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Description of key information

Based on the physico-chemical characteristics of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene and the available oral acute- and long-term toxicity data, the substance may be absorbed via the oral route, but the absorption level is expected to be low. The dermal and inhalation adsorption potential is expected to be very low, based on the physico-chemical characteristics of the substance and the available dermal and inhalation exposure data. Due to the very limited absorption of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene, the fraction of substance that may be distributed is expected to be small. There is no data that shows how the substance will be distributed, metabolised and excreted.   

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetic assessment

1. Summary

A toxicokinetic methodology confirmation test was conducted for the notified substance by Tianjing Center of Disease Control (CDC) in 2014. It is found that both MS and HPLC analytic methods are not suitable to toxicokinetic detection, thus the formal toxicokinetics study has not been conducted. However, an assessment on the toxicokinetic behaviour of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene based on its physico-chemical properties and available toxicological data were conducted.

The current results from the available toxicology studies adequately characterize the toxicity property of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene, reveal that the substance is hazardless, which can conclude that exposures to the substance causes no concern to the human health.

 

2. Available data

 

2.1 Physico-chemical properties

 

Table 1: Physico-chemical properties

CAS number

97416-84-7

English name

1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene]

Molecuar formula

C23H24Br8O2

Molecular weight

971.667

Physical state at 20 °C and 101.3 kPa

White powder

Density

1.05 x 10³ kg/m³ (23 °C)

Vapor pressure

< 4.4 x 10⁻⁷kPa (25°C)

Oxidability

No oxidability

Flammability

No flammability

Explosive

Not explosive

Octanol-water partition coefficient

log Pow > 6.5

Water solubility

< 4.2 x 10⁻⁷g/L

 

 

 

2.2 Toxicological data

 

Table 2: Available toxicological data

Acute oral toxicity

LD50 > 2000 mg/kg bw

Acute dermal toxicity

LD50 > 2000 mg/kg bw

Acute inhalation toxicity

In male and female rats: 4h LC50 > 5 mg/L

Skin irritation

Negative

Eye irritation

Negative

Skin sensitisation (LLNA)

Negative

Bacterial reverse mutation assay

Negative

Chromosome aberration test in vitro

Negative

In vitro gene mutation test

Negative

Micronucleus test

Negative

90-day repeated dose oral toxicity study

NOAEL = 1000 mg/kg bw/day

 

Reproductive/developmental screening test

500 mg/kg bw/day dose level of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene caused no reproductive and developmental toxicity to male and female rats

Please see further details as follows.

 

Acute oral toxicity

In a study performed according to the OECD guideline 425 and in compliance with GLP, 5 female Wistar strain rats was administered via oral at the dose levels of 175,550,2000 mg/kg bw of test substance respectively. Sufficient time allowed after each dose level administered to make sure the result of former treated animal come out.

There were no deaths during the study. Hunched posture was noted in two animals treated at a dose level of 2000 mg/kg bw. No other signs of systemic toxicity were noted. All animals showed expected gains in bodyweight over the study period. No abnormalities were noted at necropsy. It is concluded that LD50 of the test material in the female Wistar strain was found to be greater than 2000 mg/kg bw.

 

Acute dermal toxicity

In a study performed according to the OECD guideline 402 and in compliance with GLP,10 rats (5 males and 5 females) was exposed to test substance via dermal for 24 hours at dose level of 2000 mg/kg bw. There were no deaths; there were no signs of systemic toxicity. There were no signs of dermal irritation. Animals showed expected gains in bodyweight over the study period,except for one male which showed an expected gain in bodyweight during the first week but bodyweight loss during the second week; two females also showed no gain in bodyweight during the first week but expected gain in bodyweight during the second week and one other female which showed expected gain in bodyweight during the first week but no gain in bodyweight during the second week. No abnormalities were noted at necropsy. It is conclusion that LD50 of the test substance in rat was found to be greater than 2000 mg/kg bw.

 

Acute inhalation toxicity

In a study performed by lab which is accredited by Ministry of Public Health of China as "Toxic Chemicals Identification A Grade Agency" and according to OECD guideline 403, 10 rats (5 males and 5 females) were exposed to 5 .47 mg/L of test substance for 4 hours. There were no obvious toxic symptoms, and no deaths during observation period. The LC50 for acute inhalation toxicity was higher than 5.47 mg/L.

 

Skin irritation

In a study performed according to the OECD guideline 404 and in compliance with GLP, a single 4-hour, semi-occluded application of the test material to the intact skin of three rabbits produced no evidence of skin irritation. The test material produced a primary irritation index of 0.0 and was classified as a no irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted.

 

Eye irritation

In a study performed according to the OECD guideline 405 and in compliance with GLP, a single application of the test material to the non-irrigated eye of three rabbits produced moderate conjunctival irritation. Treated eyes appeared normal at the 48-hour observation. No corneal or iridial effects were noted during the study. All animals showed expected gain in bodyweight during the study.

 

Skin sensitisation

In a study performed according to the OECD guideline 429 and in compliance with GLP, three groups CBA/Ca mice, each of five animals, were treated with 50 μL test substance (25 μL for each ear) as a solution in dimethyl formamide at concentration of 25%, 10% or 5% w/w for 3 days continuously. There were no deaths. No sign of systemic toxicity were noted in the test or control animals during the test. Bodyweight changes of the test animals between Day 1 and Day 6 were comparable to those observed in the corresponding control group animals over the same period. The test substance was considered to be a non-sensitizer under the conditions of the test.

 

Bacterial reverse mutation assay

In a study performed according to the OECD guideline 471 and in compliance with GLP, Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 and Escherichia coli WP2uvrawere treated with the test material at five dose levels, ranging from 50 to 5000 μg/plate, in triplicate, both with and without the addition of a rat liver homogenate metabolizing system. The test substance caused no visible reduction in the growth of the bacterial background lawn at any dose of 5000 μg/plate. The test substance was considered to be non-mutagenic under the conditions of this test.

 

Chromosome aberration test in vitro

In a chromosome aberration in vitro study performed by lab accredited by Ministry of Public Health of China as "Toxic Chemicals Identification A Grade Agency" and according to OECD guideline 473, Chinese hamster lung cells (CHL) was exposed to 0.625 mg/ml, 0.312 mg/ml and 0.156 mg/ml of test substance. A short-term treatment (6 hours) was performed with a 6-hour harvest time, with and without metabolic activation. In addition, a 24-hour treatment with 24-hour harvest time without metabolic activation was performed. The results showed that the chromosomal aberrant frequency had no significant difference between the treated group and control group (P > 0.05). Within the range of dose level, the number of chromosomal aberrations was no repeatability increase or dose-related increase, also the polyploidy and endoreduplication cells were not observed.

 

In vitro gene mutation test

An in vitro gene mutation test was performed in Chinese lung fibroblasts (V79) (Yamakage, 2016). The study was conducted according to OECD guideline 476 and GLP. The cells were treated with 33.0, 65.0, 130 and 260 µg/mL for 4 h, with and without metabolic activation. Precipitation of the test substance was observed from the start of the treatment at 260 µg/mL with and without metabolic activation, and at 130 µg/mL with metabolic activation at the end of the treatment. The precipitation was not considered to affect the results. No cytotoxicity was observed at any concentration. The results of the positive controls with and without metabolic activation, and the results of the negative control without metabolic activation fell within the range of the historical control data. The mutation frequency in the negative control group with metabolic activation was higher than the historical control data range and the experiment was therefore repeated. In the 2nd experiment, the mutation frequency in the negative control group with metabolic activation fell within the range of the historical control data. The test substance did not cause an increase in mutation frequency with and without metabolic activation.

 

Micronucleus test

In a mammalian erythrocytes micronucleus test performed by lab accredited by Ministry of Public Health of China as "Toxic Chemicals Identification A Grade Agency" and according to OECD guideline 474, single maximum dose limit test was used, male and female mice were exposed to 2000 mg/kg bw of test substance by oral gavage. Results showed that there was no dose-related increase on micronucleated polychromatic erythrocytes, and no significant difference compared to control group (P > 0.05).

 

90-day repeated dose toxicity study

In a 90-day repeated dose toxicity study performed by lab accredited by Ministry of Public Health of China as "Toxic Chemicals Identification A Grade Agency" and according to OECD guideline 408, rats were administered via oral gavage at the dose levels of 1000.0, 500.0, 250.0 mg/kg bw/day of test substance for 90 days, general performance, body weight, food consumption were observed, detected the relevant index such as hematology, blood biochemistry, routine urine and urine biochemical, and performed histopathological examination on the organ.There were no toxicologically relevant effects on any parameters in the main and satellite groups.Therefore after receiving substance for 90 days, by oral (gavage) administration, the No Observed Adverse Effect Level (NOAEL) for male and female rats was 1000.0 mg/kg bw/day.

 

Reproductive /Developmental Screening Test

In a Reproductive/Developmental Screening Test performed by lab accredited by Ministry of Public Health of China as "Toxic Chemicals Identification A Grade Agency" and according to OECD guideline 421, the test rats were received substance Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene, daily, by oral (gavage) administration, 2 weeks before pairing and through paring and, for the females, through gestation until day 4 p.p.; for the males, until 28 days after paring, at the dose levels of 250.0 mg/kg bw/day, 500.0 mg/kg bw/day and 1000.0 mg/kg bw/day.

The test results showed that mating success rate, conception rate,live birth rate of each dose group had no statistically significant difference compared with control group (P > 0.05). At necropsy, there was no abnormalities found on histopathological examination, reproductive organs (such as the testis, epididymis, ovary, uterus) were found no abnormalities or lesions. The offspring from low,middle and high dose group and from the control group had no appearance deformity when be born and until day 4 p.p. Two animals of high dose level had an abnormal maternal behavior leading to cannibalism of its entire litter, which caused the born survival rate of high dose group was low control group, and the difference was statistically significant (P < 0.05). 1000 mg/kg bw/day dose level of substance caused no reproductive and developmental toxicity effect on male and female rats.

 

3. Toxicokinetic assessment

[1Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene is white organic powder, with molecular weight of 971.667, the density at 23 °C is 1.05 x 10³ kg/m³, the water solubility and vapour pressure of the substance is very low (below 4.2 x 10⁻⁷g/L and 4.4 x 10⁻⁷kPa at 25°C, respectively).

A toxicokinetic methodology confirmation test has been conducted with the notified substance. It is found that both MS and HPLC analytic methods were not suitable to toxicokinetic detection. Thus no specific study was performed on the absorption/ distribution/ metabolism/ excretion (ADME) of this substance, but based on the available toxicity information it is considered that the toxicokinetic behaviour of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene can be derived.

 

Absorption

Oral route

The possibility of systemic absorption through the intestinal wall when using oral gavage is determined by several physical and chemical properties of the substance. If considering only the log Pow (> 6.5) of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene, the systemic absorption will probably be accelerated via passive diffusion. However, it is necessary to consider some important facts such as molecular weight, water solubility to finally conclude whether the test substance can enter the systemic circulation. Generally, the smaller the molecular weight is, the easier the substance could be absorbed through intestinal wall. The molecular weight of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene is 971.667g/mol, indicates low potential of the substance be absorbed through intestinal wall and enter the systemic circulation. Moreover, Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene is barely dissolved in liquid solution, so it's not easily dissolved in gastrointestinal fluids. On the contrary, this almost insolubility in gastrointestinal fluids will prevent the contact of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene with mucosal surfaces of the gastrointestinal tract, which further limits the possibility of systemic absorption. The solid substance may be absorbed by endocytosis. For Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene, about 37% of the particles have a diameter less than 10 μm, so there is still potential for Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene to be absorbed by endocytosis. Although in the 90-day repeated dose toxicity study some hematology parameters (platelet count, prothrombin time, the percentage of neutrophils) and some biochemical index (ALP, CRE, AST and GLU) were changed, these were not toxicologically relevant and pathological and histological observation did not find any typical histologic changes and specific injury related to treatment. Moreover, no deaths and systemic toxicity were observed in the acute oral toxicity test, and the micronucleus test result was negative. So it can be concluded that the test substance may be absorbed by the oral route, but the percentage is unknown.

 

Dermal route

In the acute dermal toxicity study, 10 rats (5 males and 5 females) were exposed to 2000 mg/kg bw test substance for 24 hours. There were no deaths; there were no signs of systemic toxicity. There were no signs of dermal irritation. In the skin irritation test a single 4-hour, semi-occluded application of the test material to the intact skin of three rabbits produced no evidence of skin irritation. The test material produced a primary irritation index of 0.0 and was classified as a non-irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted. The test result of the skin sensitisation study was negative. It can be concluded that dermal route of absorption is unlikely to happen based on the physicochemical properties and the test results.

 

Inhalation route

Substance Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene is white powder at 200 °C and 101.3 kPa with very low vapour pressure (< 4.4x 10⁻⁷kPa) indicates that significant adsorption by the inhalation route would not be expected.

 

Distribution

According to physico-chemical properties and toxicological data of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene, it may be absorbed by the oral route; it is not likely to be systemically absorbed at any significant rate by dermal and inhalation route. Moreover, there were no findings indicating distribution of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene based on result of available toxicological tests.

 

Metabolism

There were no findings clearly indicating metabolism from available data.

 

Excretion

There was not conclusive evidence that the kidneys were involved with excretion of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene from available data.

 

4. Discussion

A formal toxicokinetics study has not been conducted with the notified substance. As indicated above, toxicokinetic behaviour of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene is derived from the physicochemical properties and available toxicological data. The current results from the completed toxicological studies adequately characterize the toxicity of Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene.

 

5. Conclusion

Based upon the lack of indications of hazards from all available data, it can be concluded that exposure to certain Reaction mass of 1,1'-(isopropylidene)bis[3,5-dibromo-4-(2,3-dibromo-2-methylpropoxy)benzene] and 1,3-dibromo-2-(2,3-dibromo-2-methylpropoxy)-5-{2-[3,5-dibromo-4-(2,3,3-tribromo-2-methylpropoxy)phenyl]propan-2-yl}benzene is of no concern to the human health.

 

 

REFERENCES

1. Harlan Laboratories Ltd, Project No. 0466/0358, 2010

2. Harlan Laboratories Ltd, Project No. 0466/0359, 2010

3. Tianjing CDC, study number: 20 13WT-HD-0006-01, 2014

4. Harlan Laboratories Ltd, Project No. 0466/0360, 2010

5. Harlan Laboratories Ltd, Project No. 0466/0361, 2010

6. Harlan Laboratories Ltd, Project No. 0466/0362, 2010

7. Harlan Laboratories Ltd, Project No. 0466/0366, 2010

8. Tianjing CDC, study number: 20 13WT-HD-0006-03, 2014

9. Tianjing CDC, study number: 2013WT-HD-0006-04, 2014

10. Tianjing CDC, study number: 20 13WT-HD-0006-02, 2014

11. Tianjing CDC, study number: 20 13WT-HD-0006-08, 2014