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Key value for chemical safety assessment

Additional information

Repeated dose toxicity: via oral route


In a read-across assessment, Methylaminoethanol was identified as the source chemical displaying the highest toxicity hazard when considering repeated exposure. Since no reliable conventional repeated dose oral toxicity study was available, an OECD 422 study was identified as key study and starting point for the read-across assessment.

Methylaminoethanol was given orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 50, 150 and 450 mg/kg. The duration of treatment covered pre-mating and mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation in females. At 450 mg/kg, significantly lower body weights in parental animals were accompanied with reduced food consumption and reduced general condition in single animals. Salivation was seen in all high-dose rats, likely to be related to a bad taste of the test substance or local affection of the upper digestive tract. Fertility was severely impaired at dose levels of 150 and 450 mg/kg. Although mating indices were not influenced no lifeborn pups were delivered for both test groups. The deviated levels of clinical chemistry and haematology parameters pointed to anemia and changed liver cell metabolism. The higher incidences of leucocytes in the urine in the 450 mg/kg group and in males of the 150 mg/kg group and increased incidence of higher transitional cell counts in males of 450 mg/kg group can be regarded as an affection of the urinary tract. Target organs were the kidney, testes, epididymides, ovaries, liver, and spleen. In kidneys and testes, tubular degeneration was dose dependent and assessed as an adverse effect. In ovaries, the occurrence of cysts and vacuolization of sex cord stroma was treatment-related and considered to be adverse. In the 450 mg/kg group, the infertility was linked to the reduced number of sperms (oligospermia) caused by tubular degeneration in testes. The occurrence of ovarian cysts and vacuolization of the sex cord stroma in females may also have influenced the fertility. In the 150 mg/kg group, the severity of the findings in testes or ovaries was slight and the findings did not occur in all infertile animals. Nevertheless, these lesions may have affected fertility. In the spleen, a dose-related increase in incidence and severity of extramedullary hematopoiesis occurred in animals of middle and high dose groups. Increased hemosiderin storage in females was associated with the increased relative spleen weights in females receiving 150 mg/kg and was also present in males and females of the high dose group. They were induced in response to anaemia and related to treatment. The liver weights were dose-related increased in all animals of all treatment groups. The liver was enlarged in three males and one female receiving 150 mg/kg and in three males and five females of the 450 mg/kg group. In females, the liver enlargement correlated with a minimal central hepatocellular hypertrophy that was observed in five animals receiving 150 mg/kg and in 9 animals receiving 450 mg/kg. In males, mainly a minimal fatty change of hepatocytes was observed in two animals of the 50 mg/kg group, in 8 animals receiving 150 mg/kg, and in 7 animals of the 450 mg/kg group. The liver findings were related to treatment and considered to be adaptive. Although, there were no clear histopathological correlates for the increased liver weights, a test substance-related effect could not be ruled out. There was no correlation between erosion/ ulcer in the stomach and erythrocytosis of the mesenteric lymph node (findings occurred in different animals). However, a treatment-related effect could not be ruled out but was assessed as non-adverse. All further findings were considered to be incidental or spontaneous in origin and without any relation to treatment. The LOAEL/NOAEL was set at 50 mg/kg.

In a supporting study (BASF SE, 2009), 2 -Aminoethanol hydrochloride was administered to groups of 25 male and 25 female healthy young Wistar rats (F0 parental generation) as a homogeneous addition to the food in different concentrations, which were adjusted regularly to obtain target dose levels of 0, 100, 300 and 1000 mg/kg bw/day. At least 75 days after the beginning of treatment, F0 animals were mated to produce a litter (F1 generation). The detailed description of the study results regarding reproduction toxicity is provided in the section on reproductive toxicity. Regarding general repeated dose toxicity, the dose level of 1000 mg/kg bw/day caused systemic toxicity in parental females, as was indicated by reduced food consumption and/or body weight gain during gestation and lactation. In the mid and high dose F1 animals the absolute and relative kidney weights were statistical significantly increased without histopathological correlate findings. In the high dose F0 and F1 males the test substance administration led to a decrease of absolute and relative organ weights of cauda epididymidis and epididymides. Furthermore, prostate weight and the number of homogenization resistant caudal epididymidal sperm was slightly, but significantly, decreased in the F0 males. These findings were considered to be treatment-related effects, even though histomorphological correlates were missing. Based on this study with 2 -Aminoethanol hydrochloride, the NOAEL for general systemic toxicity was set at 300 mg/kg bw/day, which - under consideration of mass proportions (62.6 % w/w 2 -Aminoethanol in 2 -Aminoethanol hydrochloride - corresponds to a NOAEL of 188 mg/kg bw/day for 2 -Aminoethanol (300 mg/kg bw/day x 0.626).


In a supporting screening study for reproductive hazards, 4 pregnant mice/dose level were exposed to the source chemical 2 -Aminoethanol by oral gavage at 500, 579, 671, 777 or 900 mg/kg bw/day for a period of 9 days (second phase 2 according to the study protocol). The NOAEL was established at 671 mg/kg bw/day based on mortality seen at higher doses levels. No histopathological examination was conducted in this study (Pareira, 1987).


In a dietary 2 -generation reproduction toxicity study (Til et al., 1972), the source chemical Disodium disulfite was shown to display a lower hazard as compared with 2 -Aminoethanol when considering repeated exposure by the oral route. In this study, 20 rats/sex received 0, 0.125, 0.25, 0.5, 1.0 or 2.0 % of Disodium disulfite in a Thiamine-containing diet (50 ppm) for 104 weeks (F0 and F1 generations) or for 30 weeks (F2 generation). Based on the occurrence of occult blood in faeces and changes in gastric morphology at dietary concentrations of 0.5 % or more, the NOAEL for local chronic toxicity in this study was represented by 0.25 % Disodium disulfite (or 0.215 % accounting for the loss of Metabisulfite) and was based on changes in gastric morphology (local irritation). The corrected dose level corresponded to a dose of 108 mg/kg bw/day. Because there was no evidence of systemic toxicity following chronic treatment, the NOAEL for systemic effects was above the highest dose of 2 % Disodium disulfite corresponding to 955 mg/kg bw/day.


Repeated dose toxcity: inhalation


A subacute inhalation toxicity study in rats (BASF SE, 2010) with the source chemical 2 -Aminoethanol was identified as key study for the assessment of the repeated dose inhalation toxicity hazard of the target chemical Bis[(2 -hydroxyethyl)ammonium] sulfite by means of a read-across assessment. In this study, groups of 5 Wistar rats/sex/concentration were nose-only exposed to a dynamic atmosphere of 2 -Aminoethanol for 6 hours per day on 5 consecutive days per week for 4 weeks. The target concentrations were 10, 50 and 150 mg/m³. A concurrent control group was exposed to conditioned air. Clinical observations, body weight determinations and food consumption determinations were performed for all animals. Ophthalmological examinations were conducted prior to exposure and towards the end of the exposure in all animals. After the last exposure, blood was sampled for the assessment of relevan hematology and clinical chemistry parameters. At the end of the treatment period, all surviving animals were subjected to gross necropsy (including macroscopic examination of the major internal organs and determination of organ weights). Selected tissues were processed histopathologically and were evaluated by light microscopy. Histological examinations were performed according to standardised methods with particular emphasis on the nasal cavity (4 levels) and the larynx (3 levels). The exposure of rats to 2 -Aminoethanol caused concentration-related lesions in larynx, trachea and lung. At the high concentration (150 mg/m³), submucosal inflammation (levels I, II) in males and females, degeneration of submucosal glands (level I) in males and females, focal epithelial necrosis (level I) in males and females, focal squamous metaplasia, (level I) in males and females; (level II) in one male and 2 females and focal epithelial hyperplasia (level II) in males and females were observed in the larynx. In the trachea, focal squamous metaplasia (carina) accompanied by inflammation was observed in males. At the mid concentration (50 mg/m³), submucosal inflammation (level I and II) in males and females and squamous metaplasia (level I and II) in few males and females in the larynx was reported. No treatment-related weight changes, gross lesions or microscopic findings were noted at the low concentration (10 mg/m³). No histopathological effects were seen in any other organ outside the respiratory tract. The NOAEC for systemic toxicity was established at the high concentration of 150 mg/m³. The NOAEC for local effects was set at the low concentration of 10 mg/m³ under the conditions of this study. Under consideration of stoichiometry and of the molecular masses of source and target chemicals, the identified NOAEC for systemic effects resulting from repeated inhalation exposure is 150 mg/m³.

According to supporting published data available for the source chemical Disodium disulfite continuous whole body inhalation exposure of beagle dogs for 290 days at 1 mg/m³ indicated substance-related local effects (altered pulmonary clearance rate, macroscopical and histological changes in the upper posterior part of the nasal cavity); no signs of systemic toxicity were reported (Ferron et al., 1990; Takenaka et al., 1994).


Repeated dose toxicity: dermal


No studies are available for dermal repeated dose toxicity.

Justification for classification or non-classification

Considering repeated dose toxicity and the source chemicals idenitifed for read-across assessment (section 13), Methylaminoethanol and 2 -Aminoethanol are currently classified with STOT SE 3; H335 according to Regulation (EC) No 1272/2008 (CLP/GHS). But none of them is classified for hazards related to repeated exposure.

Based on the source chemicals used for read-across, Bis[(2 -hydroxyethyl)ammonium] sulfite is not proposed for classification for repeated dose toxicity.