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Description of key information

A read-across acute oral toxicity study from C20-24 (OECD 423) was identified.  Read-across acute dermal toxicity studies from octadecene (OECD 402; isomerised olefins; alpha, internal, linear and branched - single carbon number) and alkenes, C20-24 (OECD  402; isomerised olefin; alpha, internal, linear and branched – multiple carbon numbers) were identified. Read-across acute inhalation studies from hexadec-1-ene (OECD 403), hex-1-ene (OECD 403) and alkenes, C10/C11/C12/C13 (OECD 403; multiple carbon number isomerised olefin) were identified.
• The oral LD50 for C20-24 was > 5000 mg/kg bw in male and female rats.
• The dermal LD50 for octadecene was >2020 mg/kg bw in male and female rabbits.
• The dermal LD50 for alkenes, C20-24 was > 2000 mg/kg bw in male and female rabbits.
• The LC50 for hex-1-ene was 110,148 mg/m3 (110.1 mg/L) for male rats.
• The LC50 for hexadec-1-ene was = 8500 mg/m3 (8.5 mg/L) for male rats.
• The LC50 for alkenes, C10/C11/C12/C13 was > 2100 mg/m3 (2.1 mg/L) in rats.

Key value for chemical safety assessment

Additional information

Acute Oral Toxicity

No acute oral toxicity data exist for icos-1-ene; therefore, a read-across study was identified for this endpoint. In read-across acute oral toxicity study with C20-24 alpha olefins (Rausina, 1982), young, fasted Fischer 344 rats (5/sex) were given a single oral dose of Gulftene 24 (i.e., C20-24 linear alpha olefin) in corn oil at a dose of 5000 mg/kg bw and observed for 14 days. No treatment-related adverse effects were noted in body weight or necropsy observations and the only clinical signs noted (yellow staining of the inguinal region, oil around mouth, and brown staining on lower jaw) all disappeared by day 5 of the study period. The oral LD50 for Gulftene 20-24 was determined to be > 5000 mg/kg in male and female rats.

The results from this read-across study indicate that structural analogues of icos-1-ene (C20-24 linear alpha olefins) are not acutely toxic by the oral route of exposure as all the reported LD50 values exceed the highest regulatory threshold fo classification (2000 mg/kg bw). Therefore, icos-1-eneis not considered to be acutely toxic by the oral exposure route. It does not meet EU criteria for classification and labelling (Dangerous Substances Directive 67/548/EEC or CLP EU Regulation 1272/2008) for this endpoint; hence an acute oral DNEL is not required.

 

Acute Dermal Toxicity

No acute dermal toxicity data exist for icos-1-ene; therefore two read across studies were identified to assess this endpoint.  In a read-across study from octadecene, a structurally-related isomerised olefin; alpha, internal, linear and branched - single carbon number, white rabbits (5/sex) were dermally treated with octadecene at a dose of 2020 mg/kg (2.35 mL/kg), undiluted, for 24 hours (Kuhn, 1993) and then observed for 14 days. No mortalities were observed. Body weights of four males and females were either depressed or unchanged between days 7 and 14. Treatment related signs included slight diarrhea in one female on days 9 and 10. No treatment-related abnormalities were observed following necropsy on day 14. Based on these results, the LD50for octadecene in rabbits was reported as > 2020 mg/kg.

The second study, involving anisomerised olefin; alpha, internal, linear and branched – multiple carbon numbers, was selected to show the span of the full carbon range and to provide sufficiently robust data for classification.In this study, groups of young adult Sprague-Dawley rats (5/sex) were dermally exposed to alkenes, C20-24, undiluted for 24 hours to 35 cm2body surface at a limit dose of 2000 mg/kg bw (Driscoll, 1998). Animals were then observed for 14 days. There were no treatment related clinical signs, necropsy findings or changes in body weight. The dermal LD50 for alkenes, C20-24 was reported as > 2000 mg/kg in male and female rabbits.  

Based on the lack of apparent significant toxicity among animals dermally exposed to octadecene or alkenes, C20-24, icos-1-ene is not considered an acute dermal hazard. Since the available data do not meet the criteria for classification and labelling (Dangerous Substances Directive 67/548/EEC and CLP EU Regulation 1272/2008) for this endpoint, an acute dermal DNEL is not required.

Acute Inhalation Toxicity

The overall dataset on the potential acute inhalation toxicity of linear alpha olefins is limited. Three potential acute inhalation toxicity of linear alpha olefin and multiple carbon number isomerised olefin substances were evaluated to build a weight of evidence for the assessment of this endpoint.  Individually, these studies were considered of limited usefulness due to inadequate reporting of the study methodologies and results; however the overall findings are useful when assessed collectively (i. e. for building a weight-of-evidence). 

 In a series of screening studies conducted by Rinehart (1967), rats were exposed to either hex-1-ene vapour (for 4 hours) or hexadec-1-ene saturated mist (for 1 hour). The study on hex-1-ene was well conducted and reported, although high exposure concentrations were used (above the 20 mg/L limit for vapours required for classification and labelling; EU CLP). No mortality was reported in the lowest dose group (95 mg/L) although mild signs of anaesthesia were noted among treated animals. 

 

In the study on hexadec-1-ene, groups of male Wistar rats (number of animals not specified) were exposed for 1 hour to hexadec-1-ene at an estimated aerosol mist concentration of 8500 mg/m3(particle size less than< 8.0 microns). Rats appeared drowsy on removal from the chamber and the fur of all animals tested was oily due to deposition of the substance. No mortality, significant changes in body weight or gross pathological changes post autopsy were observed at the end of the 14-day observation period. Since this study was conducted for screening purposes, full details of the methods and results were not presented and the findings are thus considered of limited usefulness.  

In a read-across study to a multiple carbon number iomerised olefin, rats (numbers not reported) treated with 2.1 mg/L alkenes, C10/C11/C12/C13 vapour (equivalent to 2100 mg/m3) for 4 hours, lachrymated and salivated during exposure (Blair and Sedgwick, 1980). No other toxic signs were reported during exposure or during the 14 day observation period. No gross pathology or histopathology was conducted and although body weights were taken, the results were not presented. 

Considering the limited amount of good quality information available on the acute inhalation toxicity of linear alpha olefins, the aforementioned acute inhalation studies were collectively assessed using a weight-of-evidence approach to reach a robust conclusion on the acute inhalation potential for this group of substances. The lack of apparent significant toxicity among animals exposed to olefin vapours and mists (C6 to C16 in chain length) and the low vapour pressure of these substances indicate that linear alpha olefins, including icos-1-ene, are unlikely to represent an acute inhalation hazard. Since the available data do not meet the criteria for classification and labelling (Dangerous Substances Directive 67/548/EEC and CLP EU Regulation 1272/2008) for this endpoint, an acute inhalation DNEL is not required.

Aspiration Toxicity

One key study describing the potential aspiration toxicity of linear alpha olefins was identified (Gerarde, 1963). In this study, several homologous n-alkenes (hex-1-ene through octadec-1-ene) were administered orally (as single substances) and then aspirated into the lungs of anesthetized rats. Mortality, due to cardiac arrest, respiratory paralysis, and asphyixia, was observed within 24 hours in the majority of rats dosed with 0.2 millilitres of each test substance. Mortality incidence decreased as the test substance chain length increased. The study author concluded that viscosity is the physico-chemical property most predictive of a substance’s aspiration toxicity (i. e. the lower the viscosity, the higher its potential to be aspirated).

Regulatory classification and labeling for aspiration toxicity relies on the measured or calculated kinematic viscosity of a substance at 40°C rather than results from toxicological studies with animals.There are no viscosity data available for icos-1-ene; however a read -across viscosity value was available for C20-24 alpha olefin. The reported kinematic viscosity for C20-24 alpha olefin was 6.356 cSt at 40°C (Chevron Phillips Chemical Company, 2009). The discriminating thresholds for classification for aspiration toxicity are 7 mm2/sec and 20.5 mm2/sec for EU DSD/DPD 67/548/EEC and CLP EU Regulation 1272/2008 (GHS aligned), respectively.  Based on the read-across strategy used for linear alpha olefins, it is therefore inferred that icos-1-ene is classified and labelled for aspiration toxicity as follows: R65: Harmful, may cause lung damage if swallowed according to EU DSD/DPD 67/548/EEC and Category 1; H304: May be fatal if swallowed and enters airway according to EU CLP Regulation 1272/2008 (GHS aligned). A DNEL is neither feasible nor appropriate for this endpoint.  

Justification for Read Across from Single Carbon Number Isomerised Olefins

Several criteria justify the use of the read across approach to fill data gaps for linear alpha olefin substances using single carbon number isomerised olefin analogues.  Studies indicate that changing the carbon number, the location of the double bond, or adding branching to olefins does not measurably alter their respective toxicological effects on mammalian health endpoints. Single carbon number isomerised olefins were not acutely toxic via oral or dermal routes of exposure in animal studies and are therefore considered to have minimal acute toxicity potential. No adverse effects on the F0 or F1 generation were reported at the highest dose tested from a 42-53 day reproduction/developmental toxicity screening study in rats with octadecene (C18). The toxicological profile for single carbon number isomerised olefins, outlined above, indicates a low hazard potential for human health. There do not appear to be any significant toxicological differences between single carbon number isomerised olefins and linear alpha olefins. Therefore, read across between these two categories is justified.

Justification for Read Across from Multiple Number Isomerised Olefins

Several criteria justify the use of the read across approach to fill data gaps for linear alpha olefin substances using multiple carbon number isomerised olefin analogues.  Studies indicate that changing the carbon number, the location of the double bond, or adding branching to olefins does not measurably alter their respective toxicological effects on mammalian health endpoints. Multiple carbon number isomerised olefins are considered to have minimal acute toxicity potential. Genotoxicity studies indicate that these substances are not mutagenic. No adverse systemic toxicity was observed in a 90-day repeated oral dose study in which rats were exposed to alkenes, C20-24, a multiple carbon number isomerised olefin. The toxicological profile for multiple carbon number isomerised olefins, outlined above, indicates a low hazard potential for human health. There do not appear to be any significant toxicological differences between multiple carbon number isomerised olefins and linear alpha olefins. Therefore, read across between these two categories is justified.

Justification for classification or non-classification

Based on evaluation of all the acute toxicity data discussed above, icos-1-ene does not meet the criteria for classification as an acute oral, inhalation or dermal toxicant under EU Dangerous Substances Directive 67/548/EEC or CLP EU Regulation 1272/2008 because the LD50/LC50 values reported for this substance or its structural analogues exceed the upper discriminating threshold limits for classification defined in the regulations.

 

Icos-1-ene is classified as Xn; R65, harmful (May cause lung damage if swallowed) in accordance with Dangerous Substances Directive 67/548/EEC and as Category 1 for aspiration toxicity (H304: May be fatal if swallowed and enters airway) in accordance with CLP EU Regulation 1272/2008 based on the read-across kinematic viscosity value for C20-24 alpha olefin of 6.356 cSt at 40° C.