N-methylisopropylamine

Endpoint summary

Description of key information

ORAL ROUTE
The acute toxicity of N-Methylisopropylamine (MIPA) following oral administration by gavage to Wistar rats was tested according to the Acute Toxic Class Method as described in the OECD TG 423 (BASFSE10A0834/079067, 2008). The LD50 for MIPA was set as > 50 and < 300 mg/kg bw, however, mortalities, clinical symptoms in surviving animals and pathological findings in those animals that died appears to rather be related to the corrosive potential of the test item than indicating systemic toxicity. Thus, for evaluation of systemic toxicity, the bioavailable form of MIPA, i.e. N-Methylisopropylamine-hydrochloride (MIPA-HCl) was considered.
The acute toxicity of MIPA-HCl following oral administration by gavage to Wistar rats was tested according to the Acute Toxic Class Method as described in the OECD TG 423 (BASFSE10A0413/089043, 2008). The LD50 for MIPA-HCl was set as > 2000 mg/kg bw. 
INHALATION
To assess the acute inhalation hazard potential of N-Methylisopropylamine vapours (MIPA) a GLP study was conducted according to the OECD TG 403 (BASFSE13I0834/077016, 2008). The LC50 for male and female rats was estimated to be 9.09 mg/L. Similar as for the oral route, it appears that the mortalities, clinical symptoms and pathological findings rather were related to the corrosive potential of the test item than indicating systemic toxicity.
DERMAL ROUTE
No study is available for MIPA. Nevertheless, since the test item is corrosive, no testing for the dermal route is needed according to column 2 of REACH Annex VII. 

Additional information

ACUTE ORAL TOXICITY

The acute toxicity of N-Methylisopropylamine (MIPA) following oral administration by gavage to Wistar rats was tested according to the Acute Toxic Class Method as described in the OECD TG 423 (2001); the study conduct followed GLP (BASFSE10A0834/079067, 2008). The test was conducted with female rats only, as recommended by the guideline, and following doses were tested: 2000 (one test group), 300 (one test group), 50 mg/kg bw (two test groups). Each test group consisted of 3 animals. The observation period for mortality, clinical symptoms and body weight was 21 days. All animals were subjected to necropsy.

All animals of the 2000 mg/kg bw group died within the first hour after administration. Thus, mortality at 2000 mg/kg bw was 100%. One animal of the 300 mg/kg bw group was found dead on day 2 of observation whereas a further one needed to be sacrificed on day 17 because of moribund state. Thus, mortality at 300 mg/kg bw was about 70%. All animals treated with 50 mg/kg bw survived.

Because the animals in the 2000 mg/kg bw group died immediately after administration, no clinical symptoms could be reported. Clinical symptoms of toxicity seen in the 300 mg/kg bw group included impaired general state, dyspnoea, piloerection, red to orange-red discoloration of urine, chromodacryorrhoe, reduced feces, exsiccosis, respiration noices and gasping. The findings were seen immediately after treatment and lasted up to observation day 17. No such findings were seen in the 50 mg/kg bw groups. The mean body weights in the 300 mg/kg bw group decreased during the first post-exposure observation week but increased again thereafter. The animals treated with 50 mg/kg bw showed gained weight as expected. Necropsy of the sacrificed animals revealed no abnormalities; gross pathological examination of those animals that died during the experiment revealed dark red to brown discoloration of lung, black discoloration of heart, clotted blood in the thorax, petechial bleeding in the stomach and dark discoloration of liver, stomach, spleen, heart and small intestine.

Thus, the LD50 for MIPA was set as > 50 and < 300 mg/kg bw, however, the clinical symptoms and the pathological findings in those animals that died appears to rather be related to the corrosive potential of the test item than indicating systemic toxicity. Thus, for evaluation of systemic toxicity, the bioavailable form of MIPA, i.e. N-Methylisopropylamine-hydrochloride (MIPA-HCl) was considered.

The acute toxicity of MIPA-HCl following oral administration by gavage to Wistar rats was tested according to the Acute Toxic Class Method as described in the OECD TG 423 (2001); the study conduct followed GLP (BASFSE10A0413/089043, 2008). The test was conducted with female rats only, as recommended by the guideline, and following doses were tested: 2000 (two test groups) and 300 mg/kg bw (one test group). Each test group consisted of 3 animals. The observation period for mortality, clinical symptoms and body weight was 14 days. All animals were subjected to necropsy.

No mortality occurred. All animals of the 2000 mg/kg bw group showed clinical symptoms of toxicity including impaired general state, dyspnoea, piloerection and salivation. The findings were observed from hour 0 through to study day 1 after administration. No such symptoms were seen at 300 mg/kg bw. Body weight was inconspicuous. Necropsy revealed no abnormalities.

Thus, the LD50 for MIPA-HCl was set as > 2000 mg/kg bw.

INHALATION

To assess the acute inhalation hazard potential of N-Methylisopropylamine vapours (MIPA) a GLP study was conducted according to the OECD TG 403 (BASFSE13I0834/077016, 2008) Male and female Wistar rats were whole body exposed during 4 hours to following analytical measured concentrations of the test item: 4.99 and 10.12 mg/L. Each test group comprised 5 animals per sex. 

In the test group treated with 4.99 mg/L test item, no mortality was observed in male and female animals. In the test group treated with 10.12 mg/L test item, 4/5 females and 5/5 males died either during exposure or within study day 2 after the exposure. Clinical signs of toxicity were seen in both test groups and comprised visually increased respiration, abdominal respiration, gasping, respiration sounds, eyelid closure, red crusts formation of the eyes, salivation, colourless discharge and red crust formation of the nose, wiping of the snouts, piloerection, squatting posture, attempts to escape as well as urine smeared anogenital region. Findings were observed from hour 0 of exposure through to the end of the post exposure observation period. In the group exposed to 4.99 mg/L the mean body weights of the male animals increased throughout the study period. The mean body weights of the female animals decreased during the first post exposure observation week but increased during the second week. In the group exposed to 10.12 mg/L the mean body weight of the surviving female animal decreased during the first post exposure observation week but increased during the second week. However the body weight of the surviving female animal did not reach the initial level. In the group exposed to 4.99 mg/L, gross pathological examination at necropsy revealed focal red discoloration of all lung lobes with partly sunken surface in all male animals and in one female animal at termination of the study. No gross pathological abnormalities were observed in the other four female animals. In the group exposed to 10.12 mg/L, gross pathological examination of the male and female animals died either during exposure or within study day 2 after the exposure, revealed focal red or dark red discoloration of the lung. In a few animals partly sunken surface of the lung was noted. In one male animal moderate stomach dilation with gaseous content was noted. At termination of the study, no gross pathological abnormality was noted in the one surviving female animal. Histopathology of the lung of one representative male animal revealed slight acute diffuse congestion, slight acute diffuse alveolar oedema and alveolar emphysema as well as severe to massive acute multifocal to coalescing necrosis of the bronchiolar epithelium.

Thus, under the conditions used, the LC50 for male and female rats was estimated to be 9.09 mg/L. Similar as for the oral route, it appears that the mortalities, clinical symptoms and pathological findings rather were related to the corrosive potential of the test item than indicating systemic toxicity.

Justification for classification or non-classification

For MIPA and for the acute oral route of exposure, the LD50 is between 300 and 2000 mg/kg bw, with 100% mortality reached at 2000. According to the EU Directive 67/548/EC, this implies a classification for MIPA as T R25. According to the CLP Regulation, a classification in Category 3 is warranted. Nevertheless. since the LD50 obtained for MIPA was triggered by the corrosive potential of the test item, MIPA-HCl as systemic available form of MIPA needs to be considered; for MIPA-HCl and for the oral route of exposure, the LD50 is > 2000 mg/kg bw, implying no classification according to EU Directive 67/548/EC and the the CPL Regulation 1272/2008.

For MIPA vapour and for acute inhalative route of exposure, the LC50 is ca. 9 mg/L. Thus, R20 is warranted according to the EU Directive 67/548/EC whereas classification in Category 3 in warranted according to the CLP Regulation 1272/2008.