a period of 7 days.
GLP compliance:
not specified
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 171 g (mean)
Route of administration:
inhalation: vapour
Type of inhalation exposure:
not specified
Vehicle:
other: unchanged (no vehicle)
Analytical verification of test atmosphere concentrations:
no
Remarks on duration:
1, 3 or 8 h
Concentrations:
1 h exposure: 21.39 mg/l
3 h exposure: 21.39 mg/l
8 h exposure: 12.30 mg/l
Nominal concentrations. No verification of concentration by analysis.
No. of animals per sex per dose:
1 h exposure: 6
3 h exposure: 3
8 h exposure: 3
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 7 days
- Frequency of observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs
Key result
Sex:
male/female
Dose descriptor:
other: Inhalation Risk Test
Remarks:
Saturated vapour at room temperature
Effect level:
> 21.39 mg/L air (nominal)
Exp. duration:
1 h
Remarks on result:
other: No mortalities in 3 males and 3 females exposed to saturated vapour at room temperature
Mortality:
8 h exposure: 4 animals died within 7 h, 1 animal after 24 h and 1 animal after 6 days.
3 h exposure: 3 animals died within 24 h.
1 h exposure: no mortalities.
Clinical signs:
8 h exposure: Initially escape attempts, irritation of mucous membranes, dyspnoea. After the exposure staggering and tremor, swelling of the paws.
3 h exposure: Initially escape attempts, irritation of mucous membranes, dyspnoea. 5 h post exposure crusted eyes and symptoms of corrosion. 1 animal lost the eyesight on one eye.
1 h exposure: Irritation of the mucous membrane, symptoms of corrosion.
Body weight:
The surviving animals gained weight.
Gross pathology:
Animals that died:
Serous crusts at noses and eyes. Hyperemia of the lungs.

Mortality:

   24 h  7 days      
 1 h exposure  0/12  0/12      
 3 h exposure  3/6  3/6      
 8 h exposure  4/6  6/6      

Weight (g):

   day 0  day 7      
 1 h exposure  175 193       
 3 h exposure  163 201      
 8 h exposure  170      

The inhalation of a highly enriched/saturated vapor-air-mixture caused mortality within 3 h.

There is indication that the test substance causes local irritation to exposed tissue including respiratory tract.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
18.52 µg/m³
Quality of whole database:
The study is considered to be adequate for classification and labeling purposes, the test substance was clearly specified as mono methyl piperazine of 99% purity.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are Klimisch 2 studies available on the 1-methyl piperazine available for acute oral and inhalation toxicity allowing for classification for inhalation acute toxicity. The oral toxicity study which is an old study is of acceptable quality and indicates and oral LD50 greater than 2000mg/kg bodyweight/day and therefore not classified for EU CLP. The inhalation acute toxicity study is also old, but scientifically valid at a dose of 21.39mg/l for a 3 hour exposure 50% died, this value was converted to a 4 hour value of 18.52 mg/l. Dermal acute toxicity tests are not available and due to the corrosive properties of 1-methyl piperazine it is not considered scientifically justified to carry out a study. As oral absorption is expected to be higher than dermal absorption it is unlikely that a dermal LD50 study would have provided a value that would require classification under EU CLP criteria.

Justification for selection of acute toxicity – oral endpoint

There is a Klimisch validity 2, pre-GLP oral LD50 study available for 1-methyl piperazine CAS No 109-01-3 carried to a protocol equivalent to OECD401. The oral LD50 was considered to be ca. 2258 mg/kg for males and females combined, there were some deaths at this dose level but none at the next lower dose level of 1806 mg/kg.  Therefore 1-methyl piperazine is not classified for acute oral toxicity by the criteria of EU CLP but would be category 5 against global GHS criteria.

Justification for selection of acute toxicity – inhalation endpoint

There is a Klimisch 2 validity pre-GLP inhalation toxicity study carried out to a protocol similar to OECD 403 before the guideline was available. The study showed 50% mortaility at a nominal exposure of 21.39mg/l of vapour for 3 hours.  The EU CLP and GHS criteria for acute inhalation toxicity are based on a 4 hour exposure; this can be assumed to correspond to an LC50 between 10 and 20mg/l over 4 hours and therefore classified as Category 4 for acute inhalation toxicity.  The estimated 4 hour LC50 can be derived as 3hour LC50 √3 / √4, so that is 21.39mg/l √3 / √4 = 18.52mg/l.

Justification for selection of acute toxicity – dermal endpoint

1-methyl piperazine CAS No 109-01-3 was found to be corrosive to skin; therefore it is not scientifically justified on animal welfare grounds to conduction a dermal LD50 study.  Toxicokinetic  information indicates that 1-methyl piperazine would be expected to be rapidly absorbed via the oral route of exposure.  It is therefore unlikely that a dermal LD50 study would indicate more serious acute toxicity than the oral LD50 which indicates no need for classification as it is greater than 2000mg/kg.

Justification for classification or non-classification

The oral LD50 for 1-methyl piperazine is ca. 2258mg/kg, as this is greater than 2000mg/kg, there is no requirement for classification for acute oral toxicity based on the EU CLP criteria. There is also calculated inhalation LC50 of 18.52 mg/l, 4 hour based on the 3hour value of 21.39 mg/l. This corresponds to a classification of Category 4 for acute inhalation toxicity by the EU CLP criteria. We do not have a study for acute dermal toxicity, due to the corrosive nature of the 1-methyl piperazine, performing such a study this is not scientifically justified. However as oral absorption is expected to be higher than dermal absorption it is unlikely that a dermal LD50 study would have provided a value that would require classification under EU CLP criteria.