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Additional information

Repeated dose toxicity: via oral route - systemic effects (read-across)


In a read-across assessment, 2 -(Methylamino)ethanol was identified as the source chemical displaying the highest toxicity hazard when considering repeated exposure. In the key combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (BASF SE, 2010; 95R0540/07110), the source chemical 2 -(Methylamino)ethanol in deionized water was administered to groups of 10 male and 10 female healthy young Wistar rats (F0 parental generation) by oral gavage administration at dose levels of 50, 150 or 450 mg/kg bw/day (dose volume: 10 mL/kg bw). A concurrent control group was treated with the vehicle only. The duration of treatment covered a 2 -week premating 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 13 days after the beginning of treatment, F0 animals were mated to produce a litter (F1 generation). Mortality, clinical signs including FOB and locomotor activity assessment, body weights, food consumption and parameters of clinical laboratory investigations (hematology, clinical chemistry, urinalysis) as well as fertility and developmental parameters were assessed/recorded during the study period. Following necropsy, the F0 generation animals were examined macroscopically and histopathologically. The weights of selected organs were determined.

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 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 -(Methylamino)ethanol 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 toxicity: via oral or inhalation route (waiving)

With regard to repeated dose toxicity, no additional studies are considered required for a reliable hazard assessment for the target chemical 2 -(Methylamino)ethanol, compound with Sulfur dioxide. This is considered supported by the availability of reliable data for the oral route (read-across), the low acute systemic toxicity of the target chemical (please refer to section 7.2) and the lack of relevant skin or eye irritating properties. The induction of local effects via exposure to 2 -(Methylamino)ethanol, compound with Sulfur dioxide cannot be excluded.

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).


Justification for classification or non-classification

Considering repeated dose toxicity and the source chemicals idenitifed for read-across assessment (section 13), Methylaminoethanol is currently classified with STOT SE 3; H335 according to Regulation (EC) No 1272/2008 (CLP/GHS). But neither Methyaminoethanol nor Disodium disulfite are classified for hazards related to repeated exposure. Based on the source chemicals used for read-across, 2 -(Methylamino)ethanol, compound with Sulfur dioxide is not proposed for classification for repeated dose toxicity.