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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
the study does not need to be conducted because (i) the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and (iii) there is no or no significant human exposure
Justification for type of information:
FR-245: Waiver for Extended One-Generation Reproductive Toxicity Study (EOGRT) testing.

The Registrants of the substance 2,4,6-tris (2,4,6-tribromophenoxy)-1,3,5-triazine were notified by European commission (EC letter dated 15-11-2016) regarding an Amendment of the standard information requirements in Annex IX and X of the REACH in which the OECD 443 Extended One-Generation Reproductive Toxicity Study (EOGRT) became the standard information requirement under REACH instead of the previous 2-generation reproductive toxicity study. Accordingly, the section of Reproductive Toxicity of the dossier is updated.
The registrants request to refrain from performing the (EOGRT) based on the following scientific information which was generated according to appropriate OECD guidelines and GLP.
1. According to the REACH Regulation Annex IX section 8.7.3, EOGRT should be performed “If the available repeated dose toxicity studies (e.g. 28-day or 90-day studies, OECD 421 or 422 screening studies) indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity.
This is equally stated in Chapter R.7a (P. 359): Endpoint Specific Guidance from ECHA Guidance on Information Requirements and Chemical Safety Assessment.
A 90- day oral repeat dose toxicity study in the rat with a 28 day recovery period was conducted according to OECD 408 testing guideline under GLP conditions (Mackay, 2009). The study included investigation of effects on some reproductive endpoints, in addition to the standard study design. The results showed no systemic toxicity effects and the No Observed Adverse Effect level (NOAEL) was determined as >1000mg/kg/day. No treatment related changes in sperm count and motility were observed. Vaginal lavages which were taken early morning during the 3 week period from all females, prior to termination of the animals, showed no treatment related changes in the oestrus cycle. In addition, there were no dose related changes in organ weight of ovaries, seminal vesicles, testis, ureter, uterus, vagina in comparison to control animals. Details of the data can be found in section 7. 5.1 (Repeated dose toxicity).
In summary, the 90-day repeated dose toxicity for this substance did not observe any adverse effect on reproductive organs or tissues.
2. A Developmental toxicity study was conducted according to the appropriate OECD 414 guideline and following GLP standards (Kim Kang-hyun, 2013) to evaluate the potential maternal and developmental toxicity of 2,4,6-Tris(2,4,6 tribromophenoxy)-1,3,5-triazine (also designated FR-25) in rats. Doses of 250, 500 and 1000mg/kg/day test substance were administered orally during days 5-19 of gestation. No effects of the test substance treatment were observed in maternal rats in any of the parameters examined.
At cesarean section, there were no treatment-related abnormalities in such parameters as mean gravid uterine weights, the numbers of corpora lutea and implantation, or the percent implantation index, pre- and post-implantation loss in any treated groups.
As for fetuses, the number of live fetuses, percent fetal deaths, fetal body weight, placental weights, and sex ratio in treated groups were comparable to those in the control group. Any treated groups were shown no adverse effects of test substance treatment in external, visceral and skeletal examinations of live fetuses.
Based on the results of absence of toxicity (maternal and fetuses) and absence of teratogenic findings, it is concluded that the dose level of 1000 mg/kg/day of 2,4,6-Tris(2,4,6-tribromophenoxy)-1,3,5-triazine is the no-observed-adverse-effect level (NOAEL) for maternal rats and fetuses.
In summary, from the generated scientific data and according to the REACH Regulation Annex IX it can be concluded that long term exposure to FR-245 is not likely to have adverse effect on the fertility, developmental toxicity or nor cause systemic toxicity or affect the reproductive organs. Therefore, the registrants believe that performance of the EOGRT is unnecessary scientifically, and unjustified for animal welfare reasons.
Cross-reference
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
28- Day Repeated-dose Oral toxicity study in rats with 14 days recovery period.
91- Day Repeated-dose Oral toxicity study in rats with 28 day Recovery period
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Two oral toxicity repeated dose studies were conducted on FR-245 to evaluate any possible adverse effect implication, following subacute and subchronic exposure to the substance.

A 28- Day Oral (gavage) Toxicity test in rats, with 14 days recovery period was performed with FR-245. The test material was administered to 3 groups (of 50, 250, 1000mg/kg/day), each of six male and six female rats. A control of six male and six female rats was dosed with vehicle alone. Two recovery groups, each of six male and six females, were treated with the high dose (1000mg/kg/day) or the vehicle for twenty eight consecutive days and then maintained without treatment for further fourteen days.

Oral administration of FR-245 to rats for 28 consecutive days at dose level of 1000 mg/kg/day produced no adverse effect on body weights, food consumption, hematology, blood biochemistry, urinalysis, organ weight, gross pathological and histopathological results. The No-Observed Effect Level (NOEL) was determined as>1000mg/kg/day (the highest dose level tested). Any statistically significant differences noted in hematology, blood chemistry, organ weight, clinical signs, gross pathology and histopathology were not considered treatment related since there was no dose response relationship.

A 91 Day Oral (gavage) Toxicity test in rats with 28 days recovery period was performed with FR-245. The test material was administered to 3 groups (of 100, 350 and 1000mg/kg/day), each of 10 male and 10 female rats, for 91 consecutive days. A control of 10 male and 10 female rats was dosed with vehicle alone.  Two recovery groups, each of five male and five females, were treated with the high dose (1000mg/kg/day) or the vehicle for 91 consecutive days and then maintained without treatment for further 28 days. Several endpoints of reproduction and Neurotoxicity were investigated in addition to the standard study protocol.

Daily repeat dose (oral gavage) administration of FR-245 to Sprague Dawley rats, for up to 91 consecutive days at dose levels, did not result in any adverse effects on body weights, food consumption, hematology, blood biochemistry, urinalysis, organ weight, gross pathological and histopathological results, following observation and examination throughout the in-life phase of the study, at necropsy or following histological assessment. The no-observed effect level (NOEL) was determined as >1000mg/kg/day (the highest dose level used). 

No treatment related changes in sperm count and motility were observed (data are attached in Tables 45 and 46 in section 7.8.1 of the IUCLID). Vaginal lavages which were taken early morning during the 3 week period from all females, prior to termination of the animals showed no treatment related changes in the oestrus cycle (data are attached as Appendix 40 in section 7.8.1 of the IUCLID). In addition, there were no dose related changes in organ weight of ovaries, seminal vesicles, testis, ureter, uterus, vagina in comparison to control animals.

In summary, from the results of the oral toxicity repeated dose studies it can be concluded that prolonged exposure to FR-245, which is hardly absorbed (outcome of the ADME study), is not likely to have adverse effect, nor cause systemic toxicity effect.

The substance should not be classified based on NOAEL> 1000 in both 28 day and 91 day of oral repeated dose exposure.

Data source

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine
EC Number:
426-040-2
EC Name:
2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine
Cas Number:
25713-60-4
Molecular formula:
C 21 H 6 Br 9 N 3 O 3
IUPAC Name:
tris(2,4,6-tribromophenoxy)-1,3,5-triazine

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion