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Administrative data

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Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine is an organic mono-constituent solid with a purity of 99 - 100% (w/w), with a typical concentration of 99.29% (w/w).

A full ADME toxicokinetic study in the rat is not available. In vivo studies covering the oral route (acute oral toxicity study in rats, combined repeated dose oral toxicity study with reproduction/developmental toxicity screening test in rats) and the dermal route (LLNA in mice) are available. There are no studies via the inhalation route available. The toxicokinetic analysis is based on the physicochemical and in vivo toxicological data. Further details on endpoints are available in the IUCLID 6 registration dossier.

Based on the physicochemical data and available in vivo toxicological data, absorption of 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine is expected to be moderate via the oral route, low via the dermal route with uptake enhanced due to skin irritant properties and negligible via the inhalation route. The target organ for toxicity is the kidney in males and females, with accumulation expected during repeated exposure. This would compromise any excretion via the urine.

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

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 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine  in the body.

Absorption - oral

The molecular weight of 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine (277.194 g/mol) is in the range for favourable oral absorption (<500 g/mol). It is lipophilic (log Pow 5.18 at 40°C) and it is poorly soluble in water (<0. 248 mg/L at 20°C). 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

As 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine is poorly soluble in water, low dermal uptake is expected; however, as it is a skin irritant (OECD 439/GLP), this may enhance uptake. The moderate log Pow value indicates slow transfer to the epidermis and entry into systemic circulation. The substance is a strong sensitiser in the local lymph node assay (LLNA) in mice so some uptake must occur. Overall the molecular weight, log Pow and poor water solubility indicate that dermal absorption of 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine is likely to be low, but the local skin irritant properties will enhance uptake.  

Absorption – inhalation

The particle size distribution report for 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine indicates a range of 3.311μm - 2187.762μm (D10:147.35 μm, D50: 664.594 μm, D90:1424.82 μm). This indicates that <10% of the particles are available in the inhalable fractions of air (<100 μm) and therefore it is a considered to have no or low dustiness. Exposure via the inhalation route is expected to be negligible.

2. Information from other studies in the dossier

Absorption – oral

In an acute oral toxicity test (OECD 423/GLP), 2 groups of female Wistar Crl: WI(Han) rats (3/group) were administered 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine (99.29%) in corn oil by oral gavage at a dose of 2000 mg/kg bw. One animal of step 1 was found dead 2 days post-application. All remaining animals survived until the end of the study showing signs of toxicity. The most relevant clinical findings were reduced spontaneous activity, hunched posture, piloerection, eyes half closed, diarrhoea and slight weight loss during the first study week. All animals recovered within up to 8 days post-dose. At necropsy, no treatment-related macroscopic findings were observed in any animal of any step. The LD50 (cut-off) was 2500 mg/kg bw.

In a combined repeated dose and reproduction/developmental toxicity screening test (OECD 422/GLP), 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine (99.29%) was administered to 4 groups of Wistar rats (10 animals/sex/group) by gavage in corn oil at dose levels of 0, 40 (LD), 120 (MD), and 360/240 (HD) mg/kg body weight/day, 7 days per week. Females were administered 360 mg/kg bw/day up to premating day 6; females were not dosed on premating days 7 and 8 to allow recovery from their bad health condition on premating day 6/7. Males were administered 360 mg/kg bw/day up to premating day 6. Males and females were administered 240 mg/kg bw/day from premating day 9 onwards. The animals were treated for a maximum period of 63 days in females, i.e. during 14 days of pre-mating and maximum 14 days of mating in both males and females, during the gestation period and up to post-natal day 12 in females. Males will be dosed after the mating period until the minimum total dosing period of 28 days is completed.

Treatment with the test item caused mortality in 1/10 females of the HD group (360 mg/kg bw/day). Morbidity in this female was caused by kidney lesions (tubular dilatation, tubular basophilia and tubular degeneration) caused by treatment with the test item. All remaining animals (dosed at 240 mg/kg bw/day) survived the scheduled study period. Higher total WBC and monocytes in HD females compared to controls observed at the end of the treatment period are possibly related to nephropathy-associated inflammation. No toxicologically relevant effect of the test item was observed at LD and MD levels. At the end of the treatment period a tendency towards slightly higher serum urea levels in HD males and higher serum urea levels (HD and MD group) and crea levels (HD group) were observed in female animals which were assumed to be related to nephropathy observed at the corresponding dose level. The test item had no toxicologically relevant effects on urinary parameters analysed at the end of the treatment period of this study.

Test item-related necropsy findings in the HD group consisted of enlarged kidneys (5/10 males and 8/10 females) and kidneys which were observed with an abnormal color (5/10 males), shape (1/10 females), or surface (observed in 8/10 females and 1/10 males) and correlated with histopathology lesions. No other test item-related macroscopic findings were noted in any of the groups. Marked and statistically significant higher kidney weight in females of the HD group correlates with the histopathology changes and was considered test item-related. Higher kidney weight was seen in males of the HD group. All other organ weight changes were considered of no toxicological relevance due to the absence of correlating histological lesions. Test item-related kidney nephropathy was observed in the MD and HD group. In kidneys of HD males and females there was nephropathy characterized by tubular dilatation, tubular basophilia, interstitial fibrosis, mononuclear infiltrates, tubular degeneration, mixed cell infiltrates and transitional cell hyperplasia. Nephropathy characterized by tubular dilatation, tubular basophilia and mononuclear infiltrates were observed in the kidneys of some males and females of the MD group. No renal changes were observed in animals from the LD group. Under the conditions of this study, no histological evidence of toxicity was observed in reproductive organs and tissues including testes, epididymides, prostate gland, seminal vesicles, coagulating glands, ovaries, uterus and cervix, and vagina. Further, there were no treatment-related effects on the testicular histomorphology including spermatogenesis and interstitial cell structure.

No statistically significant test item effects were observed on litter data parameters. However, a slight tendency towards a lower mean total number of pups in the HD group on PND 0 may be test item-related. Mean number of CL and IS showed statistically significantly lower in the HD group and LD and MD groups showed a tendency towards lower CL and IS numbers. Mean male litter weight and consequently total litter weight were statistically significantly lower in the HD group compared to the male control pups on PND 0, PND 4, and PND 13. It cannot be excluded that this condition is caused by treatment of parental animals with the test item. Mean pup weight and litter weight were not affected in the MD and LD groups.

It cannot be excluded that statistically significant effects on estrous cyclicity in the HD group (3/10 females) were caused by treatment with the test item. In female pups, slightly but higher, absolute and relative AGD was observed in the HD group when compared controls. Relevant effects in the estrous cyclicity and AGD could indicate the potential of a test item to serve as an endocrine disruptor. However, estrous cyclicity and AGD are not the only parameters to confirm the endocrine disruption and need to be correlated with lot of other parameters like histopathology of parental reproductive organs and their weights, litter size, sex ratio, pup thyroid/parathyroid weight and thyroxine hormone (T4). Other parameters showed no findings supporting a possible endocrine disruption modality of the test item. Based on the observed effects of the test item on health condition, body weight development, food consumption, and kidney effects, effects on anogenital distance and estrous cyclicity could be based on general toxicity in the HD group. Based on the findings of this study the NOAEL (parental/offspring) of 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine for reproductive toxicity screening is considered to be 120 mg/kg bw/day.

In contrast to the physiochemical data, the in vivo data indicates that moderate oral absorption may be expected. 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

In a dermal sensitization study in mice (OECD 429/GLP), 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine was a skin sensitiser. All animals survived throughout the test period without showing any systemic effects and all animals showed the expected weight development. However significant local effects were recorded on day 6 in all animals, which reflects the skin irritant properties noted in vitro. Together with the physiochemical data, this data indicates that absorption via the dermal route is likely to be low, but the local skin irritant properties will enhance uptake. 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

There are no studies via the inhalation route available. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, using a conservative approach.

Distribution/Metabolism/Excretion

Based on the information provided from the physicochemical data and in vivo studies, the target organ for toxicity is the kidney in males and females, with accumulation expected during repeated exposure. This would compromise any excretion via the urine.