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Description of key information

Available experimental data showed evidence of absorption and distribution of the substance or its metabolites following oral and inhalation exposure as evidenced by slight variations in some haematological and biochemical parameters, in the absolute and/or relative liver, lung and/or kidney weights, and/or pale and enlarged kidneys at necropsy. Dermal absorption of Rhodiasolv iris is negligible as demonstrated in an in vitro skin absorption assay and supported by the absence of systemic effects reported in vivo following dermal exposure (acute dermal toxicity, sensitisation).
The parent substance is expected to be hydrolysed by carboxylesterases at entry sites, as well as in various organs.
The available experimental data suggest that the parent substance and/or its metabolites are excreted in the urine.

Key value for chemical safety assessment

Absorption rate - dermal (%):
3

Additional information

Assessment of absorption, distribution, metabolisation and excretion of the substance is based on the available toxicological data and the results of an in vitro skin absorption assay.

 

Physico-chemical properties :

The substance was found soluble in water (25.196 g/L +/- 0.75%).

The partition coefficient in Octanol/water 0.89 tends to support a limited bioaccumulation potential.

Low vapour pressure (6.3 Pa at 20°C).

Boiling point: 215.6°C

 

Absorption :

·      Inhalation route:

The substance has a low volatility as evidenced by the low vapour pressure (6.3 Pa at 20°C) and elevated boiling point (215.6°C).

Literature data on similar substances have shown a potential hydrolysis of methyl esters in the upper respiratory pathway, in particular by carboxylesterases that are present in the nasal epithelium. It is thus expected that the parent substance will be undergoing rapid enzymatic hydrolysis in the upper respiratory tract and will not be absorbed further as is.

Rat studies:

The acute toxicity study by inhalation showed no mortality at up to 5.6 mg/L, and no significant effects that were indicative of systemic effects resulting from absorption (the only effects noted were local effects).

In contrast, the 14-day and the 90-day repeated dose studies showed a reduction in food consumption and body weight gain, changes in some haematological or biochemical parameters and increased kidneys and/or lung weight mainly at the 5 mg/L air which are consistent with an absorption of the parent substance or its metabolites via the lungs.

·      Oral route:

Rat studies:

There was no evidence of systemic toxicity in the acute oral toxicity study in rats at the dose 2000 mg/kg bw.

There were limited toxicological effects observed in the repeated oral toxicity study (OECD422) in which the male rats were exposed for 28 days and the female rats were exposed for 40 to 45 days depending on the day of mating and gestation duration. Animals exhibited signs of discomfort as demonstrated by moving their head through the bedding material following administration of the test substance. The main findings at the highest test dose (1000 mg/kg/day) were a slight increase in absolute and relative liver and kidney weights, which indicate that some absorption has occurred through the gastrointestinal tract following oral repeated exposure. However, there are no data on whether hydrolysis occurs in the gastrointestinal tract and whether it is the parent substance which is absorbed or its metabolites.

Limited toxicological effects were also observed in the prenatal developmental toxicity study (OECD 414; Council Regulation (EC) No 440/2008 of 30 May 2008) in which the pregnant rats were exposed from days 6 to 20 post coitum. Consistent with the repeated oral toxicity study, signs of discomfort (pushing head through the bedding material and ruffled fur) were noted in one animal given 1000 mg/kg/day. At 1000 mg/kg/day, pale and enlarged kidneys were noted in a few animals supporting the evidence of some absorption through the gastroinstestinal tract following oral repeated exposure.

Rabbit studies:

In the rabbit, the mortality, body weight loss and reduction of food consumption together with the pale and/or enlarged kidneys noted in the dose tolerance and the dose range-finding prenatal developmental toxicity studies at doses between 400 and 1000 mg/kg support the evidence of some absorption through the gastroinstestinal tract. In the prenatal developmental toxicity study (EPA test guideline OPPTS 870.3700; Council Regulation (EC) No 440/2008 of), the death of 1/20 animals given 300 mg/kg/day is consistent with an absorption through the gastroinstestinal tract although this was not correlated with any other systemic toxicity (the only effects (macroscopic changes in the stomach and digestive tract) were considered to be local effects).

·      Dermal route:

Rhodiasolv Iris was investigatedin vitroon its absorption and penetration properties on human skin, either undiluted or 50:50 v/v diluted in corn oil. The study was performed according to OECD guideline 428, using human skin samples and under dynamic non-occluded conditions. Under these conditions, 2% and 3% of the applied dose of undiluted and 50:50 diluted test material, respectively, had penetrated the skin and are considered as bioavailable portion.

The marginal capacity of Rhodiasolv Iris to absorb through the skin demonstratedin vitrois supported by the absence of systemic toxicity in the acute dermal toxicity study in rats at the dose of 2000 mg/kg bw. There were also no signs of toxicity and no sensitisation effects after cutaneous exposure on the mouse ears in the LLNA assay.

 

Distribution :

It is likely that the parent substance is rapidly metabolised to methanol and mono- and/or diacids by ubiquitous non-specific esterases present in various organs, and therefore would not remain unchanged.

In the 14-day and the 90-day repeated dose rat inhalation toxicity studies, the changes in some haematological or biochemical parameters and the increase in kidneys and/or lung weight (with no histopathological correlate) mainly at the 5 mg/L air are indicative of a systemic distribution of the parent substance or its metabolites.

No specific toxicological effects were observed in the repeated-dose oral toxicity study in which the male rats were exposed for 28 days and the female rats were exposed for 40 to 45 days depending on the day of mating and gestation duration. The main findings were a slight increase in absolute and relative liver (not statistically significant) and a statistically significant increase in absolute and relative kidney weights in females at the highest dose which suggest systemic distribution of the parent substance or its metabolites. No alterations in biochemical and haematological parameters were considered related to the treatment. There were no significant histopathological lesions at microscopical examination at the highest dose tested (1000 mg/kg b.w./day).

The functional battery observations showed no evidence of neurotoxicological effects or distribution towards the central or peripheral nervous system.

In the rat and rabbit, the pale and/or enlarged kidneys (together with the mortality, body weight loss and reduction of food consumption in the rabbit) noted at doses between 400 and 1000 mg/kg/day in the dose tolerance, dose range finding and the prenatal developmental toxicity studies support the evidence of a systemic distribution of the parent substance or its metabolites.

Analysis of the micronuclei in the bone marrow cells from the males treated by gavage for 28 days at up to 1000 mg/kg/day (OECD422 study) showed no significant toxicity to the bone marrow cells.

 

Metabolisation :

Carboxylesterases are widely distributed in the body of mammalian species and can hydrolyse various compounds, without being necessarily substrate-specific. It is expected that they would play a role in the metabolisation of the substance at various potential entry sites such as gastrointestinal tract, nasal epithelium and possibly skin, as well as in organs reached following absorption (plasma, liver, kidney,…).

No metabolic alteration was observed in the repeated-dose toxicity assay. However the slight increase (not statistically significant) in liver weight noted in the repeated-dose oral rat toxicity study (OECD 422) could be indicative of increased metabolic activity.

The outcome of thein vitromutagenicity tests (bacterial reverse mutation assay and chromosome aberration in human lymphocytes) was not affected by the presence of metabolic activation: the tests showed no mutagenic or clastogenic effects in the presence or in the absence of exogenous liver S9 metabolization system.

 

Excretion :

Owing to its low molecular weight (174.19 g/mol) and its good water solubility, the parent substance and/or its metabolites are possibly excreted in the urine.

This is supported, in the 90-day inhalation rat toxicity study, by a decrease in pH value noted mainly in males treatedmg/L air (5 when compared withcontrols). This urine acidification may be due to the presence of mono- and/or diacids generated from the hydrolysis of the parent substance.

 

Conclusion :

Available experimental data showed evidence of absorption and distribution of the substance or its metabolites following oral and inhalation exposure as evidenced by slight variations in some haematological and biochemical parameters, in the absolute and/or relative liver, lung and/or kidney weights, and/or pale and enlarged kidneys at necropsy. Dermal absorption of Rhodiasolv iris is negligible as demonstrated in an in vitro skin absorption assay and supported by the absence of systemic effects reported in vivo following dermal exposure (acute dermal toxicity, sensitisation).

The parent substance is expected to be hydrolysed by carboxylesterases at entry sites, as well as in various organs.

The available experimental data suggest that the parent substance and/or its metabolites are excreted in the urine.