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Description of key information

Short description of key information on bioaccumulation potential result:

There is limited evidence that the test substance may be absorbed via the gastro-intestinal tract but there was no evidence of absorption by the dermal route. There was also limited evidence of systemic distribution but no evidence of distribution to the central nervous system. The kidneys may be a site of metabolism and/or excretion. In addition the results of the In vitro mammalian chromosome test in the presence of S-9 mix indicates that the liver may be capable of metabolising this test substance. There was no evidence of bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

No specific toxicokinetic studies are available.

This assessment of the absorption, metabolism, distribution and excretion of BPS-MAE is derived from data produced for its notification under the requirements of EC Regulation 1907/2006 and represents the toxicokinetic assessment under Annex VIII of the Regulation. It is an updated version of the assessment submitted under the Notification of New Substances (NONS) scheme.

 

Physicochemical properties

 

BPS-MAE (4-Hydroxy-4'-(2-propenyloxy)diphenyl sulfone) is typically 99.4 % pure. The substance is a white powder. It has a melting point range of 172.3-173.7°C. The boiling temperature was not determinable as the substance decomposes starting from 197.8°C without boiling. It has a molecular weight of 290.34, a relative density of 1.32 and a vapour pressure of 2.75E-12 Pa at 25 °C. The test substance has a log Pow of 2,12. The results of the hydrolysis test indicate that the test substance is hydrolytically stable and has a half-life of > 1year at pH 4, 7 and 9 at 25 °C. The particle size distribution test indicate that 1 % by mass of the test substance is smaller than 10 mm.

 

Toxicity

 

Acute oral toxicity

A group of six female rats received a single dose of 2000 mg/kg of the test substance. There were no deaths. No clinical signs of reaction to treatment were observed in any animal during the study. No abnormalities were revealed at the macroscopic examination at study termination on Day 15. The oral LD50 was determined to be > 2000 mg/kg.

 

Acute dermal toxicity

A group of ten rats (five males and five females) received a single topical application of 2000 mg/kg of the test substance. No clinical signs of reaction to treatment were observed during the study. No dermal irritation was observed in any of the animals during the study. There were no systemic responses to treatment following a single dermal application of the test substance. No abnormalities were recorded at the macroscopic examination at study termination on Day 15. The dermal LD50 was determined to be > 2000 mg/kg.

 

Skin irritation

A single semi-occlusive application of the test substance produced no dermal irritation was observed in any animal throughout the duration of the study. No signs of toxicity or ill health were observed in any rabbit during the observation period

 

Eye irritation

No corneal damage or iridial inflammation was observed. Minimal conjuctival irritation was noted in all treated eyes one hour after treatment. All eye appeared normal at the 24-hour observation. There were no signs of toxicity or ill health in any rabbit during the observation period.

 

Sub-acute toxicity study

Four groups of rats (6/sex per test group and 12/sex per control group) were treated at 0, 40, 200 and 1000 mg/kg/day of the test substance for 28 days. Selected rats from the control and high dose groups were then allowed a 14-day period without dose administration (recovery period).

 

There were no deaths and no clinical signs, including those assessed as part of the neurobehavioural examinations, observed during the treatment period that were considered to be indicative of a reaction to treatment.

 

There were no treatment-related effects on bodyweight gain or food consumption.

 

At the haematology investigations performed at the end of the treatment period lower than control mean APTT values were noted in males receiving 200 or 1000 mg/kg/day. These differences from, controls did not follow a clear dosage relationship. Similar differences from controls were not seen at the end of the recovery period.

 

Biochemistry investigations performed at the end of the treatment period did not reveal any changes that were considered to be attributable to treatment.

 

At the end of the treatment period females receiving 1000 mg/kg/day showed higher than control kidney weights (absolute and relative). These differences from controls were not seen at the end of the recovery period.

 

Macroscopic and microscopic examinations at the end of the administration period, revealed no abnormalities related to treatment.

 

The No Observed Adverse Effect Level (NOAEL) on this study was 1000 mg/kg/day for both sexes. The No Observed Effect Level (NOEL) was also 1000 mg/kg/day for males and 200 mg/kg/day for females.

 

Mutagenicity studies

 

Ames test: No toxicity or genotoxicity was observed in the absence or presence of S-9 mix.

 

In Vitro Mammalian Chromosome Aberration Test in Human Lymphocytes: the test substance showed no evidence of mutagenic activity, in either the absence of S-9 mix however, in the presence of S-9 mix, the substance was found to be clastogenic.

 

Embryo-fetal toxicity

The influence of BPS-MAE, on embryo-fetal survival and development in Crl:CD(SD) rats was assessed following oral administration throughout gestation (Huntingdon Life Sciences ODW0002). Three groups of 22 female rats received BPS-MAE by gavage at doses of 100, 500 or 1000 mg/kg/day from Day 1 to 19 after mating. A similarly constituted Control group received the vehicle, 0.5% w/v carboxymethylcellulose sodium salt, at the same dose volume throughout the same period. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination. During the study clinical observations, bodyweight and food consumption were monitored.

Adult females were examined macroscopically at necropsy on Day 20 after mating and all fetuses were examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.

There was no effect of treatment on maternal clinical condition, bodyweight, food consumption, macropathology, mean gravid uterine weight or pregnancy outcome, embryo-fetal survival growth and development, or incidence of external or internal fetal abnormalities, at all doses.

It was therefore concluded that 1000 mg/kg/day BPS-MAE was the maternal no-observed-effect-level (NOEL) and the fetal no-observed-adverse-effect-level (NOAEL).

 

Reprotoxicity

 

The influence of BPS-MAE on gonadal function, mating behaviour and fertility in treated Crl:CD(SD) rats of the F0 generation and the survival of the F1 offspring up to weaning (Day 21 of age) following daily oral gavage administration was assessed (Huntingdon Life Sciences ODW0004). Three groups of 24 male and 24 female rats received BPS-MAE by gavage at doses of 100, 500 or 1000 mg/kg/day. Males were treated for ten weeks before pairing, throughout pairing until termination, after the majority of F1 litters had weaned (approximately 17 weeks). Females were treated for two weeks before pairing, throughout pairing, and until Day 20 of lactation. A similarly constituted Control group received the vehicle, 0.5% w/v carboxymethylcellulose sodium salt, at the same volume dose, throughout the same periods.

 

During the study, clinical condition, bodyweight, food consumption, oestrous cycles, mating performance and fertility, gestation length and parturition observations organ weight, macroscopic and microscopic pathology investigations were undertaken on the F0 adults.

 

The clinical condition, litter size and survival and sex ratio of all offspring (F1) were assessed before macroscopic pathology investigations on Day 21 of age.

 

There were no deaths, clinical signs, or signs following administration to males for 17 weeks or in females for two weeks before pairing, during gestation or lactation.

Overall mean bodyweight gain in animals receiving 500 or 1000 mg/kg/day was slightly low during the two week pre-mating period and during gestation. Bodyweight gain during lactation was high and values at the end of lactation were similar to Control.

Food consumption was slightly low in animals at 1000 mg/kg/day during the two week pre-mating period and was marginally low in animals at 500 or 1000 mg/kg/day during gestation.

 

The oestrous cycle was longer in some animals at 500 or 1000 mg/kg/day.

Pre-coital interval mating performance, conception rate and fertility were unaffected by treatment.

Gestation length was prolonged in one animal and parturition was protracted in three animals, at 1000 mg/kg/day.

Parental treatment with BPS-MAE did not affect the number of implantations, litter size, post-implantation survival, offspring survival to Day 21 of age, sex ratio or offspring clinical signs or bodyweight gain.

 

There was no affect of treatment on parental organ weight, or macroscopic or microscopic findings or macroscopic findings in the offspring.

 

The extended oestrous cycle in some animals at 500 or 1000 mg/kg/day, longer gestation length in one animal and protracted parturition in three animals at 1000 mg/kg/day were considered to be related to treatment. It was therefore considered within this study, for reproductive function, as measured by gonadal function, mating behaviour and fertility, that the no-adverse-effect level (NOEL) was 100 mg/kg/day. The unsubstantiated association with treatment of both longer gestation period and extended parturition at 1000 mg/kg/day precludes this dose as the no-observed-adverse-effect-level (NOAEL) therefore; it is considered in this study that the NOAEL was 500 mg/kg/day.

 

Assessment

 

The test substance is a powder and has a relatively high water solubility of 5.95 mg/l, a moderately low molecular weight of 290.34 and is therefore likely to be available for absorption. The log Pow of 2.12 indicates that the substance is unlikely to bioaccumulate.

 

 

Absorption:

The minor disturbances in APTT values and higher kidney weights recorded on the 28-day study, the extended oestrous cycle at 500 or 1000 mg/kg/day, and the longer gestation length in one animal and protracted parturition in three animals at 1000 mg/kg/day observed in the reprotoxicity study indicate possible absorption by the gastrointestinal tract.

There was no evidence from the dermal toxicity or skin irritation studies which indicated that the test substance was being absorbed by the dermal route.

 

Distribution: The minor disturbances in APTT values and findings in the reprotoxicity study also provided limited evidence that the test substance is distributed systemically when absorbed by the gastro-intestinal tract. There was however no evidence of distribution to the central nervous system.

 

Metabolism:

The higher kidney weights recorded on the 28-day study may be an indication of metabolism by this organ. The lack of similar findings between the treatment and recovery periods indicates that if absorption of the test substance does occur it is eliminated or metabolised and does not bioaccumulate.

Excretion:

The results of the in vitro mammalian chromosome aberration test in the presence of S-9 indicate that the liver enzymes may be capable of metabolising this test substance. The higher kidney weights recorded on the 28-day study are possibly indication of excretion by this organ. There was however no other evidence of excretion.