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Administrative data

Endpoint:
basic toxicokinetics
Adequacy of study:
other information

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion

Executive summary:

There is no reliable and relevant information source in which the toxicokinetic properties (absorption, distribution, metabolism, elimination) of MEXORYL SAB were investigated. The expected toxicokinetic behaviour is derived from the physicochemical properties and the results from the available toxicological data following the guide given in the REACH guidance document R.7c:

MEXORYL SAB is a mono constituent substance having a molecular weight of 264. It is a white powder with an estimated water solubility of 30 mg/L. Volatility was determined to be about 0.73 mmHg at 21°C (about 97 Pa) and has low lipophilic properties (log Pow = 0.32). The surface tension is about 60-64 mN/m. Detailed information can be found in section 4 of MEXORYL SAB IUCLID dossier.

Absorption:

In the oral acute toxicity study, major signs of toxicity noted in all dose groups (2530, 3000, 3557 and 4217 mg/kg bw) were hunched posture, pilo-erection, lethargy, ptosis, decreased or gasping respiration and red/brown staining around the snout or mouth. Incidents of reduced bodyweight gain or bodyweight loss were noted in all dose groups. Abnormalities noted at necropsy of animals that died during the study were haemorrhagic or abnormally red lungs, dark liver or patchy pallor of the liver, pale spleen, pale or dark kidneys, haemorrhage or sloughing of the glandular gastric epithelium and haemorrhage of the small and/or large intestines. The systemic toxic effects observed (in particular lethargy, ptosis and loss of bodyweight) show that MEXORYL SAB is absorbed by oral route at high doses.

In the dermal acute toxicity study, no systemic effects were observed at 2000 mg/kg bw: no deaths, no clinical signs and no abnormalities at necropsy. MEXORYL SAB has a low water solubility (< 100 mg/L) therefore dermal uptake is considered to be low or moderate. It is also a dry powder that would need to dissolve into the surface moisture of the skin before uptake can begin. However, MEXORYL SAB was found to be skin sensitizing therefore some uptake, even limited, must have occurred. Thus, dermal absorption of MEXORYL SAB is expected to be limited but not inexistent.

In a 4-week repeated dose toxicity study, the dose level of the high dose group was dropped from 300 to 200 mg/kg bw/day on day 13 of the treatment period because of adverse clinical signs (noisy and irregular/fast respiration), including death. Bodyweight gain was reduced slightly (13-14 %) for males of the highest dose group (associated with slight reduction in food consumption) and for females given 100 mg/kg bw/day during the treatment period. Macroscopic observations at necropsy revealed a dose-related increased incidence of stomach abnormalities for animals given 100 and 300/200 mg/kg bw/day at the end of both the treatment and treatment-free period. Microscopic pathology revealed hyperplasia of the non-glandular stomach for animals given 300/200 mg/kg bw/day, accompanied by chronic inflammation and ulceration. These effects seem related to irritant local effects located in the stomach; systemic toxicity and maybe absorption may be quite limited at this dose level. This hypothesis is confirmed by the reproduction / developmental toxicity screening test: no treatment-related effects were observed in rats exposed by oral gavage up to the highest dose tested, i.e. 100 mg/kg bw/day.

Thus, indications of oral uptake of MEXORYL SAB at high doses are given while dermal uptake would be more limited even if skin irritation after repeated dose dermal exposure as observed in the pre-developmental study, may enhance dermal absorption.

No study by inhalation was performed. However, considering both the granulometry of the powder and the physico-chemical properties of MEXORYL SAB, exposure to MEXORYL SAB by inhalation is likely to occur. Indeed, exposure by inhalation is possible based on a significant inhalable fraction of MEXORYL SAB (from 13.23% to 26.7% particles < 100 µm) and a relative high vapour pressure (97 Pa at 21°C) together with a melting point of 115°C. However, MEXORYL SAB could be absorbed only at low rate based on both its low lipophilic properties (log Pow = 0.32) and its relative low water solubility (29.7 mg/L).

Therefore the potential bioavailability of MEXORYL SAB can be considered mainly by oral route.

Distribution:

The physico-chemical information (low water solubility and low lipophilicity) indicates that distribution of MEXORYL SAB could be quite limited, as it would not have particular affinity for fatty tissues. This assumption is confirmed by the 4-week repeated dose toxicity study where the toxic effects located in the stomach may be more related to irritant local effects rather than systemic effects.

Metabolism:

No data are available but, in in vitro genotoxicity studies, differences in cytotoxicity were observed with and without metabolic activation in Ames test and MEXORYL SAB was found clastogenic in CHO cells only in presence of metabolic activation. This indicates that MEXORYL SAB may be metabolised by hepatic microsomal fractions.

No data about the metabolism of MEXORYL SAB are available. However, based on salicylic acid metabolism, glucuronidation may be expected as a potential metabolic pathway for MEXORYL SAB.

Excretion:

As no toxic effects were observed in kidneys in repeated toxicity studies, it is difficult to determine if MEXORYL SAB is excreted in urine. However, based on the physico-chemical information (low molecular weight, low water solubility), renal excretion of MEXORYL SAB and/or its metabolites cannot be excluded. Moreover, as MEXORYL SAB is considered to be potentially metabolized by glucuronidation, it could be eliminated via bile excretion.

Accumulative potential:

Based on the physico-chemical information (log Pow = 0.32 and low water solubility), it is concluded that the potential for bioaccumulation is low and it is not proposed for classification as PBT substance.

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