Registration Dossier

Administrative data

Description of key information

Twenty-eight day oral repeated dose toxicity studies (OECD 407) from alkenes, C16-18 alkenes and alkenes, C20-24 were identified.  Additionally, a 42-53 day oral screening study with alkenes, C6 (OECD 422) was identified. A 90-day oral study from alkenes, C20-24 (OECD 408) was identified. A 90-day inhalation study (OECD 413) with hex-1-ene was identified and used for read across. There were no key dermal repeated dose studies identified.
The 28-day oral toxicity study with alkenes, C16-18 found no significant treatment related signs of toxicity or mortality; the reported NOAEL for Amodrill 1000 was 1000 mg/kg/day. The 28-day oral toxicity study with alkenes, C20-24found no significant treatment related signs of toxicity or mortality; the reported NOAEL for ENDORDET O241 was 1000 mg/kg/day. A combined repeated dose/reproduction/developmental toxicity study on hex-1-ene found no significant findings among treated animals compared with controls. Mild hyaline droplet nephropathy was observed in males in the 1000 mg/kg bw group, however this was not considered toxicologically relevant to 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 read-across 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).
DNELs were not derived for multiple carbon number isomerised olefins because no adverse findings relevant to human health risk assessment were found in the studies summarised above. These results indicate that multiple carbon number isomerised olefins, as a class, possess an inherently low hazard potential with regard to human health. Therefore, derivation of DNELs is unnecessary.
This position will be updated once information is available from studies proposed on oct-1-ene and octadec-1-ene.

Key value for chemical safety assessment

Additional information

There were several key repeated dose toxicity studies for oral exposure for isomerised olefins; alpha, internal, linear and branched – multiple carbon numbers. There were no identified key studies for repeated dermal or inhalation exposure for any of the multiple carbon number isomerised olefins; however, a read-across 90-day inhalation study from hex-1-ene (linear alpha olefins) was identified.

 

Repeat Dose Oral Toxicity

 

Studies selected from multiple carbon number isomerised olefins consist of two 28 -day oral toxicity studies (Clubb, 2000; Dunster, 2008) and one combined repeated dose/ reproductive/developmental toxicity screening test (Thorsrud, 2003). A 90-day oral study on alkenes, C20-24 (Brooker, 1999) also was identified. 

 

In the 28-day study on alkenes, C16-18, short-term toxicity effects were assessed in rats exposed to Amodrill 1000 via gavage at doses of 25, 150, or 1000 mg/kg/day in corn oil for 28 days (Clubb, 2000). There were no significant treatment related signs of toxicity or mortality, the reported NOAEL for Amodrill 1000 was 1000 mg/kg/day.

 

In the 28-day study on alkenes, C20-24, short-term toxicity effects were assessed in rats exposed to ENDORDET O241 via gavage at doses of 30, 300, and 1000 mg/kg/dayfor 28 days (Dunster, 2008) There were no significant treatment related signs of toxicity or mortality, the reported NOAEL for ENDORDET O241was 1000 mg/kg/day.

 

In the combined repeated dose/reproduction/developmental toxicity study on alkenes, C6 (Thorsrud, 2003), no mortality was observed in either male or female rats at any of the doses tested. Besides post-dosing salivation among animals treated with 1000 mg/kg, no significant signs of clinical toxicity were observed at any dose level. Functional observational evaluations revealed no significant differences between the treatment and control animals and mean body weight, body weight gain, organ weights, food consumption, haematology and clinical chemistry parameters were comparable between control and treated animals. Furthermore, no significant findings were found at gross necroscopy, with the exception of mild hyaline droplet nephropathy in males in the highest dose group (1000 mg/kg bw), a finding that is not considered toxicologically relevant to humans. Therefore the NOAEL for females and males (when excluding nephropathy) in this study was considered to be 1000 mg/kg bw.

 

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 (a linear 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.

Results of studies summarised above indicate no substantial difference in toxicity between the structures that have been tested for repeated dose toxicity, however it is considered prudent to propose additional sub-chronic testing via the oral route on two additional Higher Olefins in order to extend the amount of information available. As well as providing complementary data on the potential (or otherwise) of Higher Olefins to cause systemic toxicity over the range C6 to C20-24, the results will support the read-across strategy for developmental and reproductive toxicity testing proposed elsewhere in this dossier. Additional oral sub-chronic testing of oct-1-ene and octadec-1-ene is therefore proposed. This will extend the overall amount of information available for the category, and also (after consideration of other, currently available data) permit interpolation for sub-chronic toxicity over the carbon number range C6 to C20-C24.

 

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. This position will be updated, if necessary, once information is available from studies proposed on oct-1-ene and octadec-1-ene.

Justification for Read Across:

Several criteria justify the use of the read across approach to fill data gaps for multiple carbon number isomerised olefin substances using linear alpha olefin substances. Studies indicate that changing the carbon number, the location of the double bond, or adding branching does not measurably alter effects on mammalian health endpoints. There is a consistent toxicity potency pattern for individual alpha olefins supported by a low toxicity concern for acute oral, dermal and inhalation exposure. These materials are slightly irritating to skin and slightly to non-irritating to eyes of rabbits. In repeat dose toxicity studies, hex-1-ene and tetradec-1 -ene have shown comparable levels of low toxicity, with female rats exhibiting alterations in body and organ weights and changes in certain haematological values at the higher doses tested; male rats exhibiting nephropathy presumed to be associated with the alpha2u-globulin protein. Screening studies indicate that they are not neurotoxic (for hex-1-ene and tetradec-1-ene), do not produce adverse effects on reproduction or foetal development (hex-1-ene and tetradec-1-ene), and are not genotoxic (hex-1-ene, oct-1-ene, dec-1-ene, dodec-1-ene, and tetradec-1-ene). Study results for the aforementioned endpoints indicate a low hazard potential for human health. Since the addition of branching does not measurably alter the results of studies on mammalian health endpoints, there should not be any toxicological differences between substances in multiple carbon number isomerised olefins and linear alpha olefins.  Therefore, read across between these two categories can be justified.

 

Justification for classification or non-classification

Using key information from repeated dose oral toxicity studies or read-across information from repeated dose inhalation toxicity studies performed with alkenes, C6; alkenes, C16-18; alkenes, C20-24; or hex-1-ene, it can be assumed that alkenes, C20-24 would 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 on multiple carbon number isomerised olefin substances 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, alkenes, C20 -24not classified under EU Dangerous Substances Directive 67/548/EEC or CLP EU Regulation 1272/2008 for repeated dose toxicity. This position will be re-evaluated once information is available from studies proposed on oct-1-ene and octadec-1-ene.