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Key value for chemical safety assessment

Effects on fertility

Additional information

Effects on fertility: via oral route (read-across)

 

In a read-across assessment, 2 -Aminoethanol was identified as the source chemical displaying the highest toxicity hazard when considering systemic effects (including effects on fertility) that may result from repeated exposure for 2 generations. Since no reliable reproduction toxicity study with 2 -Aminoethanol was available, a 2 -generation repeated dose dietary oral toxicity study with 2 -Aminoethanol hydrochloride (BASF SE, 2009; 75RO372/05055) was identified as key study and starting point for the read-across assessment under the assumption that the observed test substance related effects were entirely attributable to 2 -Aminoethanol (and not to Hydrochloride). 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 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 (300 and 1000 mg/kg bw/day) the absolute and relative kidney weights were statistical significantly increased without histopathological correlate findings. In the high dose F0 and F1 males (1000 mg/kg bw/day) 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 effects on fertility was set at 300 mg/kg bw/day, which - under consideration of mass proportions (62.6 % w/w 2 -Aminoethanol in 2 -Aminoethanol hydrochloride; 49.2 % w/w 2 -Aminoethanol in (2 -Hydroxyethyl)ammonium nitrate) - corresponds to a NOAEL of 188 mg/kg bw/day for 2 -Aminoethanol (300 mg/kg bw/day x 0.626) and a NOAEL of 382 mg/kg bw/day (188 mg/kg bw/day / 0.492) for the target chemical (2 -Hydroxyethyl)ammonium nitrate.

 

In a reliable supporting subacute toxicity study (Product Safety Laboratories, 2002; 11686), the source chemical Potassium nitrate was shown to display a lower hazard as compared with 2 -Aminoethanol when considering repeated exposure by the oral route. In this combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, 5 male and 10 female rats (reproduction subgroup) received single daily oral gavage treatments with Potassium nitrate in water at dose levels of 0, 50, 750 or 1500 mg/kg bw/day for at most 28 days (males) or 53 days (females, up to lactation day 4). Mortality, clinical signs, body weight and food consumption were assessed periodically during the treatment period. Gestation length, gestation index and litter size were assessed. At the end of the treatment period, all surviving parental animals were sacrificed, examined macroscopically and the weights of selected organs were determined. Tissues and organs were examined histopathologically. Litter observations included determination of number and sex of pups and survival indices, body weight (gain) determination and examination for gross anomalies. Treatment with Potassium nitrate resulted in no deaths and no signs of overt clinical toxicity. There were no substance-related effects on body weight and food consumption. Organ weights were not affected by the treatment with the test substance. There were no macroscopical lesions or microscopical findings in parental animals attributable to the treatment with the test substance. No adverse effects were seen on reproduction/developmental toxicity endpoints. Under the conditions of this study, the NOAEL for effects on reproduction and/or development was established at the high dose level of 1500 mg/kg bw/day.

Effects on developmental toxicity

Additional information

Effects on developmental toxicity: via oral route, via the dermal route (read-across)

In a prenatal developmental toxicity study (BASF AG, 1994; 60RO351/91062), pregnant Wistar rats were exposed to the source chemical 2 -Aminoethanol by gavage at dose levels of 40, 120 or 450 mg/kg bw/day on days 6 - 15 of gestation. Signs of maternal toxicity were observed at the highest dose, manifested as reduced food consumption, lower mean body weights and impaired body weight gain. Reproductive and developmental toxicity parameters were not significantly affected. Slight effects occurred in regard to pre- and post-implantation loss. In further reprotoxic studies of amines (Diethanolamine, Triethanolamine) decreased number of implants or increased resorption rates were found. It was discussed that these effects might be mediated by a disturbedcholine homeostasis rather than through a direct embryo toxicity. These effects may be inhibition of cholin-uptake in the liver, subsequent perturbation of choline-homeostasis, with subsequent impairment of C1-metabolism, DNA-methylation, lipid metabolism, and intercellular communication. Choline metabolism is connected to Phosphatidylcholine and Betaine. The latter is reported to be central for the synthesis of SAM (S-Adenosyl-Methionine), a principle methylating agent for biosynthetic pathways and maintenance of critical gene methylation patterns (Stott et al. 2004; Zeisel and Blusztajn, 1994).Demonstration of a choline-dependency of the critical window for the observed effect on pre- and postimplantation would provide a basis for evaluating the human relevance or non-relevance of these findings. Further studies are planned to investigate the mechanisms. For that reason, the NOAEL for developmental effects was thus established to correspond to 450 mg/kg bw/day, which - under consideration of mass proportions (49.2 % w/w 2 -Aminoethanol in (2 -Hydroxyethyl)ammonium nitrate) was estimated to be 915 mg/kg bw/day (450 mg/kg bw/day / 0.492) for (2 -Hydroxyethyl)ammonium nitrate. The NOAEL for maternal toxicity by the oral route was 120 mg/kg bw/day.

In another comparable to guideline prenatal developmental toxicity study (Liberacki et al., 1996) rats and rabbits were exposed to 2 -Aminoethanol dermally.

Pregnant Sprague-Dawley rats were exposed dermally to 10, 25, 75 or 225 mg/kg bw/day of 2 -Aminoethanol (Liberacki et al., 1996). Rats administered 225 mg/kg bw/day exhibited a treatment-related increased incidence of skin irritation and the body weight gain was significantly decreased during the exposure period. Despite maternal effects observed among dams in the high dose group, reproductive and developmental toxicity parameters among exposed rats were unaffected at all dose levels. The NOAEL for maternal toxicity was set at 75 mg/kg bw/day and the NOAEL for developmental toxicity was set at the highest dose level of 225 mg/kg bw/day. Thus, using the same read-across approach as for the oral route, the NOAEL for developmental toxicity by the dermal route of exposure is established at 457 mg/kg bw/day for (2 -Hydroxyethyl)ammonium nitrate in rats.

In the rabbit study (Liberacki et al., 1996; Neeper-Bradley and Kubena, 1993) exposure was via the dermal route to 10, 25 or 75 mg/kg bw/day of 2 -Aminoethanol. The rabbits in the mid and high dose group exhibited signs of skin irritation, severe at the highest dose level. No treatment-related effects were observed on reproductive and developmental toxicity parameters. The NOAEL for maternal toxicity was set at 10 mg/kg bw/day and the NOAEL for developmental toxicity was set at the highest dose level of 75 mg/kg bw/day.

In a reliable supporting study conducted as combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (Product Safety Laboratories 2002; 11686), oral gavage administration of Potassium nitrate in water to 5 male and 10 female Sprague Dawley rats/dose level at dose levels of 250, 750 or 1500 mg/kg bw/day resulted in no test substance-related adverse effects with respect to general toxicity and relevant reproduction/developmental toxicity endpoints. Under the conditions of this study, the NOAEL for maternal toxicity and the NOAEL for developmental toxicity were set at 1500 mg/kg bw/day.

Justification for classification or non-classification

Based on the results of key studies (reproduction toxicity, developmental toxicity) conducted with the relevant source chemicals 2 -Aminoethanol or 2 -Aminoethanol hydrochloride, and with special regard to minor effects on fertility seen at the limit dose level and without histopathological correlate in the key reproduction toxicity study, (2 -Hydroxyethyl)ammonium nitrate is not considered to be subject to classification for reproduction toxicity according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (GHS/CLP). There are hints that a human relevance regarding the reproductive effetcs induced by amines is missing based on cholin-metabolism which is currently under evaluation.