1-methylpiperidine

Endpoint summary

Description of key information

Acute oral toxicity: 
LD50 (male and female rat): 490 mg/kg bw, non-GLP, comparable to OECD 401, Val 2 (BASF XX/37, 1970).
Clinical signs were accelerated respiration, dypnoea, convulsions.
Acute inhalative toxicity: 
IHT: 2/12 and 6/6 rats died after 3 and 10 min exposure to an atmosphere that had been saturated at 20 degrees centigrade with the volatile parts of the compound within 3 min to 5 days and within 10 min, respectively, Val 2 (BASF XX/37, 1970). 
LC50 (male and female rat, 1 h): > 15.4 mg/L (no mortality), non-GLP, comparable to OECD 403, Val 2 (BASF/FhG, 1979).
Clinical signs are restlessness, intermittent respiration, gasping, salivation, epistaxis, paroxysmal clonic convulsions, respiratory sounds, mouth breathing, serous discharge at the nose, bloody discharge of the eyes,  mucosal irritation. 
Acute dermal toxicity: 
LD50 (male and female rabbit): > 200 mg/kg bw (no mortality), non-GLP, comparable to OECD 402, Val 2 (BASF XX/37, 1979).
LD50 (male and female rabbit): > 1000 < 2000 mg/kg bw, GLP, according to EPA OTS 798.1100 (Acute Dermal Toxicity), Val 1 (Reilly Ind./PSL 1994).
Clinical signs were severe dermal irritation, lethargy, irregular respiration and pale skin.

Additional information

There are valid in vivo data available for the assessment of the acute oral, inhalative and dermal toxicity of the test item.

Oral

In the key study, performed comparable to OECD Guideline 401 (Acute Oral Toxicity) using a standardized test method, rats (10/sex/dose) were given a single oral dose (gavage) of the test item (analytical purity: no data) at the doses of 200, 400, 500, 640, 800 and 1600 µL/kg bw (corresponding to approx. 163, 327, 408, 523, 653 and 1306 mg/kg bw; calculation based on density of 0.8165 g/cm³) (BASF XX/37, 1970). The test item was diluted in water at a concentration of 2, 4, 8 or 20 % v/v and administered at a maximum volume dosage of 12.5 mL/kg. The animals were observed subsequently for a period of 13 days. All surviving animals were killed and together with animals that died during the study subjected to gross pathology. All animals in the high dose group died within 24 hours. No animals died in the lowest two doses. Signs of systemic toxicity were sedate behaviour, accelerated respiration, dyspnea, convulsions, bow cramp, clonic cramp, exophthalmos, extensor spasms, face-down position, chewing pressure, salivation, scrubby fur. In the two low dose groups’ sedate behaviour, accelerated respiration, convulsion and scrubby fur were noted. From day 6 to 8 up to the end of the study nothing abnormal was detected in both treatment groups. There were no data about body weight gain during the study. Gross necropsy findings in deceased rats included bloody erosion at the stomach and oedema at the stomach wall. No abnormalities were noted at necropsy of sacrifized animals.

The acute oral toxicity study is acceptable (reliability 2), and does satisfy the guideline requirements for an oral toxicity test (OECD 401) in rats.

The acute oral LD 50 of the test item for male and female rats was estimated to ca. 490 mg/kg body weight.

In a second study, an acute oral toxicity study conducted according to GLP and EPA OTS 798.1175 (Acute Oral Toxicity), fasted, young adult Sprague-Dawley rats (5/sex/dose) were administered a single oral dose (gavage) of the test item (99.6 % analytical purity) at dose levels of 5, 25, 50, 200, and 500 g/kg body weight (PSL, 1994). The animals were observed for a post-dosing period of 21 days. Subsequently, all surviving animals were killed and together with animals that died during the study subjected to gross pathology.

At a dose of 5 mg/kg bw (administered as a 10% w/w solution in distilled water) no mortality and only slight transient symptoms without substance related necropsy findings were observed, whereas at the doses 25, 50, 200 and 500 mg/kg bw (administered as undiluted liquid) serious effects at the site of action and mortality were detected, caused by the strong corrosive action of the undiluted substance.

Due to the use of an undiluted highly corrosive substance in a gavage study, the study is not acceptable (reliability 3) and is disregarded.

Additionally, according to OECD Guidelines about acute oral toxicity, test substances, at doses that are known to cause marked pain and distress due to corrosive or severely irritant actions, need not to be administered. Thus the study does not satisfy the guideline requirements for an oral toxicity test (OECD 401) in rats.

Inhalative

In the key study, an acute inhalation non-GLP study, except of 1 hour exposure duration comparable to OECD 403 (Fraunhofer Gesellschaft 1979), male and female Wistar rats (10/dose/sex) were nose/head exposed to the test substance (analytical purity: 98 %) as an aerosol at analytical concentrations of 13.8 mg/L and 15.4 mg/L for 1 hour and observed for 14 days. Using an infusion pump the aerosol was pressed into a diffuser nozzle, in which filtered compressed air is supplied additionally. The pressure at the diffuser nozzle is measured by a manometer. The mist from the diffuser nozzle enters the inhalation chamber. Particle size distribution was as following: < 5 µm (89.0 %), 0.5 - 1.0 µm (10.6 %), 1.0 - 3.0 µm (0.4 %). Clinical signs, mortality, body weights, and gross pathological findings were evaluated.

No mortality was observed with both concentrations. Clinical signs were observed at both concentrations (restlessness, intermittent respiration, serous discharge at the nose, slight epistaxis, salivation, slight paroxysmal clonic convulsions, nasal sounds). Bloody discharge of the eyes was observed in 2 males of the high dose group. Beginning with day 8 up to the end of the experiment no clinical signs were detectable in the low dose group and the males of the high dose group, and beginning with day 14 in females of the high dose group.

Body weight gain was significantly reduced in the low dose group for males from day 1 to 8 and for females from day 1 to 7 compared to the control and for males and females in the high dose group from day 1 to 9. No substance related gross pathology abnormalities were observed. Petechiae at the lung and pulmonary emphysema were observed in both, the control and the treatment group.

The acute inhalative toxicity study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for an inhalative toxicity test (OECD 403) in rats (1 instead of 4 hours exposure duration).

The 1 hour LC50 values for the test item in rats were as following:

LC50 (males and females combined) > 15.4 mg/L, respectively.

 

 

In a supporting acute inhalation hazard non-GLP test comparable to OECD 403 (adopted on 1981, 12th May; inhalation hazard test), Wistar rats were nose/head exposed to an atmosphere of saturated vapour-aerosol mixture of the test substance (analytical purity: not known) at 20 °C for 3 (6/dose/sex) or 10 (3/dose/sex) minutes at a mean nominal concentration of ca.106.1 mg/L and observed for 14 days (BASF XX/37, 1970). Mortality was observed with 2/12 rats within 3 min and 5 days and 6/6 rats within 10 min after 3 and 10 min exposure, respectively.

Clinical signs were strong attempts to escape, agitation, strong mucosal irritation, and extreme gasping. On the following days bloody crusts of the eyes and nose and respiratory sounds were observed. There were no data about body weight of single animals. Data on the body weight of the whole groups indicate no or reduced body weight gain within the observation period. Gross necropsy findings in deceased rats included low grade pulmonary emphysema in all animals of the 10 min exposure duration, and in one animal of the 3 min exposure duration. In sacrificed animals no abnormalities were detected. The acute inhalative toxicity study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for an inhalative toxicity test (OECD 403) in rats (no details on animal husbandry, no analytical verification of the test atmosphere concentration in the vapour-air mixture).

These studies show that exposure of highly saturated vapour-air mixtures represents a severe hazard and there is evidence that the test substance is irritating to the respiratory system.

The inhalation hazard tests showing mortality after short exposure of animals to highly saturated vapour-air mixture of the test substance indicate a severe hazard to the respiratory system. In acute inhalation toxicity study comparable to OECD 403 no mortality was observed after exposure of the animals to an aerosol (15.4 mg/L) for 1 hour. The LC0 has to be converted to an inhalation duration of 4 hours by dividing by 4 (Haber’s law for mists) and is determined as 3.85 mg/L. Due to the considerable irritating mode of action of vapour and aerosol of the test substance, damage of the respiratory system after inhalation of the test substance can not be excluded. Additionally, 1-methylpiperidine may be demethylated by monooxygenases to piperidine, shown to be of pronounced toxicity by inhalation; the LC50 of piperidine (CAS 110-89-4) for males and females is 4.8 mg/L after 4 hours exposure duration as determined in a non-GLP but acceptable vapour inhalation toxicity study comparabel to OECD 403 (BASF 77/283, 1980). There is also the fact, that the similar structure 1-ethylpiperidine (CAS 766-09-6) is of pronounced inhalative toxicity; the LC50 for males and females after 4 hours exposure is 2.42 mg/L as shown in a non-GLP but acceptable (reliability 2) acute vapour inhalation toxicity study comparable to OECD 403 (BASF 85/207, 1987).

Accordingly, it is assumed that inhalation of the test compound 1-methylpiperidine may represent a hazard. Therefore, similar to the structural analogues, piperidine and 1-ethylpiperidine, 1-methylpiperidine is considered of pronounced toxicity after inhalation, too.

Dermal

In an acute dermal toxicity, GLP study conducted (PSL 1994) according to EPA OTS 798.1100 (Acute Dermal Toxicity), a single dermal administration of the test substance (analytical purity: 99.6 %) was performed under occlusive conditions by applying doses of 100, 300, and 1000 mg/kg body weight of the undiluted test substance on an area of approximately 10 % of the body surface of New Zealand White rabbits (5/sex/dose) for 24 hours (PSL 1994). At the end of the exposure period test sites were gently wiped with water and a clean towel to remove any residual test substance. The observation period following administration was 14 days.

Clinical signs, mortality, body weights, and gross pathological findings were evaluated. No mortality occurred at 100, 300 and 1000 mg/kg bw. The clinical symptoms noted in three animals were laxation, ano-genital staining and soft feces. Apart from severe dermal irritation at the dose site, all other animals appeared active and healthy. Gross necropsy findings at terminal sacrifice were unremarkable, all tissues and organs appeared normal.

The acute dermal toxicity study is acceptable (reliability 1), and does satisfy the guideline requirements for a dermal toxicity test (OECD 402) in rabbits.

Originally, in a limit test (2000 mg/kg) the test substance was applied dermal to two animals (PSL 1994). Both rabbits were in severe distress and adverse clinical signs (lethargy, irregular respiration and pale skin) were noted within minutes of application. Both animals died within 21 hours of application. Gross necropsy revealed discoloration of the lungs and intestines with vascular injection and gaseous distention of the intestines in one animal. The study was terminated and lower dose levels were selected for testing.

 

The LD50 for dermal exposure was reported to be > 1000 to < 2000 mg/kg body weight for rabbits.

 

In a supporting acute dermal toxicity, non-guideline study conducted similar to OECD Guideline 402, a single dermal administration of the test substance (analytical purity: > 98 %) was performed under occlusive conditions by applying 200 mg/kg body weight of the undiluted test substance on an area of almost 10 % of the estimated body surface of male and female Vienna White rabbits (5/sex) for 24 hours (BASF 77/744, 1979). At the end of the exposure period the residual test substance was rinsed and dried. The observation period following administration was 8 days. Clinical signs, mortality, body weights, and gross pathological findings were evaluated.

No mortality occurred. No systemic toxicity and no body weight gain within 8 days were observed. No substance-related gross pathological findings were observed in sacrificed animals.

The acute dermal toxicity study is acceptable (reliability 2), but does not fully satisfy the guideline requirements for a dermal toxicity test (OECD 402) in rabbits (occlusive dressing, used animals [eye irritation]).

 

The LD50 for dermal exposure was reported to be > 200 mg/kg body weight for rabbits.

 

Conclusion

The test substance is of moderate toxicity after oral uptake, inhalation and short-term skin contact.

 

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available experimental test data for oral, dermal and inhalative toxicity are reliable and suitable for the purpose of classification under Directive 67/548/EEC. As a result the substance is considered to be classified for acute inhalative toxicity (Xn, R20), acute oral toxicity (Xn, R22), and acute dermal toxicity (Xn; R21) under Directive 67/548/EEC.

 

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data for oral, inhalative and dermal toxicity are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. As a result the substance is considered to be classified for acute oral toxicity (Cat 4, H302, Harmful if swallowed), acute inhalative toxicity (Cat 3, H331, Toxic if inhaled) and for acute dermal toxicity (Cat 4, H312, Harmful in contact with skin), under Regulation (EC) No.1272/2008, as amended for the 2nd time in Commission Regulation (EU) No. 286/2011.