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Administrative data

Link to relevant study record(s)

Description of key information

The substance is readily absorbed by the dermal and oral routes.  No data are available to idicate that absorption occurs via the inhalation route.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Toxicokinetic Assessment

No specific study was performed on the absorption/distribution/metabolism/excretion (ADME) of this substance (DMI). However, data are currently available fromin vivotoxicology studies performed with this substance and are considered here.

Absorption

Due to the physicochemical properties of DMI, octanol/water partition coefficient Log Kow between -1 and 4 and high water solubility, it is expected to be well absorbed. The lack of ionisable groups and low molecular weight also favour absorption. 

 

Oral route

 

In an acute oral toxicity study, female rats in the high dose group showed general signs of toxicity and adverse effects on a wide variety of organs.   

 

Repeated oral administration of DMI to rats at doses up to 150 mg/kg/day for a period of 28 days resulted in significantly lower testes weights in comparison to controls. Macroscopic and microscopic changes in the testes, effects on the epididymides and decreased sperm production were also observed.

 

Following oral administration of DMI in a reprotoxicity screening study at dose levels of 4, 20 or 100 mg/kg/day, provided evidence that that treatment of the test substance could affect the lactating behaviour of the dams, but this could not necessarily be attributed to any toxic effects of the test substance. Histopathological changes include slight to marked atrophy of the seminiferous tubule and vacuolation of interstitial cell hyperplasia in the testes of all males. The test substance was shown to have a growth inhibition effect on offspring after birth.

 

These findings suggest that DMI causes systemic toxicity and is well-absorbed by the gastrointestinal tract of rats.

 

Dermal route

Studies available via the dermal route include acute toxicity, skin irritation, skin sensitisation and teratogenicity.

In the acute toxicity test, the test substance, dosed in a single application at 1000 and 2000 mg/kg, caused an initial decline in appetite with corresponding fall in bodyweight and amount of feces with a return to normal values after 3 days or 5 days (low dose and high dose respectively).In autopsy, no abnormality was observed in any of the animals of any group.

In the skin irritation test, 0.5 ml of the test substance was applied to intact and abraded skin on each of three New Zealand White rabbits. Each treatment site was occluded with a cotton gauze patch secured with a strip of surgical adhesive tape for the duration of the exposure period (3 minutes, 1 hour and 4 hours). A single 4-hour, semi-occluded application of the test material to the intact skin of three rabbits produced very slight erythema. All treated skin sites appeared normal at the 72-hour observation. No corrosive effects were noted. Three minute and 1-hour semi-occluded applications of the test material to intact skin of the rabbit produced no corrosive effects.

In skin sensitization study, conducted using the local lymph node assay method, there were clear signs of general toxicity in the preliminary test when mice were exposed to repeated doses of DMI.

In a teratogenicity main study, the test substance was applied dermally for 6 hours/day on days 6-15 gestation at a dose of 0, 10, 100 and 400 mg/kg/day.  All rats survived the test period and no changes in behaviour or demeanour were observed at any dose level. There was no treatment related effect at the dermal application site. A dose related decrease in feed consumption was observed during days 6 through 21 of gestation in the dams exposed to 100 and 400 mg/kg/day of test substance, resulting in statistically significant decreases in body weight and body weight gain during the dosing period.   

Based on these results DMI is considered to be systemically toxic and therefore readily absorbed by the dermal route.

Such a conclusion is supported by the United States Environmental Protection Agency, Risk Assessment Guidance, 2004, which states that chemicals such as the test substance that possess a low Kow will have limited permeability through the lipid material of the stratum corneum, but penetration by other routes (e.g., appendages such as sweat glands or hair follicles or through regions of the stratum corneum with even minor damage) may contribute significantly.

Inhalation route

No data is available on absorption after inhalation. Due to high boiling point, DMI is unlikely to be available in a vapour state.

 

Distribution, Metabolism, Excretion

The findings from oral administration in repeated dose/reprotoxicity studies and from dermal application in developmental studies provide evidence that the substance is absorbed via both oral and dermal routes. Symptoms of general systemic toxicity in the repeat dose and teratogenicity studies indicate distribution via oral and dermal routes, although the only organ for which there is evidence of accumulation is the testes in male rats.

 

No data are available for metabolism. Stability in water at pH 4, 7 and 9 suggests that the substance is unlikely to undergo abiotic degradation during, or following, absorption. 

 

The potential for absorption and distribution of the test substance, combined with its high water solubility and low molecular weight suggests that it will be readily excreted. The fact that appetite loss and low body weight gains return to normal values a few days after dosing suggest that the substance is being excreted (or possible metabolised). In the 28-day repeat dose study carried out in conjunction with the reproductive toxicity screening test, a similar improvement in body weight gain was seen in the recovery group following substance withdrawal.  

 

 

Conclusion

Results fromin vivotoxicology studies performed with the test substance reveal that it is readily absorbed via the gastrointestinal tract and the skin. There is evidence of systemic distribution including to the testes when the substance is administered via the oral route. Dermal administration shows systemic distribution through general systemic toxicity and low body weight gain. Nothing was observed in the macroscopic or microscopic investigations to suggest bioaccumulation, probably due to ready absorption and distribution across biological membranes followed by excretion (and/or metabolism).