1,2,3,4-tetrahydroisoquinoline

Endpoint summary

Description of key information

- Oral LD50 about 300 mg/kg bw for rat.
- Dermal LD50 <1000 mg/kg bw for rat (100% mortality at 1000 mg/kg bw, only this dose was tested).
- Inhalation LC50 (4-hour) 1.881 mg/L for rat (95% confidence interval 1.222 - 3.115 mg/L; test atmospheres were mixtures of liquid aerosol and vapour).

Additional information

Acute oral toxicity:

The acute oral toxicity of 1,2,3,4-Tetrahydroisoquinoline in rats was examined in a GLP-compliant study according to OECD 423 and EEC and EPA test guidelines (BASF AG, 2006a). Single doses of 300 and 50 mg/kg body weight of test material preparations in olive oil Ph.Eur./DAB were given to four groups of three fasted female Wistar rats by gavage in a sequential manner. One animal of the first 300 mg/kg group and two animals of the second 300 mg/kg group were found dead on study day 1. No mortality occurred in the 50 mg/kg groups. Clinical observations in the 300 mg/kg groups revealed impaired and poor general state, dyspnoea, staggering, ataxia, rolling convulsions, opisthotonus, extention spasm, tonic convulsions, piloerection, smeared fur, diarrhea, salivation, lacrimation, chromodacryorrhea and red clammy snout and eyelid. Findings were observed from hour 0 through to study day 6 after administration. Clinical observations in the 50 mg/kg groups revealed impaired general state, dyspnoea, piloerection, smeared fur and diarrhea. Findings were observed from hour 1 through to hour 5 after administration. The mean body weights of the surviving animals increased throughout the study period. Necropsy findings in the animals that died in the 300 mg/kg group comprised a few black erosions/ulcers in the glandular stomach and a black discoloration of the contents in the small intestine. No macroscopic pathologic abnormalities were noted in the surviving animals of the first 300 mg/kg group. The following macroscopic pathologic abnormality was noted in the surviving animal of the second 300 mg/kg group: a few black erosions/ulcers in the glandular stomach. No macroscopic pathologic abnormalities were noted in the animals of the 50 mg/kg groups at the end of the observation period. lmmunohistochemistry for tyrosine hydroxylase (specific marker to reveal dopaminergic neurons and their synaptic end terminals) of all animals of the first 300 mg/kg group and of the two animals that died of the second 300 mg/kg group revealed a slight decrease of staining intensity in the corpus striatum of forebrain sections, indicating the possibility of a diminished dopamine content in this target Iocation of dopaminergic neurons. Further pathological changes (e.g. necrotic neurons) were not detected in this first and limited, morphological examination of two brain levels.

Under the conditions of this study the median lethal dose of 1,2,3,4-Tetrahydroisoquinoline after oral administration was found to be about 300 mg/kg body weight in rats.

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Acute inhalation toxicity:

The acute inhalation toxicity (single 4-hour exposure) of 1,2,3,4-Tetrahydroisoquinoline was examined in a GLP-compliant study in rats according to OECD 403 and EEC and EPA test guidelines (BASF SE, 2009). Groups of five male and five female Wistar rats were exposed to the following measured concentrations: 0.130 (68% vapour and 32% liquid aerosol), 0.408 (17% vapour and 83% liquid aerosol), 1.119 (6% vapour and 94% liquid aerosol) and 3.113 mg/L (4% vapour and 96% liquid aerosol) (test groups 1-4, respectively). Following exposure, the animals were observed for 14 days. Animals of group 1 were exposed in a whole-body system, those of the other groups in a head-nose system. Due to the vapour pressure of the test substance, the test atmospheres consisted of both vapour and liquid aerosol fraction. Cascade impactor measurements (groups 2-4) showed particle size distributions with mass median aerodynamic diameters (MMADs) of 1.8 and 1.9 μm, which are well within the respirable range.

No mortalities occurred at 0.130 mg/L and 0.408 mg/L. At 1.119 mg/L two of five males but no females died. At 3.113 mg/L all female and three of the five male animals died or were sacrificed in a moribund state, either during exposure, after exposure on study day 0 or on study day 1.

Clinical signs in animals exposed to 0.130 mg/L comprised visually increased respiration, abdominal respiration and piloerection. Findings were observed from hour 1 of exposure through to study day 2. No clinical signs and findings were observed from study day 5 onwards. Mean body weights increased throughout the study period. No gross pathological abnormalities were noted during necropsy at termination of the post exposure observation period.

Clinical signs in animals exposed to 0.408 mg/L comprised visually increased respiration, abdominal respiration, salivation, tremor, unsteady gait and piloerection. Findings were observed from hour 1 of exposure through to study day 5. No clinical signs and findings were observed from study day 6 onwards. Mean body weights increased throughout the study period. No gross pathological abnormalities were noted during necropsy at termination of the observation period.

Clinical signs in animals exposed to 1.119 mg/L comprised abdominal respiration, gasping, labored respiration, respiration sounds, poor general state, eyelids red crusts and piloerection. Findings were observed from hour 1 of exposure through to study day 7. No clinical signs and findings were observed from study day 8 onwards. Mean body weights of the surviving animals increased throughout the study period. Gross pathological abnormalities were neither noted in the male animals that died on study day 0 nor in those sacrificed at the termination of the observation period.

At 3.113 mg/L the clinical signs of toxicity were very similar to those described above. Visually decreased respiration and abdominal position were noted additionally; but red crusts around eyelids were not seen. Findings were observed from hour 1 of exposure through to the end of the post exposure observation period. Mean body weights of the surviving male animals decreased during the first post exposure observation week but increased during the second week. Necropsy findings of the male and female animals that died on day 0 showed no gross pathological abnormalities. In the female that died on day 1 several black erosions/ulcers of the glandular stomach were observed. No gross pathological abnormalities were noted in the two male animals sacrificed at termination of the observation period.

Immunohistochemistry for tyrosine hydroxylase (specific marker to reveal dopaminergic neurons and their synaptic end terminals) of all animals exposed to 3.113 mg/L and of two control animals (1/sex) revealed no differences in the staining intensity in the nigrostriatal bundle and substantia nigra of brain sections. Further pathological changes (e.g. necrotic neurons) were not detected in this first and limited, morphological examination of brain levels.

Under the conditions of this study the LC50 for male and female rats after a single 4-hour inhalation exposure to 1,2,3,4-Tetrahydroisoquinoline as mixtures of liquid aerosol and vapour was estimated to be 1.881 mg/L (probit analysis for both sexes combined; 95% conficence interval 1.222 – 3.115 mg/L).

 

Acute dermal toxicity:

The acute dermal toxicity of 1,2,3,4-Tetrahydroisoquinoline was examined in a GLP-compliant study in rats according to OECD 402 and EEC and EPA test guidelines (the dose tested was lower than the limit of 2000 mg/kg body weight specified in these guidelines) (BASF AG, 2006b). A single dose of 1000 mg/kg body weight of the test material was applied in five male and five female Wistar rats to the clipped skin (dorsal and dorsolateral parts of the trunk) and covered by a semi-occlusive dressing for 24 hours. All animals were killed in a moribund state on study day 1. Clinical observation revealed impaired and poor general state, dyspnoea, staggering, ataxia, tremor, smeared fur, salivation, chromodacryorrhea and red or distinct yellow discolored urine. Findings were observed from hour 2 through to study day 1 after application. The following skin effects were observed on study day 1 at the application site: very slight edema, induration and dryness of the skin at the application area and red and dark-brown discolored application area. The body weights of the animals severely decreased within 1 day after application. Necropsy findings comprised a few to many black erosions/ulcers in the glandular stomach, edema in the lung, dark brown or red discoloration of the skin in the region of the application site and a black discoloration of the contents of the small intestine. Histopathological examination of the skin revealed moderate to extreme epidermal and follicular necrosis with pyknosis, and necrotic epidermis remaining in situ. Minimal inflammatory infiltrates were observed in 1 male animal.

Under the conditions of this study, indication of skin corrosivity was observed and the acute dermal median lethal dose (LD50) of 1,2,3,4-Tetrahydrolsoquinoline was less than 1000 mg/kg body weight in male and female rats.

Justification for classification or non-classification

According to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 the substance needs to be classified for acute oral toxicity as Cat.3 (H301: Toxic if swallowed) based on its LD50 value (rat) of about 300 m/kg bw, for acute dermal toxicity as Cat.2 (H310 Fatal in contact with skin) based on a presumed dermal LD50 (rat) of ≤200 mg/kg bw (100% lethality occurred at 1000 mg/kg bw), and for acute inhalation toxicity as Cat.4 (Harmful if inhaled) based on its LC50 (4-hour, rat) of 1.881 mg/L (>90% aerosol).

 

According to Directive 67/548/EEC the substance needs to be classified for acute oral toxicity as Xn; R22 Harmful if swallowed, for acute dermal toxicity as T; Toxic in contact with skin, and for acute inhalation toxicity as Xn; R20 Harmful by inhalation.