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EC number: 276-309-1 | CAS number: 72058-41-4
Toxicity to Reproduction (Screening):
Subacute NOAEL (reproduction, parental): 120 mg/kg bw/day (OECD 422/GLP)
Subacute NOAEL (development, offspring): 120 mg/kg bw/day (OECD 422/GLP)
Extended one-generation reproductive toxicity:
Results from the OECD 422/GLP study (RL1) shows no adverse effects on reproductive organs or tissues in males or females, so the extended one-generation reproductive toxicity study (OECD 443) is waived.
In a combined repeated dose and reproduction/developmental toxicity screening test (183812), 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 56 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 were dosed after the mating period until the minimum total dosing period of 28 days was completed.
Concentration analysis and homogeneity of formulation samples was determined at three concentrations, 10 mg/mL, 30 mg/mL and 90/60 mg/mL in study weeks 1, 3, 5 and in the last week of the study. The concentration of the HD dose group was reduced in week 3. Nominal concentrations were confirmed for all dose groups, as measured concentrations were within acceptance criterion of 10 %. All samples were homogenous, as COV was below or equal 10%.
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.
Clinical symptoms indicating systemic toxicity caused by test item were observed in the HD group. Due to increasingly poor health condition dosing of HD females their dosing was stopped on premating days 7 and 8 and dosing of males and females of the HD group was continued a with a reduced dose level of 240 mg/kg/day from premating day 9 onwards what led to improvement of the health condition especially in females. No clinical signs of systemic toxicity were observed at the MD and LD levels.
Treatment with the test item temporarily affected body weights of male animals of the HD group and female animals of the MD and HD groups. No effect was observed at the LD level. In correlation with effects of the test item on body weights of the HD group, a tendency towards lower food consumption was observed in male and female animals of the HD group during the first and second week of treatment. In females of the HD group statistically significantly lower food consumption was noted towards the end of the lactation 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. Statistically significant effects in MCV level and % of reticulocytes in males (HD) and platelets in females (MD and HD) were not considered adverse as values were within the range of historical control data. However, it cannot be excluded that mentioned differences were caused by treatment with the test item. 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. 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. It cannot be excluded that this condition is caused by treatment of parental animals with the test item. Though, value of lower male litter weight was within the range of historical control data. Dose-dependently lower mean pup weight on PND 0, PND 4, and PND 13 achieving statistical significance in the HD group on PND 4 and PND 13 and lower mean male and female pup weight in test item-treated groups on PND 0 resulting in significantly lower mean weight of male and female pups of the HD group were considered test item related based on the dose-dependency and statistical significance in the HD group. 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, but there is no historical data available. Also no histological evidence of toxicity was observed in the ovaries of the high dose group, compared to controls. 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. Mean AGD value of females of the HD group was within the range of historical control data, however it cannot be excluded that higher AGD is related to treatment with the test item.
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.
There is one dose range finding (DRF) study in rats available and one Combined Repeated Dose Oral Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in rats available.
Dose range finding (DRF) study
In a dose range finding study for a reproduction/developmental toxicity screening test (183813), 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine (99.29%) was administered to 5 groups of Wistar rats (3 animals/sex/group) by gavage in corn oil at dose levels of 0, 100 (LD), 300 (MD), and 1000 (HD) or 600 (HD) mg/kg body weight/day and additionally 500 (HID) mg/kg body weight/day, 7 days per week. The animals were treated for a period of 54 days, 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 3 in females. Males were dosed after the mating period until the minimum total dosing period of 28 days was completed.
Test item-related mortality occurred in 3/3 males and 3/3 females of the HD group. Subsequently, the animals were not treated with the test item on study day 3 and the high dose was reduced from 1000 mg/kg body weight/day to 600 mg/kg body weight/day from study day 4 onwards. Males of the additional group dosed with 500 mg/kg body weight/day were all euthanized in a moribund condition between treatment day 8 and 10.
Severe clinical findings in the HD group caused by treatment with 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine were reduced spontaneous activity, diarrhea, dehydration, stilted gait and sunken flanks. Gross pathological changes which may be caused by treatment with the test item were an abnormal colored stomach in one animal of the HD group and masses in the stomach of another HD animal. No mortality or clinical symptoms indicating systemic toxicity were observed at dose levels of 100 and 300 mg/kg body weight/day. At a dose level of 300 mg/kg body weight/day (MD) a slightly attenuated body weight gain was observed in males and females.
Under the conditions of the study performed, it is assumed that 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine has no toxic effects on male and female reproductive performance such as gonadal function, mating behavior, conception, development of the conceptus and parturition as well as pup-related parameters.
Based on the data generated from this dose range finding study, dose levels of 40, 120 and 360 mg/kg bw per day are suggested for the subsequent main Combined Repeated Dose Toxicity Study with Reproductive/Developmental Toxicity Screening Test (OECD 422) with 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine.
Combined Repeated Dose Oral Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
There is one combined repeated dose and reproduction/developmental toxicity screening test in rats available.
Extended one-generation reproductive toxicity:
Prenatal developmental toxicity
A testing proposal for an OECD 414/GLP study in rats has been submitted in the dossier.
Based on the available information in the dossier, the substance 4,6-dichloro-N-(1,1,3,3-tetramethylbutyl)-1,3,5-triazin-2-amine (CAS No. 72058-41-4) does not need to be classified for reproductive toxicity or for effects on or via lactation when the criteria outlined in Annex I of 1227/2008/EC are applied.
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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