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Description of key information

Repeated dose toxicity studies using rats have been conducted for seven members of this category covering C6 to C20-24. The majority of these investigations have used oral (gavage) exposure, with three sub-acute, three screening and two sub-chronic studies available for this route. One sub-acute dermal test, and one sub-chronic inhalation investigation, is also available. For the oral studies, systemic findings were typically limited to the liver and were adaptive rather than adverse; the NOAEL from these studies was 1000 mg/kg bw/day.  The inhalation NOAEC was 3,000 ppm (10,326 mg/m3). The available dermal study is inadequate for the purposes of hazard identification.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Information is available on repeat dose toxicity potential of the following members of this category:

 

Test substance identity

Route

Oral

Inhalation

Dermal

Hex-1-ene

v

v

 

Alkenes, C6

v

 

 

Oct-1-ene

 

 

v

Tetradec-1-ene

v

 

 

Alkenes, C16-18

v

 

 

Alkenes, 20-24 a

v

 

 

Alkenes, 20-24, branched and linear

v

 

 

 

Repeated Dose Oral Toxicity

Information is available from two studies that investigated the repeated dose oral toxicity of 1-hexene following sub-acute and sub-chronic exposure and from an OECD 422 screening study.

In the sub-acute investigation (Dotti et al., 1994), hex-1-ene was administered to 5 Wistar rats/sex/dose at dose levels 0, 10, 101, 1010, or 3365 mg/kg bw/day for 28 consecutive days. 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 1010 mg/kg/day. The NOAEL for local effects was reported as 101 mg/kg/day based on stomach irritation in males.

In the sub-chronic study (Dotti et al., 1994), hex-1-ene was administered to 10 Wistar rats/sex/dose at dose levels 0, 101, 350, 700, or 1010 mg/kg bw/day for 13 weeks. Male and female rats dosed at 350 mg/kg/day or greater, exhibited a greatly increased incidence of mortality (resulting in the loss of 30-40% of the treatment groups in some instances) which appeared linked to accidental administration of the test compound into the lungs. Histopathology was therefore only conducted on dead or dying animals, which revealed lesions in the lungs of a majority of animals that died during the study. Other observations showed that body weight and body weight gain were decreased with doses of 700 and 1010 mg/kg/day in males, while body weights of females remained unaffected. Food consumption was slightly decreased in these males on an absolute amount basis, but was slightly increased when consumption was standardized per kilogram body weight. Although there were several other statistically significant changes noted (haematology; clinical chemistry; urinalysis; and neurobehavior), these were not considered toxicologically significant. A NOAEL of 350 mg/kg body weight/day is derived from this study based on reduced body weight in males at 700 mg/kg/day (LOAEL) dose level. However, given an absence of equivalent body weight effects in females and no obvious evidence of alterations in clinical, haematological, urinary or neurological parameters, this is recognized as being a conservative conclusion.

In the screening reproductive/developmental toxicity (OECD 421) study on 1-hexene (Daniel, 1995), Sprague-Dawley rats (12/sex/dose) were administered the test substance via oral gavage at doses of 0, 100, 500, or 1000 mg/kg/day. Males were treated for 44 days beginning 28 days prior to mating and females were treated for 41 to 55 days beginning 14 days prior to mating through lactation day 4. No mortality or signs of treatment-related clinical toxicity were observed through the study period. Mean body weight, weight gain, food consumption, and organ weights remained unaffected by treatment. No reproductive or developmental effects were observed. There was a slight, but significant, decrease in absolute epididymal weight at all concentrations. The relative epididymal to brain weight was only significantly decreased in the low-dose group. Although the absolute epididymides weight was significantly decreased in parental males; the change was within 10% of the control, there was no dose response, there was no effects noted microscopically, and there were no effects on fertility. Therefore, this is not considered to be toxicologically significant. Pitted kidneys were observed at necropsy for 2 of 12 mid-dose males and 3 of 12 high-dose males. The predominant microscopic finding in males was the presence of large hyaline droplets in the proximal convoluted tubule that was dose related. These findings suggest hydrocarbon nephropathy, which is a toxicological effect specific to male rats and is not considered relevant to humans. A LOEL could not be established in the study. The NOAEL for systemic, reproductive, and developmental toxicity was 1000 mg/kg bw/day, which excluded the hydrocarbon nephropathy in males.

Information is available from one combined repeated dose/reproduction/developmental toxicity study that investigated the repeat dose oral toxicity potential of Alkenes C6.

In this OECD 422 screening study (Thorsrud, 2003) no mortality was observed in either male or female rats given 100, 500 or 1000 mg/kg bw/day. Besides post-dosing salivation among animals treated with 1000 mg/kg bw/day, 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 necropsy, 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/day.

Information is available from one combined repeated dose/reproduction/developmental toxicity study that has investigated the repeat dose oral toxicity of 1-tetradecene.

In this OECD 422 screening study (Daniel, 1995), male and female Sprague-Dawley Crl:CDBR VAF/Plus rats were exposed orally to 1- via gavage at doses of 0, 100, 500, or 1000 mg/kg/day (administered at 5 mL/kg of a 0, 20, 100, or 200 mg/mL concentration).  Female rats were separated into a satellite group of females used to determine systemic toxicity and neurotoxicity without breeding, while a separate group of breeding females was used to determine reproductive and developmental toxicity. Increased salvation and urine staining were observed at 500mg/kg/day above in males and breeding females and in 1000 mg/kg/day satellite females.  Hematological changes included decreased mean red blood cell count and haematocrit at 100 mg/kg/day and above in females and decreased hemoglobin and MCV values in 1000 mg/kg/day females.  Minor but statistically significant clinical chemistry findings included increased ALT levels at 500 mg/kg/day and above in males; decreased sodium levels at 100 mg/kg/day and above in females; and increased cholesterol levels at 500mg/kg/day and above in females. Hydrocarbon nephropathy was evident by pitted kidneys (at 500 mg/kg/day and above) and increased eosinophilic hyaline droplets in the proximal tubules (at 100 mg/kg/day and above) in all male treatment groups (but not considered biologically relevant to humans). Increased absolute liver weights were observed at 500mg/kg/day and above in males and females. Increased liver weights relative to brain weights were observed at 500mg/kg/day and above in males and 1000 mg/kg/day females.  Microscopic examination of the liver revealed minimal to moderate hepatocellular vaculation at 500 mg/kg/day and above in males and females. A systemic toxicity LOEL of 500 mg/kg/day was established for the satellite females based on clinical signs, hematology, clinical chemistry, organ weight, and histopathology changes in the liver. A NOEL of 100 mg/kg/day was established for satellite females. A systemic toxicity NOEL and/or LOEL in males could not be determined because the effect of hydrocarbon nephropathy was observed at all dose levels. However these findings in both sexes appear to be of limited toxicological relevance suggesting that the NOAEL for 1-tetradecene is greater than 100 mg/kg/day.

Information is available from one sub-acute study that investigated the repeat dose oral toxicity of Alkenes C16-18.

In this investigation (Clubb, 2000), Sprague-Dawley rats (5/sex/dose) were exposed to Alkenes, C16-18 (Amodrill 1000) via gavage at doses of 0, 25, 150, or 1000 mg/kg/day in corn oil for 28 days. There was no evidence of treatment-related effects on mortality, clinical signs, functional observation battery tests (FOB), hematology, clinical chemistry, or gross pathology. However, there were sporadic significant findings in the functional observation battery tests and clinical chemistry data. There was a slight, but not significant, increase in body weight and body weight gain in high-dose males. Body weight gain was also slightly increased in the other two groups, but not dose dependent. Urine volume was increased (not significantly) in high-dose males. In females, the urine volume increased in a dose-dependent manner with a statistically significant increase in the high-dose group. There was a marginal decrease in kidney-to-body weight in the high-dose group in both sexes. Although tubular regeneration was observed during histopathology exams, it also occurred in controls and cannot be definitively linked to treatment. Due to the lack of any definitive adverse effects, the reported NOAEL for Alkenes C16-18 was determined to be1000 mg/kg/day.

Information is available from one study that has investigated the sub-chronic repeat dose oral toxicity of Alkenes C20-24 alpha.

In this investigation (Brooker, 1999), Alkenes, C20-24, branched and linear, was administered via oral gavage to groups of male and female Crl: CD BR rats (10/sex/dose) at doses of 0, 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 obtained from this study.

Information is available from one study that has investigated the sub-acute dose oral toxicity of Alkenes, C20-24.

In this study (Dunster et al., 2008), Alkenes, C20-24 (ENORDET O241) was administered undiluted via gavage (once daily) to Sprague-Dawley rats (5/sex/dose) at 0, 30, 300, and 1000 mg/kg body weight/day for a period of 28 days. There were no substance related effects on mortality, organ weights, body weights, food consumption, water consumption, hematology, blood chemistry, histopathology, behavior functional performance, or sensory reactivity. The NOAEL was therefore determined to be 1000 mg/kg/day.

Repeat Dose Inhalation Toxicity

Information is available from one study that investigated the sub-chronic inhalation toxicity of 1-hexene.

In this investigation (Bennick et al., 1984), 1-hexene (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 animals/ sex/ concentration were used for neuromuscular testing, ten animals/ sex/ concentration were sacrificed after 7 weeks of exposure, and twenty animals/ sex/ concentration were sacrificed after 13 weeks of exposure. Sub-chronic inhalation of 1-hexene 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.

Repeat Dose Dermal Toxicity

Information is available from one study that has investigated the sub-acute dermal toxicity of 1-octene.

In this investigation (Monrose, 1973), alpha olefin 8 was applied to the shaved skin of six New Zealand white rabbits (3 intact and 3 abraded) at a dose level of 0.2 millilitres for 5 days/week during a 28-day period. The skin was ranked using a graded system by the study authors ranging from 1 (none) to 6 (severe). The average score for hyperaemia, exfoliation, and scab formation was approximately 2 (considered questionable). There were no other toxicity results reported. Therefore, no LOAEL or NOAEL were identified.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Repeated dose oral toxicity testing has been conducted on 6 members of this category covering C6 to C20-24. This includes 3 sub-acute, 3 screening and 2 sub-chronic studies. Systemic findings were typically limited to the liver and were adaptive rather than adverse. The NOAEL from these studies was 1000 mg/kg bw/day.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Repeated dose sub-chronic inhalation toxicity testing has been conducted on one member of this category (1-hexene). The NOAEC for systemic effects was 3000 parts per million (10,326 mg/m3) based on a lack of toxicologically relevant findings at the highest concentration tested.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Repeated dose sub-chronic inhalation toxicity testing has been conducted on one member of this category (1-hexene). The NOAEC for local effects was 3000 parts per million (10,326 mg/m3) based on a lack of toxicologically relevant findings at the highest concentration tested.

Justification for classification or non-classification

Repeated dose toxicity studies using rats have been conducted for 7 members of this category covering C6 to C20-24. The majority of these investigations have used oral (gavage) exposure.There was no evidence of systemic toxicity in any of these studies, and no classification is necessary according to the CLP regulation.