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EC number: 238-523-3
CAS number: 14516-71-3
A toxicokinetic assessment was conducted in accordance with REACH Annex
VIII 8.8.1. The substance
(UV1084) is a mono-constituent solid with a purity of ≥99% to <100% with
a typical concentration of 99.605% (w/w).
A full ADME toxicokinetic study in the rat with UV-1084 is not
available. As read-across was performed to
6,6'-di-tert-butyl-4,4'-thiodi-m-cresol (TBBC; CAS No. 96-69-5), two in
vivo studies that investigated the toxicokinetic pathway in rats
(Birnbaum et al., 1983) and dermal absorption in mice and rats (Birnbaum
and Heaney, 1987) will be included in this assessment. The toxicokinetic
analysis is based on physicochemical data, in vivo toxicokinetic studies
with TBBC and studies in the dossier from both substances.
In vivo studies in rats covering the oral routes are available (acute
oral toxicity study with UV-1084, read-across 90 day repeated dose
toxicity with TBBC). No inhalational toxicity study data is available.
Further details on endpoints are available in the IUCLID 6 registration
The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation)
are accepted for chemical risk assessment purposes.
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 UV-1084 in the body.
Absorption - oral
The range for favourable oral absorption is <500 g/mol so the molecular
weight of UV1084 is slightly above that range (572.52 g/mol). UV1084 is
poorly soluble in water (<0.205 mg/L at 20°C) and moderately lipophilic
(log Pow >3.78) These characteristics will not facilitate transport of
either via passive diffusion and absorption of UV-1084 is more likely
via the lymphatic system through micellular solubilisation.
Absorption – dermal
The water solubility of UV-1084 indicates low dermal uptake however the
moderate lipophilicity indicates there could be some systemic exposure
but it will still be low due to the molecular weight (unfavourable >500
Absorption – inhalation
UV1084 has very low volatility (<10-7 Pa) so exposure via the inhalation
route is expected to be negligible.
Based on the molecular weight, UV-1084 may not be distributed very
widely and may not accumulate due to moderate lipophilicity. UV-1084 is
expected to be excreted mainly unchanged in the faeces.
Other data in the literature
In an absorption, distribution, metabolism, and excretion study of
14C-labeled TBBC in male rats, oral treatment showed a dose-related
decrease in the rate of absorption due to a dose-related increase in
retention time in the stomach (Birnbaum et al., 1983). TBBC was
incompletely absorbed after oral treatment, although the rate of
absorption was proportional to the dose once the compound reached the
small intestine. TBBC was rapidly distributed throughout the body with
the liver being the major tissue depot. Significant amounts of the
compound were also present in blood, muscle, skin, and adipose tissue.
TBBC was initially rapidly cleared from all tissues except adipose,
although a small percentage of the total dose tended to persist in liver
and skin. Over half of the compound was excreted the first day in the
form of metabolites of TBBC, primarily via the bile into the faeces.
Little TBBC-derived radioactivity appeared in the urine; the majority of
urinary excretion occurred within the first day with a clearance
half-life of 9 hr and essentially all the radioactivity in the urine was
due to metabolites of TBBC. Metabolites of TBBC were present in the
tissues at early times after administration, but were rapidly excreted.
The major metabolites appeared to be glucuronide conjugates of the
parent compound. The authors concluded that TBBC would tend to
accumulate in liver and lipid-rich tissues upon chronic exposure, which
if by the oral route, could also result in direct damage to the
The dermal absorption of 14C-labeled TBBC was studied in female Sencar
mice and male Fischer rats (Birnbaum and Heaney, 1987). Dermal
application resulted in about 20% absorption in mice with more than 70%
of the initial body burden remaining on the treated skin site 3 days
after treatment. In rats, less than 2% of a dermal dose was absorbed.
Information from other studies in the dossier
In the acute oral toxicity data in rats (OECD 423/GLP) with UV-1084,
there were no mortalities, clinical effects, effects on body weight or
necropsy. The LD50 was >2,000 mg/kg bw. In a subchronic toxicity
read-across study (Similar to OECD 408/GLP), TBBC (99%) was administered
to groups of F344/N rats (10 animals/sex/group) in the diet at dose
levels of 0, 250, 500, 1,000, 2,500, or 5,000 ppm (15, 30/35, 60/70,
165/170 and 315/325 mg/kg bw/day for males/females) for 7 days per week
for 13 weeks. All animals survived to the end of the study. The
treatment-related effects were lesions in the liver and kidney,
primarily in 2,500 and 5,000 ppm males and females. The lesions in the
liver consisted of scattered individual cell necrosis, individual or
aggregates of enlarged Kupffer cells with abundant yellow-tan pigmented
cytoplasm (Kupffer cell hypertrophy), focal accumulations of similar
macrophages in or adjacent to the portal areas, and a slight increase in
small bile ductules in the portal areas. This finding is consistent with
hepatocellular hypertrophy and with the higher activities of serum
enzymes in the 2,500 and 5,000 ppm groups (serum alkaline phosphatase
levels were significantly higher in 2,500 and 5,000 ppm males and were
slightly higher in the females exposed to 5,000 ppm; males and females
exposed to 2,500 or 5,000 ppm TBBC had significantly higher serum
alanine levels). The kidney lesions consisted of focal, segmental
degeneration and necrosis of the proximal tubule epithelium, primarily
in the outer stripe of the outer medulla, and extensive pigmentation of
the proximal convoluted tubule epithelium. Both the size and number of
macrophages were increased in the mesenteric lymph nodes of male and
female rats exposed to 2,500 or 5,000 ppm TBBC. The NOAEL for males was
30 mg/kg bw/day and for females was 35 mg/kg bw/day, based on the liver
lesions. These studies together with the physicochemical data indicate
that there is higher systemic absorption after repeated oral
administration than acute administration, based on a worst-case scenario
appraoch. For chemical safety assessment purposes, based on the
physicochemical properties and information in the dossier, an oral
absorption rate of 50% is accepted.
Water soluble nickel compounds are well known as skin sensitisers. TBBC
is insoluble in water, highly lipophilic and has about 20% dermal
absorption in mice, (Birnbaum and Heaney, 1987) and is a skin
sensitiser. As UV-1084 is more water soluble than TBBC and moderately
lipophilic, increased dermal absorption may be expected. 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
No inhalational toxicity study data is available. For chemical safety
assessment purposes, an inhalation absorption rate of 100% is accepted
based on the most conservative approach.
Based on the molecular weight, UV-1084 may be less widely distributed
than TBBC and may accumulate less due to lower lipophilicity. UV-1084 is
expected to be excreted mainly unchanged in the faeces, similar to TBBC.
Birnbaum, Eastin, Johnson, Matthews (1983). Disposition of
4,4'-thiobis(6-t-butyl-m-cresol) in rats. Drug Metab Dispos.
Birnbaum LS and Heaney SM (1987). Dermal absorption of the antioxidant
4,4'-thiobis(6-tert-butyl-m-cresol) in Sencar mice and Fischer rats.
Toxicol Lett. 1987 Jun;37(1):13-9
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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