Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance  (butylamine)[[2,2'-thiobis[4-(1,1,3,3-tetramethylbutyl)phenolato]](2-)-O,O',S]nickel (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 dossier.

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

Additional information

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 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 mg/mol).

Absorption – inhalation

UV1084 has very low volatility (<10-7 Pa) so exposure via the inhalation route is expected to be negligible.

Distribution/Metabolism/Excretion

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 gastrointestinal tract.

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

Absorption - oral

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.

Absorption – dermal

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 accepted.

Absorption – inhalation

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.

Distribution/Metabolism/Excretion

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. Nov-Dec;11(6):537-43.

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