4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine

Endpoint summary

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, pre-natal developmental toxicity study in rats) and the dermal route (LLNA in mice, in vitro skin irritation test) 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. The moderate log Pow value indicates slow transfer to the epidermis and entry into systemic circulation; however, as it is a skin irritant (skin irritation category 2 in an OECD 439/GLP test), this may enhance uptake. 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), 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. The animals were treated for a maximum period of 56 days in females and males were 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. 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. Mean number of corpora lutea (CL) and implantation sites (IS) showed statistically significantly lower in the HD group and LD and MD groups showed a tendency towards lower CL and IS numbers. Although statistically significant, lower CL and IS values in the HD group were within the range of historical control data. However, an effect of the test item on CL and IS cannot be excluded. 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. Though, value of lower male litter weight was within the range of historical control data. Mean pup weight and litter weight were not affected in the MD and LD groups.

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 and for repeated dose toxicity (male/female) is 40 mg/kg bw/day.

In a prenatal developmental toxicity in rats (OECD 414/GLP), the test item (99.29%) was administered to pregnant Wistar, Crl: WI(Han) rats (23/dose) by oral gavage in corn oil at dose levels of 0, 50 (LD), 150 (MD) and 275/225 (HD) mg/kg bw/day daily from GD 5-19.

Test item-related mortality was observed in the HD group (2 non-pregnant dams) and no further morbidity was observed after reduction of the dose to 225 mg/kg bw/day. Test item-related effects on gross pathology lesions were observed in MD and HD groups, predominantly in the kidneys. No test item-related effect was observed on group mean T3, T4 and TSH hormone levels and thyroid/parathyroid weights from all dams. No test item-related findings at histopathological evaluation of the thyroid gland in any of the treatment groups.

 

Successful mating resulted in 21/23 pregnancies in the LD group, 21/23 in the MD group and 19/23 in the HD group compared to 22/23 pregnancies in the control group. Test item-related reduction in mean foetal weight (individual and litter basis) were observed in MD and HD groups; which could be due to the secondary effect of maternal toxicity with reduced food consumption and body weight. No test item-related effects were observed on prenatal parameters including uterine weight, number of corpora lutea, implantation sites, early and late resorptions, percent pre and post implantation loss, number of live foetuses, anogenital distance (AGD), number of male and female foetuses, sex ratios and testicular descent in treatment groups when compared to the control. No test item-related and toxicologically relevant external, visceral, craniofacial and skeletal findings were observed in the foetuses of all treatment groups when compared to the control group.

 

The NOAEL for maternal/foetal toxicity of 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine was considered to be 50 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 significant skin sensitiser. 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. Exposure to the foetus is expected to be low with any changes due to the secondary effect of maternal toxicity.