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EC number: 807-040-5
CAS number: 4538-42-5
For an assessment of toxicokinetics read across is performed to
HDI (CAS no. 822 -06 -0). For that purpose, the toxicokinetic assessment
of HDI, which is based on experimental toxicokinetic studies in animals
and volunteers, physico-chemical properties, and further toxicological
data, is cited below. Given that the read across is justified, this is
favourable to a toxicokinetic assessment solely based on PDI data, since
the toxicokinetic database of HDI is much broader than that of PDI.
(For justification of read across see document attached to the
Read across to HDI (CAS no. 822 -06 -0):
HDI is a clear colourless liquid with a low vapour pressure under normal
ambient conditions (0.007hPa at 20°C), therefore inhalation exposure to
the vapour is expected to be low. After 1 hr exposure of guinea pigs to
vapour concentrations ≥ 0.034 mg/m³ 14C-HDI the uptake of radiolabelled
HDI into blood was immediate and increased linearly to a 2-4 hr
postexposure peak (Kennedy et al., 1990). The14C-activity was cleared
from the blood rapidly (no date) to a nanomolar level which persisted
after 72 hr regardless of initial dose. Acute inhalation of HDI (vapour
+ condensation aerosol) to rats did not reveal signs of systemic
toxicity at the maximum concentration of 151 mg/m³ (Pauluhn, report no.
25999, 1997). Exposure to 55 mg/m³ and higher were followed by
concentration-dependent signs suggestive of irritation of the
respiratory tract. At concentrations of 107 mg/m³ and above increased
mortality was observed. Even life-time inhalation of HDI vapour to rats
revealed no signs of systemic toxicity (Shiotsuka, report no. 1157,
In controlled studies in human volunteers 1,6-hexamethylene diamine
(HDA) could be detected in the urine of HDI exposed persons (inhalation
exposure) after acid hydrolysis as a biomarker for excretion of HDI or
HDI-metabolites (Brorson et al., Int Arch Occup Environ Health 62,
385-389, 1990; Dalene et al., J Chromat 516, 405-413, 1990; Rosenberg
and Savolainen, Analyst 111, 1069-1071, 1986). In a study with three
volunteers each exposed to 0.012, 0.020 and 0.022 mg/m³ for 2 hours (2
days each between the exposures) the average urinary elimination
half-time for HDA in hydrolysed urine was 2.5 hr (Tinnerberget
al., Int Arch Occup Environ Health 67, 367-374, 1995). No HDA could be
found in hydrolysed plasma during the exposure days (before and half an
hour after exposure). Due to the analytical method using acid hydrolysis
these studies give some insight in potential absorption and elimination,
but not on metabolism.
At ambient temperature HDI is hydrolytically unstable (half-life in
acetonitrile/water solution 0.23 hour; Bayer AG, 1999). HDA and carbon
dioxide are found to be the main degradation products after contact with
water (Sopac and Boltromejuk,Gig. Sanit. 7,
10 -13, 1974). Due to hydrolytic instability of HDI in aqueous solutions
neither water solubility nor log Pow value were determinable. Under
physiological conditions it is expected that HDI decomposes in the GI
tract mainly into HDA and carbon dioxide. Therefore intestinal
absorption of HDI subsequent to oral ingestion may be limited. Acute
oral toxicity in rats revealed clinical symptoms at 263 mg/kg HDI as
well as deaths at 788 mg/kg HDI within the first day of treatment (Kimmerleet
al., Bayer AG, report no. 2146, 1970), possibly caused by the
decomposition product HDA.
Due to a molecular weight of 168.2 g/mol and a calculated log Pow of 3.2
dermal absorption is conceivable. Furthermore, after contact of HDI with
the surface moisture of the skin hydrolysis to HDA and carbon dioxide
can be expected as well as reaction with nucleophiles like, NH- or
SH-groups. HDI revealed corrosive properties to the skin (Schreiber,
Bayer AG, 1981). Damage to the skin surface may enhance penetration of
HDI and/or HDA. The assumption of a dermal absorption is confirmed by
the data on acute dermal toxicity and skin sensitization. In the acute
dermal toxicity study in rabbits hyperemia and swelling of the gastric
mucosa as well as distinct hyperemia of the small intestine mucosa,
peritineum, pleura, diaphragm and pancreas were seen macroscopically in
all animals at 7000 mg/kg (Mürmann, Chemische Werke Hüls, report no.
372, 1985). In a guinea pig maximization test (GPMT) a strong skin
sensitization potential could be detected for HDI (Schmidt and Bomhard,
Bayer AG, report no. 11703, 1983).
Based on the results of two in vitro genotoxicity tests (negative with
and without metabolic activation in an Ames test (Wagner and Klug, MA
Bioservices Inc., 1998) and in a HGPRT test (San and Clarke, MA
Bioservices Inc., 1998) it is concluded that DNA-reactive metabolites of
HDI will most probably not begenerated in mammals in the course of
hepatic biotransformation. This conclusion is confirmed by a negative
result in a mouse micronucleus test in vivo with vapour inhalation of
HDI (Gudi and Krsmanovic, MA Bioservices Inc., 1998).
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