A mixture of branched and linear C7-C9 alkyl 3-[3-(2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxyphenyl]propionates

Endpoint summary

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance Chiguard 5599 is a yellow to light amber liquid. It is an UVCB (a mixture of branched and linear C7-C9 alkyl 3-[3-(2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxyphenyl]propionates and Benzenepropanoic acid, 3-(1,3-dihydro-2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxy-. The C8 alkyl constituent is the main constituent (typical concentration: 91.24%). 
No studies on the toxicokinetics of the substance are available. Only limited data has been provided by ECHA via an inquiry result (06-2120047284-59-0000). No human data is available and the toxicokinetic analysis is based on physicochemical data and data from in vivo animal models. In vivo studies covering the oral route are available (acute, 28 day repeated dose, read-across subacute pre-natal developmental toxicity). In vivo studies covering the dermal route are available (skin irritation, skin sensitisation). There are no studies covering the inhalational route available. For further details on study summaries, reference is made to the IUCLID 5 registration dossier and references in Section 6 of this report. 
The available physicochemical and toxicological data suggests that oral absorption is expected to occur mainly via the lymphatic system.  The available physicochemical and toxicological data suggests that absorption of Chiguard 5599 via the dermal route is expected to be minimal. The available physicochemical data suggests that absorption of Chiguard 5599 via the inhalation route is expected to be low but no inhalation studies are available for the substance. Initial systemic exposure is likely to be to the parent compound as first-pass metabolic transformation is avoided. Chiguard 5599 may accumulate in fat during chronic exposure at high doses and the liver is a target organ for toxicity. The substance is expected to be excreted in the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

  Physicochemical properties

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 ofChiguard 5599in the body.

 Absorption

Themolecular weight of eachconstituentof Chiguard 5599 is <500g/mol andis in the range for favourable oral absorption (<500 g/mol). The calculatedlog Pow of Chiguard 5599 (9.2) indicates it is highly lipophilic and a water solubility(<0.3 mg/L at 20°C)indicatesit is slightly soluble in water. These characteristics willnot facilitate transport of Chiguard 5599 via passive diffusion and impair its ability to dissolve in gastric juices. Based on its high lipophilicity, the absorption ofChiguard 5599via the lymphatic system through micellular solubilisation by bile salts is a possibility.

The water solubility (<0.3 mg/L at 20°C) indicates low dermal uptake while the high calculated log Pow (9.2) is an indication for a high uptake into the stratum corneum but little or no penetration into the lower layers of the epidermis and dermis. Overall, the physical state, molecular weight, calculated log Powand poor water solubilityindicate that dermal absorption is unlikely.

Due to the very low vapour pressure ofChiguard 5599(0.000003 Pa at 25°C) and physical state (liquid), exposure via the inhalation route is expected to be negligible.

Distribution/Metabolism

Typically lipid-soluble substances may reach all compartments and accumulate in fat. The molecular weight (< 500 g/mol) andwater solubility (<0.3 mg/L)of Chiguard 5599 are somewhat favourable for wide distribution.The high calculated log Pow (9.2) is an indication for a high uptake into the stratum corneum, but it is likely to remain there and have little or no penetration into the lower layers of the epidermis and dermis; any Chiguard 5599 that persists after dermal exposure may be sloughed off with skin cells.

Initial systemic exposure is likely to be to the parent compound as absorption via the lymphatic system will avoid first pass metabolic transformationand based on the chemical structure, Chiguard 5599 has no groups which will dissociate in a relevant pH range (2-10) so is likely to be present in the body in a non-ionised form.

Information from other studies in the dossier

Absorption

Oral/GI absorption 

In the acute oral toxicity key study, clinical signs of piloerection, hunched posture and dyspnea were noted. The LD50 was >2000 mg/kg. The oral 28 day repeated dose key study in rats indicatedbiochemical, haematogical and organ weight changes, with the liver being a target organ.The NOAEL was 2 mg/kg bw/day.In the read-across pre-natal developmental toxicity study conducted with the structural analogue TINUVIN 1130 (EC No. 400-830-7), any foetal effects were attributed to maternal toxicity; no teratogenic effects were noted. The NOAEL (maternal and embryotoxicity) was 30 mg/kg bw/day.Thein vivostudy data together with the physicochemical information indicates that the substance is absorbed via the oral route; any absorption and systemic effects noted may be due to uptake via the lymphatic system.For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

Dermal absorption

Thein vivoskin irritation study in rabbits and skin sensitisation study in guinea pigs indicated that the substance is not irritating or sensitising. The calculated log Pow (9.2) is an indication for a high uptake into the stratum corneum, but it is likely to remain there and have little or no penetration into the lower layers of the epidermis and dermis; any Chiguard 5599 that persists after dermal exposure may be sloughed off with skin cells. As no systemic effects were noted in any dermal study, it can be assumed thatthere is negligible systemic absorption.The available dermal toxicity data together with the physicochemical dataindicates that any significant dermal absorption is unlikely.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. In general, dermal absorption will not be higher than oral absorption, so forchemicalsafetyassessment purposes a dermal absorption rate of 50% is accepted.

Respiratory absorption-Inhalation

There are no inhalational studies available.Due to the very low vapour pressure ofChiguard 5599(0.000003 Pa at 25°C) [8]) and physical form (liquid), exposure via the inhalation route is expected to be negligible.For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted,asno inhalational toxicity data is available for the substance. 

 Distribution/Accumulation

The oral 28 day repeated dose key study in rats indicatedbiochemical, haematogical and organ weight changes mainly at the top dose (500 mg/kg bw/day) and the liver is a target organ. As Chiguard 5599 is highly lipophilic, it is likely to accumulate in fat during chronic exposure with high doses.In the read-across pre-natal developmental toxicity study conducted with the structural analogue TINUVIN 1130 (EC No. 400-830-7), maternal bodyweight gain was reduced at the top dose (150 mg/kg bw/day). The only foetal effect noted was delayed ossification in litters at 150 mg/kg bw/day which was attributed to maternal toxicity. No teratogenic effects were noted. As Chiguard 5599 is highly lipophilic,the amount transferred to the fetus is assumed to be low, because the body fat of the fetus is low.

 Metabolism

There is no direct evidence to indicate how the substance is metabolised.As the liver is a target organ, detoxification of Chiguard 5599 is likely to be impaired.As Chiguard 5599 is likely to be absorbed via the lymphatic system, it will not be subject to first pass metabolism and initial systemic exposure will be to the parent compound.Based on the chemical structure, there are no hydrolysable functional groups present, so in order to facilitate excretion, the highly lipophilic parent substance is likely to be converted to polar metabolites for excretion.

Excretion

There is no direct evidence to indicate the route of excretion of the substance. Based on the molecular weight (< 500g/mol) and assuming it is converted to a morewater soluble metabolite, it is likely that excretion of any absorbed Chiguard 5599 will occur in the urine.