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Description of key information

In an oral repeated dose study with rabbits an NOAEL could not be derived. The effect seen in surviving animals was renal papillary necrosis. Effects seen in animals that died during the study were apathy, atony, and proteinuria.
In a 10 day dermal repeated dose study with rabbits a NOAEL could not be identified. Effects seen in surviving animals were skin edema and red-brown, widespread parchment-like necrosis with confluent blood discharge.
Regarding inhalation exposure, Sprague-Dawley rats that were exposed 5 hours/day, 5 days/week for 27 weeks or until death a NOAEC could not be identified. Exposure to the test substance caused reduced lifespan of the rats, histopathological changes in kidney and trachea and an increased incidence of tumours in trachea, lung, skin and breast.

Key value for chemical safety assessment

Additional information

Oral

An oral repeated dose study in rabbits is available (BASF, 1967). In this study, the 2 highest doses (1.7 and 4.2 mg/kg bw) were lethal to the animals; apathy, atony, and proteinuria were observed; both erythrocytes and, to a less extend, leukocytes were detected in the urine. Hematology appeared to be normal. Autopsy revealed renal papillary necrosis. The repeated application of 0.84 mg/kg resulted in renal papillary necrosis. Five out of 7 animals of this dose group died due to treatment with the test substance, this mortality was not dependent on the number of applications. The lowest dose was lethal to 3/4 rabbits. Pathology revealed necrosis of the renal medulla. A NOAEL was not identified.

 

Dermal

Repeated (3-4 times) application of 8.3 mg/kg bw test substance led to lethality in 3/3 rabbits within 1-2 days (BASF, 1967). Blood urea was increased and a slight leukocytosis was observed. Proteinuria was noted; both erythrocytes and leukocytes were detected in the urine sediment. Necropsy revealed in all of the deceased rabbits renal papillary necrosis and necrosis of the medulla renalis in both kidneys.

Repeated dermal exposure (10 times) to doses of 4.15 mg/kg bw was survived by three rabbits (BASF, 1967). Slight proteinurea, leukocytes and to a lesser degree erythrocytes in urine were observed. Blood urea values were normal. All parameters returned to normal within the post-exposure period of 5 weeks. Necropsy revealed in one animal renal papillary necrosis; the other two animals were without finding.

Repeated applications of 1.66 mg/kg bw (10 times) did not lead to mortality, clinical signs of toxicity or changes in body weight and blood urea (BASF, 1967). Only leukocyte counts were decreased, and traces of protein and leukocytes were found in urine. After the post-exposure period of 4 weeks, the rabbits were sacrificed and subjected to gross-pathological examination. Necropsy did not reveal any abnormalities.

 

Inhalation

From an inhalation study with Sprague-Dawley rats it can be concluded that ethyleneimine causes histopathological changes in kidney and trachea and an increased incidence of tumours in trachea, lung, skin and breast (BASF, 1978). The animals were exposed to 8.9 µg/L for 27 weeks or until death (approximately 66 weeks).

After exposure to the test substance no symptoms were observed except sporadic sneezing of single animals. The test substance exposed group showed a shortened average survival time compared to the control group. Lethality was increased during exposure to the test substance.

In the kidneys of the male animals of the test groups papillary necroses and oedema were observed. In addition, inflammatory and hyperregenerative changes of the trachea were described in test animals. The incidence of squamous epithelial metaplasia was noticeably increased in test animals compared to control animals (control group/ test group: males 1/35; females 0/2). In one female rat (test group) the formation of polyps was diagnosed. In the lungs of control and test animals squamous epithelial metaplasia accumulated. In one male test animal an adenocarcinoma of the lung was observed. A higher incidence of breast tumours (control group/test group 32/60) in females and skin tumours in males (control group/test group 1/11) indicated a correlation with the exposure to the test substance. 5 male animals from the subchronic dose group showed carcinomas. The incidence of skin tumours in females was lower: in the test group 3 tumours including one carcinoma, in the control group 2 tumours including one carcinoma.

The animals of both test substance exposed groups showed no reduction in body weight compared to the corresponding control groups. No changes of the measured haematology, clinical chemistry and urinalysis parameters were observed compared to the control group.

This study is considered as the key study.

A 24-week subchronic toxicity and carcinogenicity study with rats is also available (BASF, 1978). In this study 50 male and 50 female Sprague-Dawley rats were exposed to 10 ppm (corresponding to approx. 17.87 µg/L) on day 1 to 30 of exposure; 100 ppm (corresponding to approx. 178.7 µg/L) on day 31 and 32 of exposure; 20 ppm (corresponding to approx. 35.74 µg/L) on day 33 to 113 of exposure.

The test substance group showed a shortened average survival time compared to the control group.

During exposure to the test substance, 18% of the males and 10% of the females died, whereas all animals of the control group survived. During the post exposure observation period, 82% males and 80% females of the test substance group died, compared to 2% males and 2% females of the control group. During exposure to 100 ppm, all animals showed severe mucosal irritations and piloerection. The following days all animals showed severe mucosal irritations and intermittent respiration with sneezing.

In the kidneys of males and females papillary necrosis, papilledema and papillary bleeding were found. 48 of 50 animals showed testicular atrophy.

Squamous epithelial metaplasia (males 20, females 7), keratoacanthosis (males 2) and epidermal carcinoma (males 2) were only found in animals exposed to the test substance vapours, whereas tracheitis was found in both, control group (males 30, females 10) and dose group (males 21, females 28).

In the test substance-treated group 1 male showed a lung carcinoma, 1 male and 1 female showed a papilloma/adenoma. A higher incidence of breast tumours (control group/dose group 7/46) and skin tumours (control group/dose group 0/11) indicated a correlation with the exposure to the test substance. 1 male and 1 female of the control group had several tumours, compared to 3 males and 16 females of the dose group with multiple tumours. In the dose group 1 adrenal ganglioneuroma, 3 uterine sarcomas and 1 nephroblastoma were observed, which could not be correlated to the exposure of the test substance.

Justification for classification or non-classification

Ethyleneimine is not classified according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.