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Administrative data

Description of key information

NOAEL, rat (oral), 2 years: 50-400 mg/kg bw/d (1000-10,000 ppm)
NOAEC, rat (inhalation) 14 weeks, systemic toxicity: 0.365 mg/L air (76 ppm or 365 mg/m3)
NOAEC, rat (inhalation) 14 weeks, local toxicity: 0.053 mg/L air (10 ppm or 53 mg/m3)
LOAEC, rat (inhalation) 14 weeks, local toxicity: 0.12 mg/L air (25 ppm or 120 mg/m3)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
53 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

oral:

The toxic effects of DEAE were examined in a 2-year repeated dose feeding study (Scientific Associates Inc. 1967; Val. 2).

A total of 35 rats per sex and treated group received 200, 500 and 1000 ppm of test material in feed (the high dose group was gradually increased to 10,000 ppm), corresponding to ca. 11, 25 and 50 mg/kg bw/day (the high dose group was gradually increased to 400 mg/kg bw/day). The control group comprised 60 animals/sex and received feed without test material.

None of the treated animals displayed gross signs of substance-induced toxicity. Adverse signs occurred mainly in the last 6 months in all groups and were associated with aging (this included general poorer health and an increase in mortality). According to the report, since the incidence of mortality of the DEAE-treated groups compared favourably with the controls, DEAE did not produce any earlier or greater numbers of deaths at any dose level. Instances of anorexia were also reported in this study, but the data on individual animals was not given. In the last 12 weeks of the study the high dose male body weight was on average 8.6 % (maximum 11%) lower than the controls. No significant hematological changes were seen. In both sexes of the high dose group, the hematocrit and hemoglobin values were slightly decreased at the 720 day time point. At necropsy, deviations in organ weights were within the expected weight limits for the respective organs and no dose- response relationship could be evidenced.

Gross pathology at 6 months was inconspicuous. At 12 months one case of slight testicular atrophy was grossly observed in one 200 ppm-dosed male. At 24 months, i.e. at the end of the study period, testicular atrophy was observed in 3/18 (17%) animals of the 200 ppm dose group, 2/17 (12%) animals of the 500 ppm dose group and 4/15 (27%) animals of the 1000-10,000 ppm dose group; no testicular atrophy was observed in the 34 control males which had been sacrificed at test ending. Only one high dose female had gonad atrophy, but the finding is considered to be fortuitous.

In the high dose group, 3 cases of gonad atrophy were grossly described as slight atrophy in one testis, and this was confirmed histologically; the fourth case was not grossly observed, but the histologic description indicated that 2/3 of the testis had a "moderately severe" generalized degree of atrophy present with only Sertoli cells which remained within most of the seminiferous tubules. According to the sponsor, the lack of testicular atrophy in the controls was surprising given the historical control range of this lesion (data not available). It should be noted that this is not an unusual lesion in ageing rats (Glaister, Principles of Toxicological Pathology, Taylor & Francis, London, 223 pp, 1986). It should be emphasized that in the six month samples, the more appropriate time point for examining reproductive toxicity, no testicular effects were observed. The atrophy often occurred bilaterally.

Despite the fact, that in the males of the high dose group, the incidence of testicular atrophy was clearly increased compared to control (27% versus 0%), the finding is considered to rather be related to the age of the animals than to be treatment-related. In fact, according to James RW and Heywood R (Age-related variations in the testes of Sprague-Dawley rats. Toxicol. Letters Vol 4(4): 257-261, 1979) spontaneous variations in testicular weight and histology are rarely encountered in rats maintained for 13- or 26-week observation periods, however, rats maintained for longer periods tend to show an increasing incidence of testicular atrophy. According to these 2 authors, changes in pituitary gonadotrophin secretion and androgen production observed in ageing male rats support the hypothesis that testicular atrophy is a senescent phenomenon. Thus, even if atrophy of rat testis is considered to be a useful index of chemical toxicity (Ribelin WE, Atrophy of rat testis as index of chemical toxicity, Arch Pathol 75: 229-235, 1963), age-related atrophy must be considered in studies exceeding 12 months’ duration as it is the case in the present study.

Thus, in accordance with the opinion reported in the OECD SIDS on 2-diethylaminoethanol published 2004, the finding “testicular atrophy” was considered to be not treatment-related for the following reasons:

1) the finding was not dose-dependent (17% in the low dose, 12% in the mid dose and 27% in the high dose group);

2) a similar finding was not seen in the 6 month old males sacrificed at interim and at a time point considered to be the more appropriate to assess induction of gonad lesions (James and Heywood, 1979);

3) six months later, only one 12 month old male showed testicular atrophy, which further belonged to the mid dose group;

4) the finding is not an unusual one in aging rats (James and Heywood, 1979; Glaister, 1986);

5) referring to the absence of testicular atrophy in the control group (0%), the sponsor mentioned that the lack of testicular atrophy in the controls was surprising given the historical control range of this lesion; unfortunately, no historical control data were included in the study report. However, according to the OECD SIDS (2004), in a study conducted nearly 35 years later, it was reported that the incidence of testicular atrophy found in control 31 week old Charles River CrJ: (SD) rats was 20% (Sugimoto et al., Background data on organ weights and histopathological lesions in the Crj:CD(SD)IGS rats for 4-, 13-, and 26 week repeated-dose toxicity studies, in Maeda, Y. and Inoue, H. (eds.) Biological Reference Data on CD(SD) IGS Study Group - 2000, Yokohama, 2001: 79 - 87; also cited in OECD SIDS 2004). According to, the type of rat used in the 1960s was probably a Sprague-Dawley (personal communication, P.A. Mirley, 24 June 2002, cited in OECD SIDS 2004). Thus, the testicular finding in this study with 2 year oldalbino rats is not surprising, and the lack of testicular atrophy in the 34 control males most likely was a result of the randomness of the group assignments. Thus, as conclusion, the testicular atrophy observed in particular in the high dose males was considered to rather be age-related than treatment-related. Therefore, the NOAEL was set at 1000 ppm, i.e., 50 mg/kg bw/day, in this 2 year feeding study with rat. 

In a 1 year feeding study groups of beagle dogs (3 males/3 females) were fed levels of 500, 1000, 5000 or 10000 ppm for 365 days (20, 40, 200, and 400 mg/kg bw/d); (Scientific Associates Inc.1966; Val. 2). All animals at the high concentration died between 18 and 35 days of treatment. Animals at the second highest concentration were taken off treatment after 39 days. The 4 survivors from this group were administered 2,000 ppm of the chemical via gelatin capsules on days 134 through day 365. A control group received basal dog meal only. No pronounced treatment-related findings at body weight, organ weights, haematology, clinical chemistry and urinalysis were observed in the blood in any group. Gross necropsy of the animals that died in the first 180 days showed congestion and hemorrhages of the lungs, congestion of the kidneys, reddish mottled coloration of the spleen, hardness of the liver, and numerous enlarged and congested lymph nodes. Microscopic examination of the tissues of the 5000 (2000) ppm group showed atrophy of the thyroid gland (one male and three females) and gonads (three males). Thus, in the present study, the NOAEL was set at 500 ppm, corresponding to ca. 20 mg/kg bw/day. Referring to the testes atrophy, Hottendorf and Hirth (1974) had examined the pathological findings of 1000 animals aged between 8 and 20 months for the purpose of establishing a pathologic profile of gross and microscopic spontaneous occurring lesions in Beagle Dogs (Hottendorf and Hirth, Lesions of spontaneous subclinical diseases in Beagle Dogs, Vet pathol Vol 11: 240-257, 1974). Especially referring to the reproduction organs, atrophy, hyperplasia, giant cell formation and epididymitis in the testes and/or prostate were reported as typical spontaneous occurring lesions. The authors pointed out that the findings indicate that the term “normal”, when applied to experimental Beagle dogs, is an extremely relative term, since the dogs considered for establishment of the pathological profile were young, commercially bred, and clinically healthy. Thus, according to the authors, attention must be given to the fact that spontaneous occurring alterations such as those described above may significantly affect a dog's reaction to high doses of drugs/toxicants and other stressful experimental procedures and must be invoked in the evaluation of experimentally induced changes.

James and Heywood also investigated age-related variations in the testes and prostate of Beagle Dog (James RW and Heywood R, Age-related variations in the testes and prostate of Beagle Dog, Toxicology Vol. 12: 273 -279, 1979). Sufficient data were available to assess the age-related variations occurring in the testes and prostate of a sample of 198 male Beagles aged from 37 weeks to 7.75 years at the time of examination. Age-related differences were apparent in the distribution of total testicular weight. The results of this survey confirmed that spontaneous variations in the weight and morphology of the Beagle testes and prostate may influence the assessment of toxicological data.

In the present study, testes atrophy had been reported ported for the 3 male dogs initially treated with 5000 and then with 2000 ppm. Taking into consideration the observations reported above (Hottendorf and Hirth, 1974; James and Heywood, 1979) and the small number of animals used in the present study, and since severe toxicity was evidenced at the dose level where testes atrophy was seen, the finding was seen as non-specific secondary response to the metabolic or toxic insult of the test substance.

Inhalation:

In a 14 week inhalation study according to U.S. EPA guidelines, 20 rats/dose/sex were exposed to 0, 11, 25 or 76 ppm (approx. 0, 53, 120 or 365 mg/m3) of DEAE for 6h/day, 5 days/week for 14 weeks using a whole body exposure method (Exxon 1990; Val. 1). Half of the animals were terminated at the end of week 14; the remaining animals were given a four week post-exposure recovery period prior to sacrifice. During exposure, dose-dependent transient signs of mild to moderate respiratory irritation (sneeze-like sounds or rales) were noted. Histological changes in the nasal cavities and turbinates were noted in the middle and high dose groups sacrificed in the 14th week of exposure. These consisted of an increased incidence and severity of focal hyperplasia alone or in association with squamous metaplasia of the respiratory epithelium, and multi-focal mixed infiltrations of inflammatory cells in the nasal mucosa. The study indicated that DEAE lacked systemic toxic properties, and the point of contact (eyes and upper respiratory tract) was the site of action. Since no systemic toxicological effects were observed, the NOAEC for systemic toxicity was the highest dose tested, i.e. 0.365 mg/l (76 ppm). The NOAEC for local toxicity, based on the lack of observed effects in the nasal cavity/turbinates, was 0.053 mg/l (11 ppm). The noises or rales were considered an adaptive effect, but not an adverse effect, since no histological changes were observed at this concentration. However, since an effect (rales) was seen at the lowest concentration, a NOEC was not reached. In a range-finding study, the inhalative exposure of rats over two weeks (6 hr/day, 5 days/week) with 10, 56 and 301 ppm (0.048, 0.272 and 1.463 mg/l) caused mortality at the high dose group (Exxon 1988; Val. 2., Hinz 1992; Val 2.). Animals showed signs ocular, nasal, and respiratory distress during and immediately after exposure. Rats exposed to 301 ppm lost weight throughout the study and had a lower food and water consumption. The surviving animals exhibited a number of gross changes but autolytic changes precluded meaningful necropsy evaluations in animals that died as a result of exposure to DEAE. Inflammation of the nasal turbinate and lateral wall mucosa was noted in the 56 ppm group. The epithelium in the infiltrated areas appeared to be flattened, with early squamous cell metaplasia evident in one male of the 56 ppm group. The histopathological changes were dose-related and most evident in the 56 ppm group. The 10 ppm was basically free of abnormalities.

Justification for classification or non-classification

EU classification according to Annex I of Directive 67/548/EEC: none

EU classification according to EC/1272/2008 (CLP): none