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EC number: 221-312-5
CAS number: 3064-73-1
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.
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)
. 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.
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
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.
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.
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
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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