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Description of key information

The following oral read-across repeated dose studies were identified: a 28-day oral study (OECD 407) from hex-1-ene; a 43 to 51-day oral study (OECD 422) from tetradec-1-ene (i.e., a reproductive/developmental screening toxicity study); and a 90-day oral study from alkenes, C20-24 (OECD 408).  A read-across 90-day inhalation (OECD 413) study from hex-1-ene was identified.  There were no key dermal repeated dose studies identified.
For the 28-day oral study from hex-1-ene, the NOAEL for systemic toxicity was reported as 1010 mg/kg/day. The NOAEL for local effects was reported as 101 mg/kg/day based on stomach irritation in males. For the 43 to 51-day oral study from tetradec-1-ene (i.e., the reproductive/developmental toxicity study), a systemic toxicity NOAEL of 1000 mg/kg/day was established for the satellite females. Increased liver weights associated with minimal to moderate hepatocellular vacuolation were observed in females and males in the mid- and high- dose group (500 mg/kg bw and 1000 mg/kg bw/day), although these changes were considered to be adaptive rather than adverse. In addition, the presence of large hyaline drops noted in the kidneys of paternal males at all dose levels suggests hydrocarbon nephropathy, which is a toxicological effect specific to male rats and is not considered a biologically relevant endpoint in humans. The 90-day oral toxicity study with alkenes, C20-24 found no significant treatment related signs of toxicity or mortality; the reported NOAEL was 1000 mg/kg/day. For the key 90-day inhalation study from hex-1-ene, no relevant adverse effects were observed at the highest dose tested (3000 ppm corresponding with 10.3 mg/L hex-1-ene).

Key value for chemical safety assessment

Additional information

Repeated dose toxicity studies on oral and inhalation exposure were identified for linear alpha olefins. A supporting repeated dose study on dermal exposure was identified from oct-1-ene; however, because there was only one dose level examined and systemic toxicity was not evaluated, it was not considered key. An oral repeated dose toxicity study was identified from isomerised olefins; alpha, internal, linear and branched – multiple carbon numbers, specifically alkenes, C20 -24.

 

Repeated Oral Dose Toxicity

Repeated dose toxicity studies from linear alpha olefins consist of the following: one 28 -day oral toxicity study on hex-1-ene (Dotti, 1994); one combined repeated dose/ reproductive/developmental toxicity screening test on tetradec-1-ene (Daniel, 1995); and one 90-day inhalation toxicity study on hex-1-ene (Bennick et al., 1984). A 90-day oral toxicity study was identified on hex-1-ene, however, due to high mortality as a result of a dosing error, this study was not considered key. Key studies selected from linear alpha olefins are summarized below. A 90 -day oral toxicity study on alkenes, C20 -24 also was identified and is discussed below (Brooker, 1999).

 

In a 28-day oral repeated dose toxicity study, hex-1-ene was administered to 5 Wistar rats/sex/dose at dose levels 0, 10, 101, 1010, or 3365 mg/kg bw/day (administered as undiluted compound at volumes of 15 µL/kg, 150 µL/kg, 1.5 mL/kg, or 5.0 mL/kg) for 28 consecutive days (Dotti et al., 1994). There were several indications of toxicity in the 3365 mg/kg/day group (mainly in males) including clinical signs, decreased body weight, changes in clinical chemistry, and reduced spleen weight. Body weight was also decreased in 1010-mg/kg/day males. In addition, macroscopic findings in the males indicate stomach irritation in the 1010 and 3365 mg/kg/day groups. The NOAEL for systemic toxicity was reported as 1010mg/kg/day. The NOAEL for local effects was reported as 101 mg/kg/day based on stomach irritation in males. 

  

In the oral repeated dose/reproductive/developmental screening study with tetradec-1 -ene (Daniel, 1995), signs of systemic toxicity (increased liver weights associated with minimal to moderate hepatocellular vacuolation) were observed in females and males in the mid- and high- dose group (500 mg/kg bw/day and 1000 mg/kg bw/day). These effects were considered to be adaptive rather than adverse. The reported NOAEL was 1000 mg/kg bw/day.

 

With regards to longer-term studies, a 90-day oral study on alkenes, C20-24 was identified (Brooker, 1999). In this study, alkenes, C20-24, branched and linear, were administered via oral gavage to groups of male and female Crl: CD BR rats (10 per sex per dose) at doses of 0 (vehicle control – corn oil), 100, 500, or 1000 mg/kg/day for a period of 13 weeks. An additional 10 rats per sex per group for control and high-dose groups were observed through a subsequent 4-week recovery period. At the end of the 90 day exposure period, group mean liver weights in high-dose females (1000 mg/kg bw/day) were significantly higher than controls, as were the mean adrenal weights in high-dose males (1000 mg/kg bw/day) and mid- and high-dose females (500 and 1000 mg/kg bw/day).

 

Histopathology revealed minimal centrilobular hepatocyte hypertrophy and an increase in the incidence of adrenal cortical hypertrophy in high-dose females (1000 mg/kg bw/day). These effects were not observed in animals at the end of the 4 week recovery period, thus it is possible that the adrenal cortical hypertrophy may have been stress-related, particularly since adrenal hypertrophy was observed in all groups of female rats, including controls and was only elevated above control levels at the highest dose level, where all animals were affected. Liver hypertrophy is a common response in rodents that may in part be an adaptive response associated with chemical treatment and thus increased metabolic burden on the liver. It is generally considered to be caused by accumulation of glycogen and or triglycerides, possibly an indirect effect related to consumption of food, or to glycogen metabolism, rather than a direct toxic effect of the olefin (Schulte-Hermann, 1974). In this instance, the absence of associated biochemical changes (e. g. decreases in serum ALT levels) and the reversibility of the effects are suggestive of adaptive responses. Considering the nature, severity and reversibility of the observed effects a NOAEL of 1000 mg/kg bw is proposed for this study.

 

Repeated Inhalation Dose Toxicity

A 90-day inhalation study with hex-1-ene (Bennick et al., 1984) was selected as the key inhalation study. In this study, Neodene 6 alpha olefin was administered to forty Fischer 344 rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 300, 1000, or 3000 parts per million (corresponding to 0; 1033; 3442; or 10, 326 mg/m3) for 6 hours a day, 5 days a week, for 13 weeks. Ten of the animals/sex/concentration were used for neuromuscular testing, ten of the animals/sex/concentration were sacrificed after 7 weeks of exposure, and twenty animals/sex/concentration were sacrificed after 13 weeks of exposure.

Subchronic inhalation of Neodene 6 alpha olefin for 13 weeks did not produce any adverse respiratory, neuromuscular, or testicular effects in rats. Decreased body weight was observed in 3000 -ppm females (statistically significant) and males (statistically significant only sporadically). Decreased absolute liver and kidney weights were observed in 3000-ppm females; however, these findings were considered secondary to reduced body weight in the absence of histopathological findings in these organs. There were statistically significant differences in haematology and clinical chemistry values, but the changes were slight (generally within 5% of the control), were not dose related, and/or not associated with any histopathology findings.Increased phosphorus levels were reported in males at all treatment levels and females exposed to 1000 and 3000 ppm hex-1-ene. The toxicological significance of these findings is doubtful. The NOAEC is 3000 parts per million (10,326 mg/m3) based on a lack of toxicologically relevant findings at the highest concentration tested.

DNELs were not derived for linear alpha olefins because no adverse findings relevant to human health risk assessment were found in the studies summarised above.  These results indicate linear alpha olefins, as a class, possess an inherently low hazard potential with regard to human health. Therefore, derivation of DNELs is unnecessary.

Justification for Read Across

Several criteria justify the use of the read across approach to fill data gaps for linear alpha olefins substance using multiple carbon number isomerised olefinsubstance analogues. Studies indicate that changing the carbon number, the location of the double bond, or adding branching does not measurably alter the effects on mammalian health endpoints. There is a consistent toxicity potency pattern for isomerised olefins with a range of carbon numbers and they are considered to have minimal acute toxicity potential. Genotoxicity studies indicate that these materials 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. The toxicological profile of multiple carbon number isomerised olefins alkenes described above indicates a low hazard potential for human health. There do not appear to be any significant toxicological differences betweenmultiple carbon number isomerised olefins isomerised olefins with a range of carbon numbers and linear alpha olefins. Therefore, read across between these two categories can be justified.

Justification for classification or non-classification

Using read-across information from repeated dose oral or inhalation toxicity studies performed with linear alpha olefins or multiple carbon number isomerised olefins that showed no systemic effects (any compound), it can be assumed that icos-1-ene does not produce significant systemic toxicity when administered orally or via inhalation. Although there were no repeated dose toxicity studies identified for dermal exposure, acute dermal toxicity data suggests that absorption via the dermal route is not significant and that dermal toxicity is not a significant cause for concern. Additionally, it is generally assumed that exposure via the oral route leads to greater absorption of the substance compared with exposures via the dermal route. Oral exposure studies within linear alpha olefins and multiple carbon number isomerised olefins did not report any potential for serious or severe toxicity by this route of exposure, therefore it is unlikely that toxicity via dermal exposure poses a significant risk. Therefore, icos-1-ene is not classified under EU Dangerous Substances Directive 67/548/EEC or CLP EU Regulation 1272/2008 for repeated dose toxicity.