2,2'-iminodiethanol

Endpoint summary

Description of key information

Short description of key information on absorption rate: 
Dermal absorption of DEA appeared to be species-dependent based on the available in vivo and in vitro studies.

Additional information

1. Physical-chemical properties

DEA (MW 105.14 g/mol) is a liquid with a measured melting point of 27.4°C, a measured boiling point of 268-271°C at 996.9-1013 hPa and a measured vapour pressure of 0.0028 hPa at 25°C. The octanol-water partition coefficient (log Pow) is -2.18 at 25 °C and the substance is fully miscible with water.

 

2. Data from acute and repeated dose toxicity studies

Acute toxicity data indicate moderate toxicity: the LD50 for males and females combined was 1600 mg/kg bw. Reported clinical signs were tumbling, staggering gait, twitches, convulsions, dyspnoea, abdominal lateral position and scrubby coat. Gross pathology revealed hydrothorax, local adhesions of the gut and signs of irritation on gastro-intestinal tract (BASF AG, 1966). Due to its extremely low vapour pressure, exposure to DEA vapour is unlikely. An inhalation risk test showed no mortality in rats after an 8 h exposure to an atmosphere enriched with vapour (BASF AG, 1966).

After repeated inhalation, dermal and oral exposure systemic effects were observed indicating that DEA becomes bioavailable and reaches organs. Target organs are kidneys, blood and liver (BASF AG, 1996 and 2002a; NTP, 1992; NTP, 1999; Munson et al, 1992a,b).

 

Nose-only exposure of rats to DEA aerosols for 3 months resulted in systemic effects such as anaemia, adaptive liver and kidney effects, damage of male reproductive organs and upper respiratory tract irritation. No functional or morphological evidence of neurotoxicity was observed. The NOAEC for systemic effects was 15 mg/m³ and the NOAEC for upper respiratory tract irritation was 3 mg/m³.

 

Repeated unoccluded dermal application of ethanolic DEA solutions in subacute and subchronic studies with rats and mice led to mortality at high dose levels (≥500 mg/kg bw/day in rats; ≥1500 mg/kg bw/day in mice). In rats, systemic signs of toxicity consisted predominantly of anaemia and nephropathy. In addition, liver weights were increased without a histopathological correlate. In mice, systemic effects occurred mainly in the form of liver and kidney damage. In both species, local skin irritation was observed. A NOAEL for systemic effects or local skin irritation could not be achieved (LOAEL 32 mg/kg bw/day in rats; 80 mg/kg bw/day in mice).

The 2 years dermal carcinogenicity studies with rats and mice also showed systemic effects. The overall dermal LOAEL based on the 13 weeks and 2 years studies is concluded to be 8 mg/kg bw/day. Critical effects appear to be kidney (nephropathy) and liver toxicity, anaemia and dermal hyperkeratosis/acanthosis. Besides anaemia, nephropathy was observed at the lowest tested dose in the 13 weeks dermal toxicity study (32 mg/kg bw/day). After 13 weeks effects on the kidneys are not yet masked by ageing and appear a treatment related adverse effect. Therefore, the observation of nephropathy in females at the lowest tested dermal dose of 8 mg/kg bw/day in the 2 years study, which was somewhat masked by ageing, is also considered adverse. In males this effect was completely masked by the ageing process after 2 years of exposure.

 

In rats, subchronic oral treatment via the drinking water caused mortality at the high dose in males (5000 ppm). Impaired body weight gains were observed down to 320 ppm in females and 630 ppm in males. Systemic effects consisted of anaemia, nephrotoxicity, cortical vacuolization of adrenal glands and demyelinization of brain/spinal cord without any neurofunctional finding. In males, damage of reproductive organs in the form of testicular degeneration and associated weight changes and impaired spermatology was observed. Based on anaemia observed, a LOAEL of 25/14 mg/kg bw/day was achieved in males/females.

In the subchronic oral study in mice, mortality was observed in males at ≥5000 ppm and in females at ≥2500 ppm. Body weight gain was decreased in both species down to a concentration of 1250 ppm (females) or 2500 ppm (males). Systemic effects consisted of hepato- and nephrotoxicity and myocardial degeneration. The most sensitive effect was necrotic liver damage at all concentrations. A LOAEL of 104/142 mg/kg bw/day was noted in males/females.

 

In subacute (14 days) oral screening examinations in rats and mice DEA revealed some immune-modulating effects at dose levels with overt signs of systemic toxicity. The most sensitive parameter was red blood cell alteration with a LOAEL of 50/100 mg/kg bw/day in rats and mice, respectively, based on reduced numbers of reticulocytes.

 

3. Absorption, distribution, metabolism, excretion

DEA is well absorbed following oral administration in rats (57%) and to a lower degree after dermal administration (3-16% in rats; 25 – 60% in mice). When applied dermally, DEA appears to facilitate its own absorption, as higher doses were more completely absorbed than lower doses.

DEA (20 mg/cm²) applied to skin preparationsin vitroshowed penetration rates of 6.7% (mouse) > 2.8% (rabbit) >0.56% (rat) > 0.23% (human).

Distribution to the tissues was similar via all routes examined. DEA is cleared from the tissues with a half-life of approximately 6 days. The highest concentrations are observed in liver and kidney.

Metabolism after oral administration revealed non-metabolised DEA and smaller proportions of N-methyl-DEA (N-MDEA), N,N-dimethyl-DEA (N’N-DMDEA) and DEA-phosphates co-eluting with phosphatidyl ethanolamine and phosphatidyl choline. After digestion 30% of the phospholipids were identified as ceramides and the remaining 70% as phosphoglycerides.

DEA is excreted primarily in urine as the parent molecule (25-36%), with lesser amounts of O-phosphorylated and N-methylated metabolites.

Accumulation of DEA at high levels in liver and kidney isassumed by a mechanism that normally conserves ethanolamine, a normal constituent of phospholipids. DEA is incorporated as the head group to form aberrant phospholipids, presumably via the same enzymatic pathways that normally utilize ethanolamine.

Discussion on bioaccumulation potential result:

DEA is well absorbed following oral administration in rats (57%).Distribution to the tissues was similar via all routes examined. DEA is cleared from the tissues with a half-life of approximately 6 days. The highest concentrations are observed in liver and kidney.

Metabolism after oral administration revealed non-metabolized DEA and smaller proportions of N-methyl-DEA (N-MDEA), N,N-dimethyl-DEA (N’N-DMDEA) and DEA-phosphates co-eluting with phosphatidyl ethanolamine and phosphatidyl choline. After digestion 30% of the phospholipids were identified as ceramides and the remaining 70% as phosphoglycerides.

DEA is excreted primarily in urine as the parent molecule (25-36%), with lesser amounts of O-phosphorylated and N-methylated metabolites.

Accumulation of DEA at high levels in liver and kidney isassumed by a mechanism that normally conserves ethanolamine, a normal constituent of phospholipids. DEA is incorporated as the head group to form aberrant phospholipids, presumably via the same enzymatic pathways that normally utilize ethanolamine.

Discussion on absorption rate:

Dermal administration (in vivo) resulted in the following absorption figures: 3-16% in rats; 25-60% in mice. When applied dermally, DEA appears to facilitate its own absorption, as higher doses were more completely absorbed than lower doses.

DEA (20 mg/cm²) applied to skin preparations in vitro showed penetration rates of 6.7% (mouse), > 2.8 % (rabbit), >0.56% (rat) and > 0.23% (human).