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EC number: 203-680-9 | CAS number: 109-55-7
Repeated dose toxicity: oral In a 28 days repeated dose oral toxicity study conducted on rats, the NOAEL was 50 mg/kg bw/day and the LOAEL was found to be 250 mg/kg bw.
In a 90 days repeated dose oral toxicity study with the structurally related Diethylaminopropylamine (as pH-neutralized dose formulations) conducted on rats, the NOAEL was established at 750 mg/kg/day in males and 250 mg/kg/day in females.
In a 13-week subchronic study with the structurally related ethylene diamine (EDA) conducted on rats, no NOAEL could be established. The LOAEL was 100 mg/kg bw/day based on the eye effects. In a 3-months subchronic study with the structurally related ethylenediammonium dichloride (EDA*2HCL) on rats, the NOAEL was considered to be approximately 50 mg/kg bw/day for EDA*2HCl (corresponding to 22 mg/kg bw/day of EDA).
In a combined chronic toxicity and carcinogenicity with the structurally related ethylenediammonium dichloride (EDA*2HCL) there was no evidence for a carcinogenic potential ofEDA*2HCLin male and female F344 rats. The NOAEL for chronic toxicity was 20 mg/kg bw/day for EDA*2HCl (corresponding to 9 mg/kg bw/day of EDA).
Repeated dose toxicity: inhalation In a 6-week subsacute inhalation toxicity study with the structurally related ethylene diamine (EDA) on rats, the NOAEC for subacute inhalation was 59 ppm
(corresponding to 144 mg/m3).
Repeated dose toxicity: dermal In a dermal carcinogenicity study with the structurally related ethylene diamine (EDA) in mice, there was no evidence for a carcinogenic potential of EDA after life-time
dermal administration. The NOAEL was 8.3 mg/kg bw/day (25 µL 1% solution/per mouse).
Table 1. Mean body weight change/Mean body weight (expressed in g)
Body weight change
. Days 1 to 4
. Days 4 to 8
. Days 8 to 11
. Days 11 to 14
. Days 1 to 14
% compared to controls
. Day 1
. Day 14
-: not applicable; *: p<0.05 and **: p<0.01, statistically significant.
Table 2. Mean food consumption (expressed in g/animal/day)
-: not applicable.
Table 3. Organ weights
Exam. animals / Num. of animals
- Final body weight
Statistically significant from controls: *: p<0.05.
The significance concerned the organ weights values and not the percentages.
Six male and one female rat from the 1600 mg/kg group died during the in-life phase of the study. All animals in the lower dose groups survived to the end of the study.
Animals in the two highest doses exhibited gasping, sneezing and squinting of both eyes shortly after dose administration. In some animals from the 600 and 800 mg/kg groups, there was a discoloration of the eye while others exhibited a purple color. Subsequently, rats from both dose groups developed white masses in their eyes. Bilateral pupil dilation was noted in all survivng rats receiving 600 or 800 mg/kg during week 11 or 12 of the study. All of these eye abnormalities appeared to be irreversible. Ophthalmoscopic examination revealed bilateral cataracts in 3 of 6 males and 7 of 10 females after receiving 800 mg/kg for 6 weeks. Hemorrhage in the posterior chamber of the eye and debris floating in the anterior chamber was also observed in two other rats from this group. Eight male and eight female rats in the 600 mg/kg group also had bilateral cataracts after 12 weeks.
Retinal atrophy and posterior chamber hemorrhage were also observed in some animals.
Body weight gains were decreased in male and female rats administered 200 - 800 mg/kg. In males, the differential change in body weight ranged from -47% in the 800 mg/kg group to -20% in the 200 mg/kg group. In females, the differential change in body weight ranged from -50% in the 800 mg/kg group to -2.2% in the 200 mg/kg group. Body weight values of the low dose group were comparable to control values. Liver, heart or lung to body weight ratios were unaffected in either sex. Increases in the right kidney, brain and right testicle (male only) to body weight ratios appeared to be the result of lower body weights in the respective dose groups and not the result of any differences between actual organ weights of the dosed groups and controls. Thymus to body weight mean ratios of the dose group decreased as a function of increasing dose at 200 mg/kg in males and 600 mg/kg in females.
At necropsy, cloudy appearing lens were observed in most of the 600 mg/kg and all of the surviving 800 mg/kg rats. In addition, several of the female rats from the 600 and 800mg/kg groups appeared to have smaller uterine horns and female rats from the 800 mg/kg group had small ovaries than controls. Histopathologic changes were noted in the eyes, kidneys and uterus. Eye lesions were present to some degree in every dose group. In the more severe cases the retina was lacking all the normal layers while in less severe cases there was only rosetting and focal cellular losses. In many cases there were ghost-like cells near the lenticular surface of the lens, mineralized debris in the lens and a globular irregular appearance to the lens material. The iris was adherent to the anterior surface of the lens in most affected eyes. Renal tubular lesions were only observed in the 600 and 800 mg/kg groups. These lesions were characterized by degeneration, regeneration and occasional necrosis of the tubular epithelium especially at the corticomedullary junciton. Mineralization of renal tubules in the papillary ducts of Bellini was also observed. Uterine lesions included atrophy of the myometrium and endometrium in the two highest doses. No ovarian lesions were seen in the rats examined microscopically. The thymus did not appear to be affected.
Doses attained were close to the dose goal, for males, 20, 100 and 350 mg/kg/day, females 20, 100 and 360 mg/kg/day.
A slight increase in diet consumption of EDA treated females between 5 - 15 months, otherwise no significant differences from control.
Increases in water consumption were observed for both males and females from the high dose group at 12 and 18 month and for females from the high dose group at 24 month associated with increased urine volume and decreased urine specific gravity.
There was a significant reduction in body weight gain in male rats of the high dose group throughout the whole study course and in female rats of the high dose group from the 18th month until termination. A significant increase of body weight gain in female rats of the intermediate dose group from day 21 until the 21st month was noted.
As shown in Tables 1 and 2, mortality for groups ingesting EDA was comparable to control values during the first 18 months of the study. After 22 months, mortality in males and females ingesting EDA were elevated from both control groups. In addition, the mortality rate in female rats ingesting 100 mg/kg/day was increased after 24 months.
Significant reduction in the absolute weights of liver, kidney, spleen (male) and increase of the relative weights of liver, kidney, heart, brain (females) in rats of the high dose group. No substance-related changes in hematologic data, clinical chemistry values and urinalysis except a decrease in erythrocyte count, hemoglobin concentration, hematocrit (male) and serum albumin concentration (female) in rats of the high dose group. Significantly higher incidence of hepatocellular pleomorphism in female rats of the intermediate and the high dose group; rhinitis and tracheitis were seen with greater frequency in high dose males at 12, 18 and 24 months and in high dose females at 18 months; at 24 months, rhinitis persisted at a significantly greater frequency in high dose females while tracheitis did not; lower incidence of pituitary adenomas and testicular interstitial cell adenoma in the high dose group (incidence ratio: 2/4 in comparison to 25/26 and 12/15 in the control groups); all other tumor incidences did not differ significantly from control.
Table 1: Cumulative % Mortality of Male Rats after 18 Months
Dose Level, mg/kg/day
a,a First letter denotes significantly different from control group A and second letter denotes same from control group B (p0.05).
Table 2:Cumulative % Mortality of Female Rats after 18 Months
High dose group: Diet and water consumption significantly reduced in the high dose female rats. Significant reduction in body weight gain of both sexes in the high dose group; significant reduction in absolute weights of liver and heart (both sexes), adrenal and brain (female), kidney and spleen (male) in the high dose group; increase of relative weight of brain (both sexes), spleen and heart (female) and testis in the high dose group. Significant elevation of alkaline phosphatase activity in males and females. Significant elevation of alanine aminotransferase activity in males and females of high dose groups. Increased mean corpuscular volumes in males and females. Significant increase of mean corpuscular hemoglobin and significant depression of hematocrit and hemoglobin values; significant depression of red blood cell counts, serum glucose level and urinary pH (from 6.0 to 5.0) and significant elevation of aspartate aminotransferase activity in both sexes of the high dose group; hepatocellular pleomorphism in 7/10 female and 2/10 male (control: 0/10 of each sex) in high dose group, hepatocellular degeneration and significant increased prevalence of tracheitis in male of the high dose group.
Intermediate dose group: Water consumption significantly reduced in female rats. Significant elevation of alanine aminotransferase activity in males of intermediate dose groups. Increased mean corpuscular volumes in females. Low dose group: Water consumption significantly reduced in female rats. Significant elevation of alkaline phosphatase activity in males, this effect was not noted in the intermediate dose group.
132 ppm: The death of 4/30 animals was attributed to lung infection (not substance-related); slight depilation; body weight gain and relative weights of liver and kidney were not affected; no substance-related macroscopic or histologic changes.
225 ppm: The death of 16/30 was substance-related and another 10 death were considered not to be substance-related; the 4 rats which survived showed significantly lower weight gain and higher relative weights of liver and kidney; cloudy swelling of the liver and of the loop and convoluted tubules of the kidney; lung congestion was observed in exposed as well as in control rats in similar proportions. 484 ppm: All rats died within 20 days of initial exposure; depilation was first observed on the 6th day of exposure; cloudy swelling of the liver (in 23/28 animals), cloudy swelling and degeneration of convoluted tubules (in 7/28 animals); congestion of the lung (in 17/28 animals) and of the adrenal cortex (in 5/28 animals). 59 ppm: No effect on weight gain or organ weights. No depilation. No significant damage to examined tissues; lung, liver and kidney.
Mean survival time of the exposure group for substance 2 (598 days) was shorter than that of the singly housed control group (626 days); no treatment-related macroscopic or histopathologic findings; one mouse of the exposure group had a dermal fibrosis at application site and another one had a mammary adenocarcinoma. One sebaceous adenoma of the skin of the thorax was noted in the control group individually housed.
In the exposure group for substance 1, 1 mouse had a myxosarcoma at the base of the tail, and 11 animals had mild to moderate dermal fibrosis, suggesting skin irritation. Survival time did not differ from negative control groups.
In the 3-methylcholanthrene group, 39 of 40 mice had skin tumors including 37 with confirmed squamous cell carcinomas.
A 28-day oral toxicity study according to OECD guideline 407 was performed on Wistar rats exposed to the test substance at 0, 10, 50, and 250 mg/kg bw/day. One of five high dose males showed impaired respiration. Four out of ten high dose females died. Decreased spontaneous activity, stilted gait, swollen abdomen, and impaired respiration were observed between days 11 and 24, mainly in the females that died. In the four high-dose females that died, macroscopically discoloration of lungs with multiple red spots on its surfaces and foamy content were observed among other findings. Histopathology revealed lesions, which included congestion of organs, pulmonary hemorrhage, and edema. In addition, one of the females exhibited marked loss of lymphatic follicles of the spleen with massive marginal zone and periarteriolar lymphoid sheath atrophy. The high-dose male rat that exhibited clinical signs had focal ballooning degeneration of the squamous epithelium of the fore-stomach. These data demonstrate that DMAPA induces clinical symptoms, systemic toxicity in male and additionally mortality in female rats when administered 28 times during 29 days at the dose level of 250 mg/kg body weight. The female rats seem to be more sensitive. Although a direct systemic-toxic effect on the respiratory tract cannot be excluded, it can be considered as more likely that the observed findings are related to the oral treatment with this corrosive substance. Due to gavage either local placement in the laryngeal/pharyngeal area or secondary aspiration after reflux from the stomach/esophagus appeared reasonable as noted for other corrosive substances too. The NOAEL was 50 mg/kg bw/day (Hoechst 1996; reliability score: 1).
The potential toxicity of the test item, diethylaminopropylamine(as pH-neutralized dose formulations), was evaluated following daily oral administration (gavage) to rats for 2 weeks in order to assist the selection of dose-levels for a further OECD TG 408 study to be performed in the same species. Three groups of five male and five female Sprague-Dawley rats received the test item, by daily oral administration (gavage) for 14 days, at dose-levels of 100, 300 or 1000 mg/kg bw/day. The test item was administered as a solution in the vehicle (drinking water treated by reverse osmosis) at a constant dosage‑volume of 5 mL/kg/day.The pH of the dosing solutions was adjusted to 8.0 (± 0.5) using a solution of hydrochloric acid. A control group of five males and five females received the vehicle alone under the same experimental conditions. No unscheduled death occurred during the study. Ptyalism was observed at 1000 mg/kg bw/day (1/5 males and 4/5 females). Lower body weight gain was observed at 1000 mg/kg bw/day in males and females over the first 3 days of the study together with slight lower food consumption. This effect was present in a lesser extent in males throughout the study and resulted in a lower final body weight. No macroscopic findings were attributed to treatment with the test item. Slight hyperplasia of squamous cells associated with minimal to slight hyperkeratosis was observed at 1000 mg/kg bw/day in the forestomach of 5/5 males and 4/5 females and was considered to be non-adverse. No treatment-related effects were observed at 100 and 300 mg/kg bw/day (Consortium Alkylamines 42759 TSR).
In a standard subchronic toxicity study (OECD TG 408/GLP) with the structurally related DEAPA Sprague-Dawley rats were treated daily by gavage with the test item for 13 weeks. Male and female rats received dietary target doses of 0, 50, 250 or 750 mg/kg bw/d of DEAPA. During the treatment period, three females given 750 mg/kg bw/d showed clinical signs which were considered to be adverse (i.e. hunched posture, dyspnea, abdominal, loud breathing and/or bent head). One female given 750 mg/kg bw/d more severely affected, showed signs of very poor clinical condition and was sacrificed in week 11. Body weight gain was slightly lower but not adversely effected in males given 750 mg/kg bw/d. Food consumption was not affected by the test item treatment. No ophthalmology findings were observed at the end of the treatment period. Estrous cycle was not altered by the test item treatment. The epididymal sperm motility and morphology and the spermatozoa count were unaffected by the test item treatment. At hematology only minimal to very slight alterations were noted what were finally considered as not adverse. The same was true for none adverse findings in clinical chemistry and urinalysis. Moreover, all changes in hematology, clinical chemistry and urinalysis were completely reversible. At the end of the treatment period, only minor and non-adverse findings were noted in isolated organs and/or animals by histopathology at 750 mg/kg bw/d in both sexes and at 250 mg/kg bw/d in single females. Especially in the females, some of them may be considered as stress-related and due to the irritant potential. Finally, the NOAEL for males was considered to be 750 mg/kg bw/d, and for females 250 mg/kg bw/d predominantly due to the severe clinical findings including death (Consortium Alkylamines 42760 TCR).
There is a subchronic study with the structurally related ethylene diamine (EDA) available (Peters, 1982, reliability score: 2). In this 13-week study, rats received the test substance at doses of 0, 100, 200, 400, 600 or 800 mg/kg bw/day by gavage on weekdays only. At the highest dose, 6 male and 1 female of 10 rats/sex died during the study. Decreased body weight gains were noted in 200 - 800 mg/kg bw/day group of males and in the 400 - 800 mg/kg bw/day group of females. These changes ranged from –20% in 200 mg/kg bw/day male group to –47% in 800 mg/kg bw/day male group and –10% in 400 mg/kg bw/day female group to –50% in 800 mg/kg bw/day female group. Males appeared to be more severely affected than females. Thymus to body weight mean ratios of the dose group decreased as a function of increasing dose at 200 mg/kg bw/day in males and 600 mg/kg in females. However, there were no accompanying histopathologic changes. Histopathologic changes were noted in the eyes, kidneys and uterus. Eye lesions were present to some degree in 100-800 mg/kg bw/day rats. In the more severe cases the retina was lacking all the normal layers while in less severe cases there was only rosetting and focal cellular losses. Renal tubular lesions were only observed in the 600 and 800 mg/kg bw/day groups. These lesions were characterized by degeneration, regeneration and occasional necrosis of the tubular epithelium. Hypoplasia of the uterus was noted in the high dose group and was attributed to inanition. No NOAEL could be established in this 90 day rat oral gavage study. The LOAEL was 100 mg/kg bw/day based on the eye effects.
In an additionally subchronic study with the structurally related ethylenediammonium dichloride (EDA*2HCL, Yang et al., 1983, reliability score: 2, see read across justification section 13), male and female rats were received dietary target doses of 0, 50, 250 or 1000 mg/kg bw/day of EDA-2HCl for three months. There were no deaths and no abnormal clinical signs noted during the study. Body weight gains were significantly decreased in the high dose group which affected a number of absolute and relative organ weights in both males and females. Water consumption was comparable to control values at all dose levels in males but was decreased in a dose-response manner in female rats at all 3 dose levels. Slight reductions in serum glucose levels and an elevation of alkaline phosphatase, AST and ALT activities were observed in the high dose group. An elevation of ALT activity was also observed in the intermediate dose male rats. Urinary pH in t he high dose group was decreased in both males and females. There were no dose-related gross lesions in any animal on the study. The most significant histopathologic lesion, hepatocellular pleomorphism, was observed primarily in the high dose female and, to a lesser extent, in male rats. The LOAEL was 250 mg/kg bw/day. Since the water consumption was only slightly decreased at 50 mg/kg bw/day, the NOAEL was considered to be approximately 50 mg/kg bw/day for EDA*2HCl (corresponding to 22 mg/kg bw/day of EDA).
With the structurally related ethylenediammonium dichloride (EDA*2HCL) there is a combined chronic toxicity and carcinogenicity study available (Hermansky et al., 1999, reliability score: 2, see section 13, read across justification). Groups of each 100 F344 rats per sex received the test substance orally via the feed at adjusted dose levels of 0, 20, 100, 350 mg/kg bw/day (males) or 0, 20, 100 and 360 mg/kg bw/day (females). Mortality was comparable to controls during the first 18 months of the study. After 22 months, mortality in males and females increased at the high dose and in females at 100 mg/kg bw/day after 24 months. There was a significant reduction in body weight gain in male rats and female rats of the high dose group. Significant increases of the relative weights of predominantly the liver and kidney were noted in rats of the high dose group. Significantly higher incidence of hepatocellular pleomorphism in female rats of the intermediate and the high dose groups; rhinitis and tracheitis were also observed in high dose males and females.There was no evidence for a carcinogenic potential ofEDA*2HCLin male and female F344 rats, when administered via the diet over the course of 2 years.The NOAEL for chronic toxicity was 20 mg/kg bw/day for EDA*2HCl (corresponding to 9 mg/kg bw/day of EDA).
With the structurally related ethylene diamine (EDA) there is a subacute inhalation toxicity study available (Pozzani and Carpenter, 1954, reliability score: 2, see section 13, read across justification). In this 6 week study four exposure groups of 30 Sherman rats (15 females/15 males) were exposed to EDA vapour for 7 h/day for 5 days per week at concentrations of 59, 182, 225 and 484 ppm. Each exposure group was compared to a control group.After termination, liver and kidney weights were recoded and samples of liver, lung, heart, kidney adrenal gland and spleen were taken for histological examinations. There was a concentration related increase in mortalities, body weight reductions and indication for liver, kidney and lung damage, especially at the highest concentration.The NOAEC for subacute inhalation was 59 ppm (corresponding to 144 mg/m3).
With the structurally related ethylene diamine (EDA) there is a dermal carcinogenicity study available (DePass et al., 1984, reliability score: 2, see section 13, read across justification).Male CH3 mice received 25μl of an 1% aqueous solution of EDA, the maximum tolerated dose for local effects,to the clipped skin on the backthree times weekly for their complete life span. Two EDA samples from different producers were tested on groups of 50 mice. A negative control group was treated with water and a positive control group received 0.1% of 3 -methylcholanthrene in acetone.Ten mice were intermittently sacrificed at 18 months. Complete necropsies were performed on all mice at intermittent and terminal sacrifice. The dorsal skin from all animals plus all gross lesions of animals at terminal sacrifice as well as all livers, kidneys and lungs from the 18 month sacrifice were examined histopathologically.There were no treatment-related macroscopic or histopathological findings. No skin tumors were observed in the EDA treated animals. In the positive control group, 98% of the animals revealed skin tumors. Thus, there was no evidence for a carcinogenic potential of EDA after life-time dermal administration in male C3H mice. The NOAEL was 8.3 mg/kg bw/day (25 µL 1% solution/per mouse).
Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result, the substance is not considered to be classified under Regulation (EC) No 1272/2008, as amended for the ninth time in Regulation (EU)No 2016/1179.
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