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Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance Tetra(isobutyl)thioperoxydicarbamic acid (TiBTD) is an organic yellow mono-constituent solid with a purity of >97% to <99%, with a typical concentration of 99%.

A full ADME toxicokinetic study in the rat is not available.  The toxicokinetic analysis is based on the physicochemical and in vivo toxicological data. In vivo studies covering the oral (acute, 90-day repeated dose toxicity and pre-natal developmental toxicity in rats) and dermal routes (skin sensitisation in guinea pigs) are available. An acute inhalational toxicity study in the rat is available. Further details on endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical data and available in vivo toxicological data, absorption via the oral, dermal and inhalational routes is expected to be low; distribution is unlikely throughout the body and it is likely that TiBTD is excreted mainly unchanged in the faeces.

The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:
high bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

1. Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of TiBTD in the body.

 

Absorption - oral

The molecular weight of TiBTD (408 g/mol) is the range for favourable oral absorption (<500 g/mol). It is highly lipophilic (log Pow 7.30 (calculated)) and it is highly insoluble in water (<0.0488 mg/L at 25°C). These characteristics will not facilitate transport of TiBTD via passive diffusion. Oral absorption is expected to be low but if absorption does occur, it is likely via the lymphatic system through micellular solubilisation, based on the lipophilicity.

 

Absorption – dermal

As TiBTD is highly insoluble in water, low dermal uptake is expected. The high log Pow value (calculated) indicates a high uptake into the stratum corneum but little or no penetration into the lower layers of the epidermis and dermis. Overall the molecular weight, calculated log Pow and water insolubility indicate that dermal absorption of TiBTD is unlikely.  

 

Absorption – inhalation

The particle size distribution report for TiBTD indicates a range of 0.138μm - 60.259μm (d(0.1) 3.116μm, d(0.5) 9.942μm, d(0.9) 25.553μm) [7]. This indicates that 100% of the particles are available in the inhalable fractions of air (<100 μm). Particles with aerodynamic diameters of above 1-5 μm have the greatest probability of settling in the nasopharyngeal region whereas particles with aerodynamic diameters below 1-5 μm are most likely to settle in the tracheo-bronchial or pulmonary regions. As there are fractions in both these categories, the substance is likely to be distributed throughout the respiratory tract upon inhalation. Greater than 50% of particles will be able to penetrate the alveolar region of the respiratory tract (<15 µm). As a water-insoluble dust, TiBTD could be coughed or sneezed out of the body or swallowed (refer to oral absorption). Based on the water insolubility (<0.0488 mg/L at 25°C) and lipophilicity (log Pow 7.30 (calculated)), it is likely that any absorption will be low and occur via micellular solubilisation and the lymphatic system. However, due to the very low vapour pressure of TiBTD (1.27 × 10-5 Pa at 20°C), exposure via the inhalation route is expected to be negligible.

 

Metabolism/Excretion

Based on the available information, it is likely that the substance is excreted mainly unchanged in the faeces.

 

2. Information from other studies in the dossier

Absorption – oral

In an acute oral toxicity study in female Wistar rats (OECD 423/GLP), there were no test-item related effects; the LD50 (female) was >2000 mg/kg bw.

In a repeated dose toxicity study (OECD 408/GLP), WILLING TiBTD (97%) was administered to Crl:WI Wistar rats (10/sex/dose) by gavage in 1% (w/v) aqueous methylcellulose at dose levels of 0, 100 (Low dose), 300 (Mid dose) and 1000 (High dose) mg/kg bw/day daily for 90 days. A statistically significant lower body weight (-11.2%) and body weight gain (-23.7%) was seen in High dose males with the difference between controls and High dose appearing later in the study. The overall High dose weight gain was significantly affected in males. A similar trend was seen in High dose females (-24.3% lower overall weight gain) but generally without statistical significance. The High dose group growth rates were below the historical control minimums in both sexes; the lower growth rates were attributed to a treatment effect. The Mid and Low dose groups were not affected. There were no treatment-related effects on food consumption, behaviour, ophthalmoscopy, clinical pathology, macroscopic or microscopic, sperm or thyroid hormone (T3, T4, TSH) parameters, and no evidence of endocrine disruptor activity. The no observed adverse effect level (NOAEL) for systemic toxicity in male and female Wistar rats for WILLING TiBTD is considered to be 300 mg/kg bw/day (based on a reduction in body weight at the High dose level).

In a prenatal developmental toxicity in rats (OECD 414/GLP), WILLING TiBTD (97%) was administered to pregnant Crl:WI (Han) rats (25/dose) by oral gavage in 1% (w/v) aqueous methylcellulose at dose levels of 0, 100 (low dose), 300 (mid dose) and 1000 (high dose) mg/kg bw/day daily for 14 days (GD 6-19).  No mortality or clinical observations were recorded in any of the dose groups. Test item-related adverse effects on body weight parameters and food consumption were observed in the High dose group (1000 mg/kg bw/day), when compared to controls. No test item-related effects were noted in the Mid dose (300 mg/kg bw/day) or Low dose (100 mg/kg bw/day) groups. There were no treatment-related effects on macroscopic or microscopic parameters, thyroid hormone (T3, T4, TSH) levels, thyroid organ weights, placentas and intrauterine parameters in the test item treated animals when compared to the controls in dams. Reduced foetal body weights were recorded in the High dose group (1000 mg/kg bw/day); the differences were considered to be possibly treatment related, but in the presence of significant maternal toxicity, not a direct effect of the test item (i.e. secondary non-specific consequence of maternal toxicity effects). No effect was noted in Mid and Low dose groups (300 and 100 mg/kg bw/day, respectively). There were no test item-related effects on external, visceral or skeletal development of the foetuses in the study.  No endocrine disrupter effect was identified in the study (based on the lack of effects on thyroid hormones and thyroid histopathology for dams, and anogenital distance for foetuses). The following NOAELs were derived: NOAEL for maternal/foetotoxicity toxicity: 300 mg/kg bw/day; NOAEL for embryotoxicity/teratogenicity: 1000 mg/kg bw/day.

Together with the physiochemical data, this indicates that oral absorption is low. For chemical safety assessment purposes, an oral absorption rate of 50% is accepted.

 

Absorption – dermal

In a dermal sensitization study (similar to OECD 406/GLP; Buehler method) in Hartley-derived albino guinea pigs, TiBTD (no vehicle) caused a positive skin reaction (slight patchy erythema) in 1 of 10 animals. There were no reactions in the control group. The exposed animals showed no other negative clinical symptoms throughout the experiment. The body weight of animals increased during the study and it was not affected by the treatment. TiBTD is not a skin sensitizer in a guinea pig Buehler assay. As there was one positive reaction, there was some absorption but taken together with the physicochemical data, dermal absorption is likely to be low. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Absorption – inhalation

In an acute inhalation toxicity study (OECD 403/GLP), CRL: (WI) Wistar strain rats were exposed to a test atmosphere of 50 % w/w TiBTD formulated in acetone for 4 hours (nose only) at a target concentration of 5 mg/L. The mean achieved concentration was 4.96 ± 0.32 mg/L (MMAD: 1.51 µm; GSD: 2.00). No deaths occurred during the study. Laboured respiration (slight) was recorded in 1 of 10 animals on the day of exposure. The animals were symptom free from Day 1. During the observation period, normal body weight gain was observed. Upon necropsy, there were no external or internal findings that could be detected. The LC50 male/female was > 5 mg/L. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, using a conservative approach.

 

Distribution/Metabolism/Excretion

Based on the in vivo oral studies, the substance is not widely distributed throughout the body or to the foetus. As indicated by the physicochemical data, it is likely that the substance is excreted mainly unchanged in the faeces.