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EC number: 212-990-3 | CAS number: 903-19-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
There are no studies available in which the toxicokinetic behaviour of 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (AF-317) (CAS No. 903-19-5) was investigated. An assessment of the toxicokinetic behaviour of the substance 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (AF-317) was conducted to the extent that can be derived from the relevant available information:
- Absorption: Oral absorption is possible, dermal absorption is predicted to be low; due to limited information regarding inhalation, a worst-case approach was applied and absorption via inhalation is assumed to be as high as via the oral route
- Distribution and accumulation: After absorption the substance is distributed within the body and has the potential to accumulate unless there is a high metabolic clearance.
- Metabolism: hydroxylation and / or oxidation, leading to more water-soluble metabolites, is likely in a first step; the second step is assumed to be Phase II metabolism (i.e. conjugation processes with sulphate or glucuronic acid) to promote excretion
- Excretion: via bile and / or urine (water-soluble metabolites); non-absorbed substance could directly be excreted via faeces
Key value for chemical safety assessment
Additional information
There are no studies available in which the toxicokinetic behaviour of 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (AF-317) (CAS No. 903-19-5) was investigated.
In accordance with Annex VIII, Column 1, 8.8.1, of Regulation (EC) 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of the substance 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (AF-317) was conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2017).
Physico-chemical properties
2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (AF-317) is an organic, mono-constituent substance with a molecular weight of 334.54 g/mol. It is a fine brown powder at 20 °C with occasionally lumps. Melting began during decomposition (indicated by a darkening in colour), starting at 132°C and ending at 133 °C. The water solubility is 0.027 mg/L at 20°Cand pH 7.4 . The log Pow was estimated to be 5.814 at 25°C (pH 5-6), and the vapour pressure was approximately 2.01E-5 Pa at 20 °C.
Absorption
Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).
Oral
In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds can be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed. Solids must be dissolved before absorption; the degree depends on the water solubility (ECHA, 2017).
Some of the physico-chemical characteristics (log Pow, water solubility and physical state) of 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (AF-317) are in a range that indicate poor absorption from the GI-tract following oral ingestion, while the molecular weight favours uptake. Micellular solubilisation is likely to occur; although it is unclear to what degree it will affect the total absorption rate of the substance.
In a study in which rats were administered a single dose of 2 g/kg bw 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (AF-317) (CAS 903-19-5) there was no mortality (Key, 1996). Piloerection was observed in all rats within 5 min of dosing, and has resolved completely in all instances by three hours after dosing. Slightly low bodyweight gains were recorded for 2/5 male rats on both Day 8 and 15, all other rats achieved satisfactory bodyweight gains throughout the study. No macroscopic abnormalities were observed for animals killed on day 15. Based on the results of the conducted study, a LD50 of > 2000 mg/kg bw was derived for male and female rats.
In an oral combined repeated dose toxicity and reproductive and developmental toxicity study performed with 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (AF-317) the NOAEL was estimated to be 10 mg/kg bw/day for both male and female rats since centrilobular hepatocellular hypertrophy and changes in liver weight were observed in the livers of males and females in the 50 mg/kg group during repeated administration of 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (CAS 903-19-5) to parent animals (Key, 2010). In addition, low haemoglobin was observed in males and females in the 50 mg/kg and higher groups. The observed treatment-related effects indicate that the substance is absorbed following oral administration.
In conclusion, the log Pow, water solubility and physical state of 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (CAS 903-19-5) suggest that oral absorption is likely to be very low. A vehicle may be necessary to increase the absorption rate; in the described oral tests methylcellulose or olive oil were applied as vehicles and test substance-related effects were observed. Based on the observed treatment-related effects the potential for absorption via the oral route is considered to be high.
Dermal
The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L; low to moderate if it is between 1 - 100 mg/L; and moderate to high if it is between 100 - 10000 mg/L. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if the water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).
2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (AF-317) has a molecular weight of 334.54 g/mol, but is a solid with a very low water solubility. The log Pow is 5.814, which means that the uptake into the stratum corneum is predicted to be high and the rate of transfer between the stratum corneum and the epidermis will be slow (ECHA, 2017). However, the substance needs to dissolve into the surface moisture of the skin before uptake into the stratum corneum can begin and this first step will be very limited due to the low water solubility.
In an acute dermal toxicity study 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (CAS 903-19-5) in propylene glycol was applied to the skin of male and female Wistar rats at a dose level of 2000 mg/kg bw under occlusive conditions (Key, 1998). The LD50 value was derived to be > 2000 mg/kg bw. Red staining of the head, neck and / or periorbital region was noted in 2/5 males and 1/5 females on Day 2. Erythema (grade 1), scales and scabs were seen in the treated skin-area among 2/5 males and 3/5 females between Days 3 and 6. Brown staining of the skin on the back by the test substance was noted in 2/5 females on Day 2. The changes noted in mean body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity. Pelvic dilatation in the right kidney, found in one female at macroscopic post mortem examination, is commonly noted among rats of this age and strain and was therefore not considered to be toxicologically significant. No further abnormalities were noted among the animals. This indicates a very low skin penetration level (although an appropriate vehicle was used) and / or low acute dermal toxicity.
If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2017).
The available data for 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (CAS 903-19-5) shows that erythema (grade 1), scales and scabs was observed in the treated skin-area of 2/5 male and 3/5 female Wistar rats between Days 3 and 6 in an acute dermal toxicity study (Key, 1998). However, no indications of skin irritating effects were seen in an in vivo skin irritation study in rabbits (Key, 1996), leading to the conclusion that 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone has no skin irritancy potential. The result of the skin sensitisation test performed in guinea pigs with 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (CAS 903-19-5) was negative (Key, 1996). Thus, it is concluded that enhanced skin penetration of the substance based on skin damage is not expected.
Based on a QSAR calculated dermal absorption a value of 8.656E-05 mg/cm2/event (very low) was predicted for 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (Dermwin v.2.02, EPI Suite).
Overall, based on the available information, the dermal absorption potential of 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (CAS 903-19-5) is predicted to be very low.
Inhalation
Substances that can be inhaled include gases, vapours, liquid aerosols (both liquid substances and solid substances in solution) and finely divided powders/dusts. To be readily soluble in blood, a gas or vapour must be soluble in water and increasing water solubility would increase the amount absorbed per breath. However, the gas or vapour must also be sufficiently lipophilic to cross the alveolar and capillary membranes. Therefore, a moderate log P value (between -1 and 4) would be favourable for absorption. Generally, liquids, solids in solution and water-soluble dusts would readily diffuse/dissolve into the mucus lining the respiratory tract. Lipophilic substances (log P > 0) would then have the potential to be absorbed directly across the respiratory tract epithelium (ECHA, 2017).
Isohexadecyl 12-[(1-oxooctadecyl)oxy]octadecanoate is a solid with a low water solubility and a low vapour pressure (< 0.0001 Pa at 20 °C), and therefore low volatility. Therefore, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered to be limited. However, the substance may be available for inhalatory absorption after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). As the substance is fomulated in a matrix and thus, there is no spraying application, availability via aerosols is not relevant. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. No data with respect to inhalation toxicity is available. Due to the limited information available a worst case approach is applied, and absorption via inhalation is assumed to be as high as via the oral route.
Distribution and accumulation
Distribution of a compound within the body depends on the physico-chemical properties of the substance, especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2017).
In the oral combined repeated dose toxicity and reproductive and developmental toxicity study effects were seen in the liver, kidney and blood, which indicates that the substance is distributed to tissues and organs throughout the body (Key, 2010). Due to the lipophilic character of 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone it has the potential to accumulate within the body unless there is a high metabolic clearance.
Metabolism
There is no data on the metabolism of 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (CAS 903-19-5) available. As discussed before, if absorption of 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone (CAS 903-19-5) occures it is distributed within the body and reaches the liver, which is the organ with the greatest capacity for metabolism, and the kidney, where excretion processes, leading to excretion via the urine, take place. The effects observed in the liver and kidney indicate that these organs are involved in the metabolism and / or excretion of the parent substance and / or metabolites. Due to the structure, it is likely that metabolic processes like hydroxylation and / or oxidation take place leading to more water-soluble metabolites. In a second step Phase II metabolism (i.e. conjugation processes with sulphate or glucuronic acid) are likely to promote excretion.
Excretion
Water-soluble metabolites could be excreted via the bile and / or urine. Non-absorbed substance could directly be excreted via the faeces.
References
ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, version 3.0, June 2017.
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.
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