Polymer with 2-Butyne-1,4-Diol and (Chloromethyl-)Oxirane, Brominated, Dehydrochlorinated, Methoxylated

Endpoint summary

Additional information

No data are available that describe the toxicokinetics of Polyol IXOL M125, therefore relevant substance properties and data from toxicity studies indicating systemic bioavailability were taken together to assess the general toxicokinetics of the substance.

 

Physical-chemical properties

Polyol IXOL M125 is a dark-brown liquid with a molecular weight of 467 g/mol.The log Pow of the different constituents of Polyol IXOL M125 varies between 0 and 3, with most of the substances exhibiting a log Pow between 1 and 3. Its solubility in water is 4.1 g/L.

 

Data from acute and repeated dose toxicity studies

Acute oral and inhalation toxicity studies

The available acute oral toxicity (dose levels: 250, 500, 1000 and 2000 mg/kg bw) revealed effects which indicate systemic availability of the substance (Duphar B.V., 1986). Mortality was observed in the dose groups above 250 mg/kg bw. Clinical signs were mainly indicative of effects on the autonomic nervous system (ptosis, diminished respiratory rate, respiratory difficulties, piloerection and hypothermia), on the central nervous system (apathy and positional passivity), on motor coordination (abnormal gait, abnormal body posture, diminished locomotor activity, loss of righting-reflex) and on muscle tone (decreased abdominal and limb tone and paralysis). Autopsy of rats that died as a result of treatment, revealed effects on the gastro-intestinal tract (irritation), kidneys (pale), liver (pale), lungs (red spots) and thymus (red spots).

The acute inhalation toxicity study (6 hours per day, 5 days per week, over a 7-day period exposure to 0.5, 1.7, or 4.9 g/m3.) showed increased kidney and liver weights (TNO triskelion BV 2012). Histopathological examination of the upper airways revealed treatment-related changes in the larynx at all concentration levels and microscopic changes in the nasal tissues of animals of the high concentration and a few animals of the mid concentration group.

Subacute (28 days) inhalation toxicity study

In a sub-acute (28-day) inhalation toxicity (TNO Triskelion BV 2012), groups of 5 male and 5 female rats were exposed nose-only to target concentrations of 0.1, 0.3 or 1 mg/m3 Polyol IXOL M125 for 6 hours/day, 5 days/week in a 28-day period, resulting in 20 exposure days.

In all animals of the control and high concentration group, blood was sampled to determine the concentration of bromide in blood, as a marker for systemic availability of the test material. Bromide concentrations (± standard deviation) in blood sampled immediately after exposure on day 14/15 were 0.14 (± 0.01) and 0.15 (± 0.00) mmol/kg for males and females of the control group, and 5.25 (± 0.46) and 6.60 (± 0.71) mmol/kg for males and females of the high concentration group, respectively. Blood sampled the next day after the start of exposure contained 0.13 (± 0.01) and 0.14 (± 0.01) mmol/kg bromide for males and females of the control group, and still 4.70 (± 0.34) and 6.07 (± 0.63) mmol/kg for males and females of the high concentration group, respectively. This indicates the systemic availability of the test compound upon inhalation, as measured by the blood bromide concentration.

No treatment-related clinical abnormalities, differences in food consumption and body weight, and changes in haematology parameters were observed. Investigation of clinical chemistry parameters revealed a decreased plasma activity of alkaline phosphatase in females of the high concentration group. Absolute and relative weights of the kidneys and liver were statistically significantly increased in females of the high concentration group (liver weights could not be determined in males, because these organs were used for unscheduled DNA synthesis). Analysis of sperm parameters did not reveal any treatment-related abnormalities with respect to sperm morphology, motility and count. In addition, no organ weight changes or histopathological abnormalities were found in the male reproductive tissues. Macroscopic examination at necropsy did not show any treatment-related gross pathology. Microscopic examination revealed treatment-related changes in the larynx, consisting of focal, keratinizing squamous metaplasia in the epiglottis, accompanied by focal epithelial hyperplasia in some animals. The metaplasia was observed at all concentration levels, occurred in a concentration-dependent fashion with respect to incidence and severity, and reached statistical significance in males and females of the mid and high concentration groups.

 

Absorption figures used for the DNEL derivation

In the absence of substance specific quantitative data on absorption, 100% absorption is assumed for the inhalation and oral route. Both the results of the acute and sub-acute study indicate absorption of the test substance. Secondly, the water-soluble of polyol IXOL M125 allows it to readily dissolve into the gastrointestinal fluids. Furthermore, the molecular weight below 500 makes the test substance favorable for adsorption. Finally, the moderate log P makes the substance favorable for absorption by passive diffusion. This suggests that Polyol IXOL M125 may be readily absorbed by the gastrointestinal and respiratory tract. Furthermore, as the log P is inside the range of -1 to 4, and in addition the molecular weight is below 500 g/mol, a default value for dermal absorption of 100% is used for external dermal exposure.