O-ethylhydroxylamine

Endpoint summary

Description of key information

LOAEL = 10.8 ppm (0.03 mg/l = 10.8 ppm = 30 mg/m3)
NOAEL = < 10.8 ppm (0.03 mg/l = 10.8 ppm = 30 mg/m3)

Additional information

In a subchronic (28 day) inhalation toxicity study, an aqueous solution of Substance H109360 (50% (w/v) (approx. 46.4% ethoxyamine and approx. 5% ethanol) was administered to five Wistar rats (8 weeks old)/sex/concentration by whole body exposure at concentrations of 0, 10.8, 59, 105 ppm (0.03, 0.15, 0.26 mg/l) (chemical analysis) for 6 hours per day, 5 days/week for a total of 28 days. Target concentrations were 0, 5, 50 and 50 ppm. Nominal concentration calculated form weight loss of the formulation were 0, 10.1, 61.3 and 123 ppm (0, 0.025, 0.153 and 0.306 mg/ml). A satellite recovery group (5 animals/sex/dose) was maintained for an extra 14 days without treatment for controls and the highest dose following the termination of treatment.

 

Exposure to concentrations of up to 105 ppm of the organic amine did not result in severe clinical toxicity and no mortality occurred in any dose. Clinical abnormalities recorded were indicative of a mild, non-specific response to exposure with some indications of respiratory tract irritation (noisy breathing) in a few animals exposed to 105 ppm. Minor histopathological changes were also seen in the respiratory tract. Body weights of animals (both sexes) in the highest dose group and males of the 52 ppm dose group were reduced a day after the first exposure. Thereafter, the day-to-day weight gain of all groups was similar to controls. The overall weight gain of those exposed to 105 ppm remained lower than controls due to their initial weight loss. These effects on the bodyweight were reflected by small reductions in food consumption in the 105 ppm dose group during the exposure phase and up till day 8 of the study. The predominant effects observed were centred around the blood system. Animals of the 59 and 105 ppm dose group developed haematological changes indicative of macrocytic anaemia (decreased haemoglobin, haemotocrit and red cell count with increased mean cell volume and mean cell haemoglobin). Females were affected slightly more than males. There was evidence of a similar, though mild, effect at 10.8 ppm. In addition to these changes there were marked, dose-related, increases in spleen weights and spleen to bodyweight ratios in all test groups at the end of the exposure period. These were associated with splenic congestion, extramedullary haemopoiesis and haemosiderosis. The result of systolic blood pressure measurements made to determine if the splenic changes may be a consequence of the test substance affecting blood pressure remained inconclusive. There was a small increase in heart weight in some test animals (59 and 105 ppm) which is thought to be a compensating consequence of anaemic effects. There was minimal extramedullary haemopoiesis and a few iron-containing Kupffer cells in the livers of animals exposed to 105 ppm. These are considered to be associated with the splenic changes. Clinical chemistry indicated no signs of overt toxicity.

 

Following the recovery period of 14 days there was evidence of resolution of these changes. Spleen weights in the group exposed to 105 ppm were reduced in comparison to those recorded at the end of the exposure period but were still higher than controls. Congestion within the spleen had reduced although haemosiderin deposition was increased. Liver weights and liver-bodyweight ratios were also increased. These probably reflect the recovery processes occuring at this time. The haematological profile suggests a recovery with initial over-compensation for the anaemia. It is considered that following a further period of recovery there would be complete resolution of the effects seen in this study.

 

The may reflect a haemolytic component of the anaemia and the development of methaemaglobinaemia. Although methaemoglobin formation was not positively indentified in this study, it is known that amines can induce methaemaglobinaemia and haemolysis, although this is normally associated with aromatic amines. The LOAEL in this study is 10.8 ppm, based on induction of macrocytic anemia (decreased hemoglobin, hematocrit and red cell count with increased mean cell volume and mean cell hemoglobin) as well as splenic congestion seen from the lowest concentration tested. A NOAEL could not be determined.

 

This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement (OECD 412) for a subchronic inhalation study in the rat.

Conclusion:

Repeated inhalation exposure to low concentrations may affect certain organs.

Repeated dose toxicity: inhalation - systemic effects (target organ) cardiovascular / hematological: hematopoiesis; cardiovascular / hematological: spleen

Justification for classification or non-classification

Ethoxyamine is listed in Annex I of EU directive No. 67/548/EEC and carries the classification of R48/23. This classfication will be maintained.

Ethoxyamine is listed in Annex VI of EU Regulation (EC) No. 1272/2008 as STOT RE 1 (H370). This classification will be maintained.