N4,N4'-hexane-1,6-diylbis[N-butyl-6-chloro-N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine]

Endpoint summary

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance N4,N4'-hexane-1,6-diylbis[N-butyl-6-chloro-N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] is an organic mono-constituent solid.

A full ADME toxicokinetic study in the rat is not available. The toxicokinetic analysis is based on the in vivo animal models and physicochemical data. In vivo studies covering the oral and inhalational route (acute) are available. An in vivo study covering the dermal route (LLNA in mice) is available. Testing proposals have been submitted for an OECD 408/GLP study in rats and an OECD 414/GLP study in rats; this assessment will be updated when the results from those studies are available. Further details on endpoints are available in the IUCLID 6 registration dossier.

Based on the in vivo available data, N4,N4’-hexane-1,6-diylbis[N-butyl-6-chloro-N,N’-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] is poorly absorbed via the oral route; absorption via the dermal and inhalational route occurs. Based on the physicochemical data, N4,N4’-hexane-1,6-diylbis[N-butyl-6-chloro-N,N’-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] is not likely to be widely distributed, and is expected to be excreted unchanged in the faeces.

The absorption rates of 50% (oral), 10% (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 (%):

10

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 N4,N4’-hexane-1,6-diylbis[N-butyl-6-chloro-N,N’-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] in the body.

Absorption - oral

The molecular weight of N4,N4’-hexane-1,6-diylbis[N-butyl-6-chloro-N,N’-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] is 1042 g/mol which is unfavourable for oral absorption (>1000 g/mol). The log Kow (> 4.72 at 22.5°C) indicates it is very lipophilic and the water solubility (< 0.02 mg/L at 20°C) indicates it is almost insoluble in water. 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 and poor water solubility.

Absorption – dermal

The molecular weight is in the unfavourable range (>500 g/mol) and the log Kow and water solubility of N4,N4’-hexane-1,6-diylbis[N-butyl-6-chloro-N,N’-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] indicate low dermal absorption.

Absorption – inhalation

The particle size distribution report for N4,N4’-hexane-1,6-diylbis[N-butyl-6-chloro-N,N’-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] indicated a range of 0.113μm – 859μm (D(10): 1.23μm; D(50): 16.1μm; D(90): 161μm), therefore it is considered to have medium dustiness. As at least 50% of the particles are available in the inhalable fractions of air (<100 μm), exposure via inhalation is expected to occur. Due to the water insolubility and lipophilicity, micelle formation may also occur, similar to oral absorption.

Distribution/Metabolism/Excretion

Based on the molecular weight, water solubility and log Kow, N4,N4’-hexane-1,6-diylbis[N-butyl-6-chloro-N,N’-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] is not likely to be widely distributed, and is expected to be excreted unchanged in the faeces.

   

2. Information from other studies in the dossier

Absorption – oral

In an acute oral toxicity test (OECD 423/GLP), 3 groups of female Wistar Crl: WI(Han) rats (3/group) were administered N4,N4'-hexane-1,6-diylbis[N-butyl-6-chloro-N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] (91%) in corn oil by oral gavage at a dose of 300 and 2000 mg/kg bw. Animals were then observed for 14 days. All animals of the first and second steps treated with the test item at a dose of 300 mg/kg bw and 2000 mg/kg bw, respectively, survived until the end of the study. The animals of the first step did not show any signs of toxicity. The only clinical finding observed was piloerection in animals of the second step. One animal of step 3 treated with the test item at a dose of 2000 mg/kg bw was found dead on day 8 post-application. All remaining animals survived until the end of the study, showing slight signs of toxicity, which were fully reversible by the end of the observation period. The most relevant clinical findings findings in the animals of the third step were diarrhoea and piloerection.  At necropsy, no treatment-related macroscopic findings were observed in any animal of any step. The LD50 (cut-off) was 2500 mg/kg bw.

Testing proposals have been submitted for an OECD 408/GLP study in rats and an OECD 414/GLP study in rats; this assessment will be updated when the results from those studies are available.

Based on the physicochemical data and available in vivo toxicological data, oral absorption is expected to be low. For chemical safety assessment purposes, an oral absorption rate of 50% is accepted.

Absorption – dermal

In a dermal sensitization study (OECD 429/GLP) with N4,N4'-hexane-1,6-diylbis[N-butyl-6-chloro-N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] (91%), young adult CBA/CaOlaHsd mice (5 females/group) were tested in the Local Lymph Node Assay. The doses tested were 12.5, 25 and 50% (w/v) in AOO (4:1 (v/v) acetone/olive oil). The reliability of the test system was confirmed by a positive control test with 1% phenylenediamine in AOO that was performed concurrently, using 5 animals. The positive control, 1% phenylenediamine, gave the appropriate response (stimulation index 4.4 ± 0.9). All animals survived throughout the test period without showing any signs of systemic toxicity or local irritation. All animals treated with the test item showed test item residues at the application sites within the days 2-4. Sticky fur was observed at the application sites of all animals treated with the test item at the concentrations 12.5% or 25% from day 3 or 4 until day 6. All animals showed the expected weight development, which allows for a weight loss of up to 2 g throughout the study. The SI values were 5.6 ±0.5, 7.3 ±2.3, 4.8 ±2.6 at concentrations of 12.5%, 25% and 50% (w/v), respectively. Each of the tested concentrations exceeded the stimulation index of 3. The EC3 value could not be calculated due to the lack of a dose-response relationship of the data obtained. In this study, N4,N4’-hexane-1,6-diylbis [N-butyl-6-chloro-N,N’-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5-triazine-2,4-diamine] is considered to be a dermal sensitiser.

As the substance is a dermal sensitiser, dermal absorption occurs. 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. As the molecular weight is 1042 g/mol and the log Kow is > 4.72, for chemical safety assessment purposes a dermal absorption rate of 10% is accepted.

Absorption – inhalation

In an acute inhalation toxicity study (OECD 403/GLP), 4 groups of young adult Sprague-Dawley rats (5/sex) were exposed to a test atmosphere of N4, N4'-hexane-1,6-diylbis[N-butyl-6-chloro-N,N'-bis(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,5- triazine-2,4-diamine] (91%) for 4 hours (nose only) at  mean actual concentrations of 5.04±0.13 (group 1), 2.04±0.06 (group 2), 0.55±0.04 mg/L (group 3) or 0.056±0.016 mg/L (group 4). Animals were then observed for 14 days. The MMAD was 1.88-2.19 μm and GSD was 2.25-2.46.  In group 1, all animals were found dead at chamber removal. Gross necropsy of the decedents revealed discoloration of the lungs and distention of the stomach and/or liquid in the trachea. In group 2, 8 animals (5/5 males, 3/5 females) were found dead at chamber removal.  Two animals died (2/5 females) within one hour of exposure to the test atmosphere. Gross necropsy of the decedents revealed discoloration of the lungs and/or liquid in the trachea. In group 3, 4 males and 5 females died within two days of exposure to the test atmosphere.  Prior to death, the animals were hypoactive and exhibited irregular respiration and/or prone posture.  Following exposure, one surviving animal was hypoactive and exhibited irregular respiration.  However, the animal recovered by Day 4 and appeared active and healthy for the remainder of the study and gained body weight over the 14-day observation period.  Gross necropsy of the decedents revealed discoloration of the lungs and/or liquid in the trachea. No gross abnormalities were noted for the euthanized animal when necropsied at the conclusion of the 14-day observation period. In group 4, all animals survived exposure to the test atmosphere. Following exposure, all rats exhibited irregular respiration.  However, all animals recovered by Day 3 and appeared active and healthy for the remainder of the 14-day observation period and gained body weight during the study. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period. The LC50 Males was 0.38 mg/L (95% C.I. 0.06 - 2.31). The data does not permit calculation of the LC50 for females by Probit Analysis.  The LC50 for females is estimated to be between 0.056 mg/L and 0.55 mg/L

As there is clear toxicity via the inhalation route, inhalational absorption occurs. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted.

Distribution/Metabolism/Excretion

Testing proposals have been submitted for an OECD 408/GLP study in rats and an OECD 414/GLP study in rats; this section will be updated when the results from those studies are available.