3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane;bis(2,4-dicumylphenyl) neopentyl diphosphite

Endpoint summary

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane is a white solid powder. It is an organic monoconstituent, with a purity of >99% to <100% with a typical concentration of 99.18%.

No studies on the toxicokinetics of the substance are available. Only limited data has been provided by ECHA via an inquiry result. No human data is available and the toxicokinetic analysis is based on data from physicochemical data, in vivo animal models.. In vivo studies covering the oral route are available (acute, 28 day repeated dose, screening for reproduction/developmental toxicity). An in vivo study covering the dermal route is available (skin sensitisation). There are no studies covering the inhalational route available. For further details on study summaries, reference is made to the appropriate sections in the IUCLID 6 registration dossier.

Based on the physicochemical data and available in vivo toxicological data, absorption via the oral, dermal and inhalational routes is expected to be low. 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane is not likely to be widely distributed or accumulate and will be excreted unchanged in the faeces.

The absorption rates of 50% (oral), 10% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

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 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane in the body. This information can be combined with the in vivo study data for the toxicokinetic assessment.

1.Physicochemical properties

Absorption – oral

The molecular weight of 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane is 852.983 g/mol and is above the range for favourable oral absorption (<500 g/mol). The log P (> 6 at 22°C) indicates it’s highly lipophilic and the water solubility (< 0.05 mg/L at 20°C) indicates it is insoluble in water. These characteristics will not facilitate transport of 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane via passive diffusion. 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.

Absorption – dermal

As 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane is insoluble in water, low dermal uptake is expected. The high log Pow value indicates a high uptake into the stratum corneum but little or no penetration into the lower layers of the epidermis and dermis. Overall the molecular weight, log P and water insolubility indicate that dermal absorption of 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane is unlikely.

Absorption – inhalation

3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane has a very low vapour pressure (1.0E-23 Pa at 25˚ C) but is also considered a very dusty solid. The particle size distribution report indicates a range of 0.02550 μm to 2500 μm (D(10): 3.15 μm, D(50): 12.66 μm, D(90): 25.12 μm). This indicates that 90% of the particles are available in the inhalable fractions of air (<100 μm). Particles with aerodynamic diameters of above 1-5 μm have the greatest probability of settling in the nasopharyngeal region whereas particles with aerodynamic diameters below 1-5 μm are most likely to settle in the tracheo-bronchial or pulmonary regions. As there are fractions in both categories, the substance is likely to be distributed throughout the respiratory tract upon inhalation. As a water-insoluble dust, the substance could be coughed or sneezed out of the body or swallowed (refer to oral absorption). Based on the water insolubility (< 0.05 mg/L at 20°C) and lipophilicity (> 6 at 22°C)), it is likely that any absorption will be low and occur via micellular solubilisation and the lymphatic system.

Distribution/Metabolism/Excretion

Based on the high molecular weight, water insolubility and log P, 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane is not likely to be widely distributed or accumulate and will be excreted unchanged in the faeces.

2. Information from other studies in the dossier

Absorption – oral

In an acute oral toxicity study (EPA-guideline 798.1175 (based on Directive 92/69/EEC,B.1)/GLP), Sprague Dawley rats (5/dose/sex) were administered 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane in 0.5 % aqueous methylcellulose by gavage at doses of 2000, 3150 and 5000 mg/kg bw and observed for 14 days. All animals survived through the 14-day observation period. The body weight was within the normal range. Light colored feces were observed in all animals on day 1. With the exception of one female rat exhibiting decreased feces on day 10 and 11, the animals appeared normal. No findings considered treatment related were noted at necropsy. The LD50 (male/female) was >5000 mg/kg bw.

In a sub-acute toxicity study (Directive 92/69 EEC, B.7/GLP), 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane was administered by oral gavage to Sprague Dawley rats (5/sex/group) in corn oil at 0, 62.5, 200 or 500 mg/kg bw/day for 28 days, 7 days per week. After 28 days test duration, all animals survived the scheduled treatment period. There were no effects on body weights or food consumption. There were no test article-related clinical signs noted in any dose group. There were no treatment related effects on hematology, clinical biochemistry and urinalysis data at termination of the treatment nor at the end of the treatment-free recovery period which could be considered of toxicological significance.  However, a few minor findings with statistical significance were recorded between the control and treated rats of group 4 at termination of the treatment and/or recovery period; the toxicological relevance of these statistical findings is considered to be doubtful. There was no difference in organ weights, macroscopic and histopathological findings between control and treated rats. The NOAEL for repeated dose toxicity in males and females was established as 200 mg/kg bw/day (nominal).

In a reproduction/developmental toxicity screening test (OECD 421/GLP), 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane (99.3%) was administered to Wistar rats (15 animals/sex/group) by gavage in corn oil at dose levels of 0, 250, 500 or 1000 mg/kg bw/day, 7 days per week. Dosing of both the sexes was initiated 2 weeks prior to mating and continued during the mating period. After mating, the male rats were further dosed up to and including the day before scheduled sacrifice. Females were further dosed during pregnancy and up to post-partum day 3. There were non-treatment-related mortalities in parental animals. There were no effects on the following parameters in parental animals: clinical signs, body weight, food consumption, organ weights, gross pathological effects, histopathological effects, reproductive performance, duration of pregnancy, pre-implantation loss, parturition index, or live birth index. The NOAEL was >1000 mg/kg bw//day. There were non-treatment-related mortalities in F1 animals. There were no effects on the following parameters in F1 animals: clinical signs, food consumption, fetal body weight changes, reduction in number of live offspring, changes in sex ratio, changes in litter size and weights, changes in postnatal survival and external malformations. The NOAEL was >1000 mg/kg bw/day.

Together with the physiochemical data, this indicates that oral absorption is low. 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 (Directive 92/69 EEC, B.6 maximization test/GLP) with 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane in ethanol, Himalayan guinea pigs were tested in a maximisation test. For induction, 5% of the test item in ethanol (intradermal application) and 50% of the test item in ethanol (epidermal application) was used. For challenge, 50% of the test item in ethanol was used for epidermal application. The evaluation of skin reactions after challenge was carried out at 24 and 48 hrs. Neither erythema nor oedema were observed in the animals of the test group and the control group after the intradermal and epidermal induction. 0/20 of the test item animals showed positive skin reactions and 0/10 of the control animals showed positive skin reactions. Based on these results, the substance is not sensitising.

Together with the physicochemical data, this indicates that dermal absorption is likely to be low. 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. So, a dermal absorption rate of 10% is accepted.

Absorption – inhalation

No inhalational toxicity study data is available. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, using a conservative approach.

Distribution/Metabolism/Excretion

Based on the results of the repeated dose toxicity and reproduction/developmental toxicity screening test in male and female rats, 3,9-bis[2,4-bis(1-methyl-1-phenylethyl)phenoxy]-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane did not produce test item-related adverse effects on reproduction and development or general toxicity. The distribution is very limited and no accumulation is expected. It’s likely to be excreted unchanged in the faeces.