1-methylpiperazine

Endpoint summary

Description of key information

There are Klimisch 2 studies available for 1 -methyl piperazine available for acute oral and inhalation toxicity allowing for classification for inhalation acute toxicity.  

An acute dermal toxicity tests is not available; due to the corrosive properties of 1 -methyl piperazine it is not considered scientifically justified to carry out such 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 - 15 November 1967

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

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:

no

Remarks:

pre-GLP

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Monomethylpiperazin
- Analytical purity: 99 %

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system 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:

no

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 died 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:

other: 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

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	8	0/5	0/5	0/5	0/5
722	female	8	0/5	0/5	0/5	0/5

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

Based on the results of this study, the acute oral LD50 was estimated to be ca. 2258 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

ca. 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 - 13 November 1967

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: BASF-Test: Test was based on the Inhalation Hazard (Inhalation Risk) test and was performed in principle according to OECD Guideline 403.
The test is aimed to demonstrate 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:

no

Remarks:

pre-GLP

Test type:

other: inhalation hazard test

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Monomethylpiperazin
- Analytical purity: 99 %

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 171 g (mean)

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

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:

no

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:

LC50

Effect level:

> 21.39 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

1 h

Remarks on result:

other: No mortalities in 6 males and 6 females exposed to saturated vapour at room temperature

Sex:

male/female

Dose descriptor:

LC50

Effect level:

21.39 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

3 h

Remarks on result:

other: 50% mortality; exposed to saturated vapour at room temperature

Sex:

male/female

Dose descriptor:

LC100

Effect level:

12.3 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

8 h

Remarks on result:

other: 100% mortality; 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:

other: see below

Body weight:

The surviving animals gained weight.

Gross pathology:

Animals that died: serous crusts at noses and eyes, hyperemia of the lungs.

Other findings:

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

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

Mean 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.

Conclusions:

The inhalation of a highly enriched/saturated vapor-air-mixture caused mortality within 3 h. The test substance causes local irritation to exposed tissue including respiratory tract.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

18.52 mg/L air

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

oral:

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 (BASF, 1986).

inhalation:

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 (BASF, 1968).

dermal:

No data are available. 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. 2258 mg/kg, as this is greater than 2000 mg/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 3 hour 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.