Registration Dossier

Administrative data

Description of key information

Guideline repeat dose toxicity studies in rats have been conducted for fourteen members of the higher olefin category, covering C6 to C20-24. The majority of these investigations (27 studies) have used oral (gavage) exposure, with three sub-acute (28-day), nine screening (OECD 421/422), and seven sub-chronic (90-day) studies available for this route. Two sub-acute dermal, two sub-acute inhalation and one sub-chronic inhalation tests, are also available; eight short-term repeat dose range-finding studies are also available. For the oral studies, systemic toxicity findings were typically limited to body weight, liver changes, and effects on clinical chemistry parameters as well as organ weights. Some of the effects observed were adaptive rather than adverse. While most of the studies revealed no systemic toxicity at doses up to 1000 mg/Kg bw/day, a conservative NOAEL for this category was determined to be 100 mg/Kg bw/day, based on minor effects observed with some category members.

 

The inhalation toxicity NOAEC was determined to be 3,000 ppm (10,326 mg/m3). 

 

The available dermal studies are considered inadequate for the purposes of hazard identification but sufficient oral and inhalation studies are available.

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

Repeated dose toxicity data are available for the following members of the higher olefin Category:

Test substance identity

Route

 

Oral

Inhalation

Dermal

Hex-1-ene

 

Alkenes, C6

 

 

Oct-1-ene

 

Nonene

Branched

 

 

Decene

 

 

Tetradec-1-ene

 

 

Hexadecene

 

 

C12-16 α Olefins

 

 

Alkenes,

C16-18

 

 

Octadec-1-ene

 

 

Octadecene

 

 

Alkenes,

C20-24 α

 

 

Alkenes, C20-24

Branched and Linear

 

 

Hydrocarbons, C12-30

 

 

Repeated Dose Oral Toxicity

Information is available from multiple studies that investigated the oral repeat dose toxicity in rats, for members of the higher olefin category. Studies covered substances in the range C6 to C20-24, following sub-acute as well as sub-chronic exposure.

C6 members of the category

The oral repeat dose toxicity of Alkenes C6 was evaluated in an OECD 422 screening study (Thorsrud, 2003). No mortality was observed in male or female rats administered 100, 500 or 1000 mg/Kg bw/day. Besides post-exposure salivation at 1000 mg/Kg bw/day, no significant signs of toxicity were observed at any dose level. 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/day). This kidney effect is not considered to be toxicologically relevant to humans. Therefore, the NOAEL for male and female rats (excluding nephropathy) in this study was determined to be 1000 mg/Kg bw/day.

In an oral sub-chronic toxicity study (Dotti et al., 1994), hex-1-ene was administered to Wistar rats at 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 an increased incidence of mortality, which appeared linked to accidental administration of the test compound into the lungs. Body weight and body weight gain decreases were observed in male rats dosed at 700 and 1010 mg/Kg/day. However, body weight of females remained unaffected. A NOAEL of 350 mg/Kg body weight/day was derived from this study based on reduced body weight in male rats at 700 mg/Kg/day (LOAEL). However, given the absence of equivalent body weight effects in females and no obvious evidence of alterations in clinical, haematological, urinary or neurological parameters, this is considered to be a conservative conclusion.

In one screening reproductive/developmental toxicity study (Daniel, 1995), 1 -hexene was administered via gavage to twelve Sprague-Dawley rats/sex/dose 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.

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. The NOAEL for systemic toxicity was 1000 mg/kg/day, which excluded the hydrocarbon nephropathy in males.

Additional supporting data are available from a sub-acute investigation (Dotti et al., 1994). Hex-1-ene was administered to Wistar rats (5/sex/dose) at 0, 10, 101, 1010, or 3365 mg/Kg bw/day for 28 consecutive days. Several signs of toxicity were seen 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. Additionally, macroscopic findings in the males indicated stomach irritation in the 1010 and 3365 mg/Kg/day groups. The NOAEL for systemic toxicity was reported to be 1010 mg/Kg/day. The NOAEL for local effects was reported as 101 mg/Kg/day based on stomach irritation in males.

In a range finding oral repeat dose toxicity study (Harlan Laboratories 2015), hex-1-ene (CAS# 592-41-6) was administered to male and female rats for fourteen days, at doses up to 1000 mg/Kg bw/day. No significant effects were reported.

C8 members of the category

The oral repeat dose toxicity potential of Oct-1-ene (CAS# 111-66-0) was evaluated in a sub-chronic study (Envigo Research Limited, 2015). The material was administrated to rats by gavage, at dose levels of 100, 300 and 1000 mg/Kg bw/day for 90 consecutive days. Treatment - related effects were seen in males of all dose groups and females treated at 300 and 1000 mg/Kg bw/day.

 

Pathological examination revealed an increased incidence and severity of hyaline droplets and granular casts in kidneys of males from all treatment groups. This finding was consistent with alpha-2u-globulin nephropathy, the presence of which was confirmed histochemically. Acanthosis, hyperkeratosis and submucosal inflammation was evident in the forestomach of animals of either sex dosed at 300 and 1000 mg/Kg bw/day, consistent with a local irritant effect. Increased incidences of alveolar macrophages were observed in animals of either sex dosed at 1000 mg/Kg bw/day and in females at 100 mg/Kg bw/day. This finding is considered to be a result of local irritation following aspiration of micro droplets of the test material (gavage route exposure) and, therefore not considered to be treatment-related.

 

The NOAEL was determined to be 1000 mg/Kg bw/day for female and male rats as the findings were not considered to be true systemic toxicity.

 

An oral (gavage) combined repeat dose reproduction/developmental toxicity screening study (OECD 422) was performed on the test material Oct-1-ene CAS 111-66-0 (Harlan Laboratories 2014).

After eight weeks treatment clinical signs were detected in animals of either sex treated with 1000 mg/Kg bw/day and in males treated with 300 mg/Kg bw/day. Increased salivation was evident throughout the treatment period, but no alteration of the physical condition was observed. No difference between animals treated and controls were detected in body weight development and food consumption. In contrast, the water consumption was increased in animals of either sex treated with 1000 mg/Kg bw/day. Increased salivation and increased water consumption might be related to unpalatability problems and irritancy of the stomach. Microscopic investigations of the stomachs showed epithelial hyperplasia in animals of either sex treated with 1000 mg/Kg bw/day and thickening of the stomach in one female treated with 1000 mg/Kg bw/day at necropsy. The findings are considered a result of local irritation rather than any adverse systemic toxicity of the test item. All parameters related to blood and chemistry examinations and reproductive system showed no treatment-related effects. The NOAEL for systemic toxicity was considered to be 1000 mg/Kg bw/day.

 

Data are also available from a range finding oral repeat dose toxicity study (Harlan Laboratories 2013) in rats. Oct-1-ene (CAS# 111-66-0) was administered to male and female rats for 14 days at doses up to 1000 mg/Kg bw/day No significant treatment-related effects were reported.

C9 members of the category

In a key study (Harlan Laboratories 2015), Nonene, branched (CAS# 97280-95-0) was administered to rats by gavage, at dose levels of 20, 100 and 500 mg/Kg bw/day for 90 consecutive days.

Organ weight changes were detected in females dosed at 500 mg/Kg bw/day while microscopic liver and thyroid changes were observed in females dosed at 100 and 500 mg/Kg bw/day and in males at 500 mg/Kg bw/day. These findings were considered to be an adaptive response to treatment. Stomach changes were observed in male rats dosed at 500 mg/Kg bw/day. This finding was considered to be a caused by local irritation rather than true systemic toxicity. Granular casts were seen in the kidneys of male rats, but further investigations confirmed this finding correlated to hyaline droplet and alpha 2 u globulin formation, , which is a male rat specific finding that is not considered relevant to humans.. Based on the results of this study, the NOAEL was determined to be 500 mg/Kg bw/day for female and male rats.

 

In a supporting OECD 422 study (Harlan Laboratories 2014), the test material Nonene, branched (CAS# 97280-95-0) was administrated to rats by gavage, at dose levels of 100, 300, 1000 mg/Kg bw day for 8 weeks (pre-pairing, gestation and early lactation for female).

 

No test material related mortality was observed through the study period. Clinical signs were detected in animals of either sex treated with 300 and 1000 mg/Kg bw/day during the study. Episodes of increased salivation were reported from Day 8 onwards. The physical condition of males treated with 1000 mg/Kg bw/day was also affected with reductions in body weight development during Weeks 1 and 3 of treatment. Subsequently, a reduction in overall body weight gain in these males and a slight reduction in food efficiency during week 1, was evident. A reduction in haemoglobin was also observed in these males. Water consumption was also significantly increased for animals of either sex from all treatment groups throughout the treatment period. Observations of this nature are often reported when a test material formulation is unpalatable or irritant and can be associated with gastric irritancy rather than be attributable to systemic toxicity. This was supported microscopically with stomach changes identified as epithelial hyperplasia in the forestomach in animals of either sex treated with 1000 mg/Kg bw/day and in males treated with 300 mg/Kg bw/day. This finding was considered to be the result of local irritancy of the test material and therefore cannot be considered indicative of true systemic toxicity.

 

Although there were some statistically significant differences in treated animals from controls for the blood chemical parameters measured, these differences were considered not to be of toxicological significance. Macroscopic findings detected at necropsy were confined to enlarged, pale and mottled kidneys and a dark liver in a number of males treated with 1000 mg/Kg bw/day. One male treated with 300 mg/Kg bw/day also had enlarged kidneys.

 

Histopathological examination of the liver revealed hepatocellular hypertrophy in animals of either sex treated with 1000 and 300 mg/Kg bw/day and in males treated with 100 mg/Kg bw/day. Organ weight data supported this finding with increased absolute and relative liver weights observed in these animals. In the absence of any degenerative or inflammatory changes, this condition is considered to be adaptive in nature.

 

Microscopic examination of the thyroid revealed increased incidence and severity of follicular cell hypertrophy/hyperplasia in animals of either sex treated with 1000 and 300 mg/Kg bw/day and in males treated with 100 mg/Kg bw/day. Males treated with 1000 and 300 mg/Kg bw/day also showed hypertrophic/vacuolated cells in the pituitary. The thyroid, liver and pituitary changes are characteristic of a consequence of hepatocellular induction as a result of enhanced hepatic metabolism. As a side effect of hepatic induction an increased liver metabolism of thyroid hormones T3 and T4 can occur. This subsequently leads to an enhanced thyroid gland production of these hormones as a consequence of a negative feedback stimulation of TSH production. The appearance of thyroid follicular cell hypertrophy and hypertrophic/vacuolated cells in the pituitary are themselves considered to be a result of this process. The thyroid and pituitary changes were considered to be adaptive in nature.

 

Microscopic examination also revealed effects in the kidneys of males from all treatment groups. Tubular basophilia and hyaline droplets was present in males from all treated groups. These tubular findings were also accompanied by tubular degeneration/debris in males treated with 1000 and 300 mg/Kg bw/day. The hyaline droplets can be directly linked to accumulation of alpha 2u-globulin, which is unique to the male rat. This finding is commonly observed in male rats following treatment with some hydrocarbons and is not predictive of any adverse effect in humans. The remaining kidney findings consisting of tubular degeneration/debris may be considered to represent an adverse effect of the test item, however immunohistochemical staining demonstrated that these findings were correlated to the same condition as hyaline droplets.

 

Based on the results observed, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was determined to be 1000 mg/Kg bw/day.

Supporting data are also available from a range finding oral repeat dose toxicity study in rats (Harlan Laboratories 2013). Nonene, branched (CAS# 97280-95-0) was administered to male and female rats for 14 days, at doses up to 1000 mg/Kg bw/day. No significant treatment-related effects were reported.

C10 members of the category

An OECD 422 screening study (Harlan Laboratories 2014) was conducted using the test material Decene (CAS# 25993-53-1). Male and female rats were treated by gavage at doses of 100, 300 and 1000 mg/Kg bw/day for approximately six weeks. No signs of clinical toxicity or treatment-related adverse effects were observed on body weight or food and water consumption. Microscopic stomach changes were observed in one male at 300 mg/Kg bw/day and in both sexes at 1000 mg/Kg bw/day. Based on this finding, the dosage of 100 mg/kg bw/day was considered to represent a No Observed Effect Level (NOEL) for adult toxicity. These effects are however considered to have occurred due to a local irritant effect, rather than true systemic toxicity and this finding is considered to have limited relevance to human toxicity. The NOAEL for systemic toxicity was considered to be 1000 mg/Kg bw/day.

Data are available from a range finding oral repeat dose toxicity study (Harlan Laboratories 2013). Decene (CAS# 25339 -53 -1) was administered to male and female rats by gavage at doses of 250, 500, and 1000 mg/Kg bw/day for fourteen days. Increase salivation was recorded in male animals dosed at 1000 mg/Kg bw/day from Day 7 onwards. One female dosed at 250 mg/Kg bw/day showed noisy respiration between Days 7 to 10. However, this finding was not considered to represent systemic toxicity. No treatment-related adverse effects were observed on body weight or water and food consumption and no macroscopic abnormalities were detected. The NOEL was 1000 mg/Kg/day.

C14 members of the category

The oral repeat dose toxicity of tetradec-1-ene was evaluated in an OECD 422 screening study (Daniel, 1995). In this study, the test material (1-Tetradecene; CAS# 1120-36-1) was administered via oral gavage to Sprague-Dawley Crl:CD® BR VAF/Plus® rats (12 males and 20 females/dose) at doses of 0, 100, 500, or 1000 mg/Kg/day in corn oil. The F0 females were treated for 28 days prior to mating until the day prior to euthanasia (43-47 days). A satellite group of F0 females were added for neurotoxicity, clinical pathology and histopathological evaluations. Twelve F0 females assigned to a breeding phase were treated for 14 days prior to mating, during mating, gestation, and lactation until the day prior to euthanasia (42-51 days).

 

Oral administration of the test material to virgin females and F0 parental animals produced minor clinical signs (salivation and urine staining) and dose-related hydrocarbon nephropathy in male rats in the 100, 500, and 1000 mg/Kg/day groups. This finding in male rats is commonly associated with hydrocarbon nephropathy and is not believed to pose any risk to humans. In the satellite females, minor decreases were observed in the mean red cell count and hematocrit in 100, 500 and 1000mg/Kg/day groups, as well as in haemoglobin and MCV in the 1000 mg/Kg/day group. Similar changes, though no statistically significant were observed in males. Therefore, the biological significance of these changes in the females is not clear.

 

In males, statistically significant minor increases in ALT were observed in 500 and 1000 mg/Kg/day groups. In satellite females, there were statistically significant decreases in sodium in 100, 500 and 1000 mg/Kg/day groups and increases in cholesterol in the 500 and 1000mg/Kg/day groups. The changes of ALT sodium and cholesterol were observed in one sex and therefore were considered of no biological significance.

 

Minimal to moderate hepatocyte cytoplasmic vacuolation was observed in the livers of male and female rats at dosages of 500 and 1000 mg/Kg/day and correlated with increased liver weights at same tested doses. However, only the statistically significant increase of liver weight to brain weight ratio was seen in 1000 mg/Kg/day group females. The hepatocellular vacuolation was clearly related to the test item administration. However, in the absence of any other histopathological changes in liver as well as in the absence of significant effects on liver function (as indicated by the measured clinical chemistry parameters) the hepatocellular vacuolation might be considered to represent an adaptive response.

 

There were no other apparent test-article related histopathologic findings seen in any other tissues or organs examined. A statistically significant decrease in spleen weight relative to brain weight was noted in the 1000 mg/Kg/day group females. In addition, a statistically significant increase in absolute kidney weight was observed in 500 mg/Kg/day group females. These changes in female organs were not believed to be biologically meaningful because no test article-related lesions were seen histologically in these organs.

C16-18 members of the category

Short-term toxicity effects of alkenes, C16-18 were assessed in a study in rats exposed via gavage at doses of 25, 150, or 1000 mg/Kg/day (in corn oil) for 28 days (Clubb, 2000).  There was no mortality observed and clinical signs and hematological functions were unaffected by treatment. Gross pathology revealed no remarkable findings. Sporadic significant findings were observed in the functional observation battery tests and clinical chemistry parameters. Slight (but not significant) increases in body weight and body weight gain were observed in high-dose group males. Body weight gain was also slightly increased in the other two groups, but was 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. A marginal decrease in kidney-to-body weight ratio in the high-dose group in both sexes was also observed. Although tubular regeneration was observed during histopathology examinations, it was also observed in control animals and therefore could not be definitively linked to treatment with the test material. Due to the lack of any definitive treatment-related adverse effects, the NOAEL was determined to be 1000 mg/Kg/day.

In an OECD 422 study (Harlan Laboratories 2014), the test material Hexadecene (CAS# 26952-14-7) was administrated via gavage at dosages of 100, 300 and 1000 mg/Kg bw/day for approximately six weeks. No mortality occurred during the the study. Increased post-dosing salivation in both sexes and increased water intake for males were observed. In addition, a minimal or moderate peribronchiolar inflammation was recorded at 1000 mg/Kg/day. Further investigations confirmed that this was due to accidental aspiration of the test material during the dosing procedure at 1000 mg/Kg bw/day. These findings are considered to be a consequence of palatability/slight irritancy of the test item rather than representing any systemic toxicity. The dose level of 1000 mg/Kg bw/day represents the NOEL for systemic toxicity.

Supporting data are available from a range finding oral repeat dose toxicity study (Harlan Laboratories 2013) in rats. Hexadecene (CAS# 26952-14-7) was administered to male and female rats by gavage at doses up to 1000 mg/Kg bw/day. No significant treatment-related effects were reported.

C18 members of the category

In a key Guideline (OECD 408) oral repeated dose toxicity study (Harlan Laboratories, 2015), the test material (Octadec-1-ene; CAS No. 112-88-9) was administered to rats (10/sex/dose) by gavage at dose levels of 20,100, and 500 mg/Kg bw/day for 90 consecutive days. A control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP). Clinical signs, functional observations, bodyweight change, dietary intake and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all animals at the end of the study. Ophthalmoscopic examination was also performed on control group and high dose animals. All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues was performed.

 

No mortality was observed through the study period. Clinical signs were confined to increased salivation detected in animals of either sex treated with 500 mg/Kg bw/day. Observations of this nature are commonly observed following the oral administration of an unpalatable or slightly irritant test material formulation and do not necessarily represent an adverse effect of treatment. No adverse effect was apparent for body weight or food consumption in treated animals throughout the treatment period. Although there were some statistically significant differences in treated animals from controls for the hematological and blood chemical parameters measured, these differences were considered not to be of toxicological significance. At gross necropsy, one control female, four females treated with 20 mg/Kg bw/day, one female treated with 100 mg/Kg bw/day, and one female treated with 500 mg/Kg bw/day had reddened lungs. In the absence of any associated histopathological correlates, the intergroup differences were considered of no toxicological significance.

 

Oral administration of the test material to rats for a period of ninety days at dose levels of up to 500 mg/Kg bw/day, resulted in microscopic changes in the mesenteric lymph nodes of animals of either sex treated with 500 mg/Kg bw/day and minor microscopic adrenal changes in females treated with 500 mg/Kg bw/day. A minimal or mild inflammatory cell infiltrate was present in the periglandular fat surrounding the mesenteric lymph nodes in animals of either sex treated with 500 mg/Kg bw/day. The infiltrate was mixed in character, principally composed of lymphocytes and neutrophils and tended to have a perivascular or perilymphatic orientation. Although the origin of the finding is uncertain it might have resulted from local irritation of material from the gut reaching the drainage nodes. However, there was no evidence of local irritation to the gut mucosa. However, in the absence of any other associated pathological changes at the low severity levels noted the change is considered likely to be non-adverse. The statement of laboratory is provided as an attachment to this IUCLID record.

Microscopic examination of adrenal sections did reveal minimal or mild diffuse cortical hypertrophy in two females treated with 500 mg/Kg bw/day. However, in the absence of any significant difference in mean organ weight this minor difference was considered of equivocal biological significance and most likely stress-related or the result of individual variation.

 

Based on the results observed, the ‘No Observed Effect Level’ (NOEL) for systemic toxicity was considered to be 100 mg/Kg bw/day.

 

In a key study (Envigo Research, 2015), the daily oral gavage administration of Octadecene CAS 27070-58-2 to rats for a period of ninety consecutive days at dosages of 100, 300 or 1000 mg/kg bw/day was well tolerated and was not associated with any obvious signs of systemic toxicity for animals of either sex.  At 1000 mg/kg bw/day and, to a much lesser extent, 300 mg/kg bw/day, treatment was associated with increased post-dosing salivation for both sexes but this was considered to reflect distaste or slight irritancy of the dosing formulations rather than any systemic effect of treatment.  There were no effects of treatment indicated by body weight performance, food and water consumption, food conversion efficiency, functional observations or ophthalmic examinations.  

 

Intergroup differences for hematology and blood chemistry parameters did not indicate any  clear effect of treatment and the few mean values that attained statistical significance when compared with control were considered to be incidental and of no toxicological significance.  There were no statistically significant differences apparent for organ weights and neither macroscopic nor subsequent microscopic examination of tissues revealed any treatment related effects.

 

Based on the results of this study, the No Observed Effect Level (NOEL) for systemic toxicity was considered to be 1000 mg/kg bw/day.

 

In a supporting OECD 422 repeated dose, reproductive/developmental toxicity screening study (Harlan Laboratories 2014), the test material (Octadec-1-ene UVCB; CAS# 112-88-9) was administered by gavage to WistarHan™: RccHan™: WISTstrain rats (12/sex/dose), for up to eight weeks (including a two-week prepairing phase, pairing, gestation and early lactation for females), at dose levels of 100, 300 and 1000 mg/Kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Arachis oil BP).

 

Clinical signs, behavioral assessments, body weight change and food and water consumption were monitored during the study. Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex. Extensive functional observations were performed on five selected males from each dose group after the completion of the pairing phase, and for five selected parental females from each dose group on Day 4 post-partum. Hematology and blood chemistry were evaluated prior to termination on five selected males and females from each dose group. Adult males were terminated on Day 43, followed by the termination of all females and offspring on Day 5 post partum. Any female which did not produce a pregnancy was terminated on or after Day 25 post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

 

No mortality was observed through the study period. Clinical signs were confined to increased salivation detected in animals of either sex treated with 1000 and 300 mg/Kg bw/day. Observations of this nature are commonly observed following the oral administration of an unpalatable or slightly irritant test item formulation and do not necessarily represent an adverse effect of treatment.

 

No adverse effect was apparent for body weight or food consumption in treated animals throughout the treatment period. Although there were some statistically significant differences in treated animals from controls for the hematological and blood chemical parameters measured, these differences were considered not to be of toxicological significance. No macroscopic abnormalities were evident in treated animals; however microscopic examination revealed changes in the mesenteric lymph nodes and spleen. A minimal or mild inflammatory cell infiltrate was present in the periglandular fat surrounding the mesenteric lymph nodes in animals of either sex treated with 1000 and 300 mg/Kg bw/day. The infiltrate was mixed in character, principally composed of lymphocytes and neutrophils and tended to have a perivascular or perilymphatic orientation. Although the origin of the finding is uncertain it might have resulted from local irritation of material from the gut reaching the drainage nodes however there was no evidence of local irritation to the gut mucosa. However, in the absence of any other associated pathological changes at the low severity levels noted the change is considered likely to be non-adverse. The statement of laboratory is provided as an attachment to this IUCLID record.

The incidence and severity of extramedullary hematopoiesis was increased in the spleen in animals of either sex treated with 1000 mg/Kg bw/day and in females treated with 300 mg/Kg bw/day. The inter-group differences in females were not clearly dosage-related and taking into account the low number of animals examined, the absence of supportive intergroup differences in hematological values or bone marrow findings, these differences were considered more likely to have arisen as a result of individual variation, or possibly as a response to blood loss during parturition, than to be test item related. There were no statistically significant differences in adult organ weights that, in the absence of any evidence of histopathological change, were considered to be of any toxicological significance.

 

Based on the results observed, the ‘No Observed Effect Level’ (NOEL) for systemic toxicity was considered to be 100 mg/Kg bw/day.

 

In a screening reproduction/developmental toxicity study (Thorsrud, 2003), octadecene, dissolved in corn oil, was administered to Sprague-Dawley rats (12 sex/dose) by gavage at dose levels of 0, 100, 500, or 1000 mg/Kg/day for 42 days. No mortality was observed through the study period. No treatment-related or dose-dependent signs of clinical toxicity were noted in rats at any dose level and gross necroscopy revealed no remarkable differences between octadecene treated and control animals. Based on the lack of adverse systemic effects observed in the study, the systemic toxicity NOAEL for octadecene was reported as 1000 mg/Kg/day.

 

Additional supporting data are also available from two range finding oral repeat dose toxicity studies (Harlan Laboratories, 2013 and Harlan Laboratories, 2015) that were conducted to test the oral repeat dose toxicity of Octadec-1-ene (CAS# 112-88-9) and Octadecene (CAS# 27070-58-2), respectively. Both test materials were administered to male and female rats at doses up to 1000 mg/Kg bw/day for 14 days. No significant treatment-related effects were reported. The NOEL was 1000 mg/Kg/day.

C12-30 members of the category

In an oral repeat dose toxicity study (Envigo Research Ltd., 2015), the test material (Hydrocarbons, C12-30, olefin-rich, ethylene polymn by product - CAS# 68911 -05 -7) was administered to rats by gavage, at dose levels of 100, 300 and 1000 mg/Kg bw/day for 90 consecutive days. Increased post dosing salivation was observed in two animals but was not considered treatment-related. Body weight, food and water consumption were unaffected by treatment and histopathology did not reveal any treatment- related effects. Based on the results of this study, the NOEL for systemic toxicity of Hydrocarbons, C12-30, olefin-rich, ethylene polymn by product, was 1000 mg/Kg bw/day.

 

Supporting data are also available from a range finding oral repeat dose toxicity study (Harlan Laboratories, 2015) conducted in rats. Hydrocarbons, C12-30, olefin-rich, ethylene polymn by product (CAS# 68911-05-7) was administered to male and female rats for 14 days, at doses up to 1000 mg/Kg bw/day. No treatment-related effects were reported and the NOEL was 1000 mg/Kg/day.

C20-24 members of the category

In a Key study (Brooker, 1999), the test material (C20-C24 alkenes, branched and linear) was administered via gavage to male and female Crl:CD BR rats (10/sex/dose) at doses of 0 (vehicle control – corn oil), 100, 500, or 1000 mg/Kg bw/day for a period of 13 weeks. An additional 10 rats/sex/dose for control and high-dose groups were observed through a subsequent 4-week recovery period. 

 

There were no signs of clinical toxicity or mortality observed at any dose level. Body weight, food consumption, and neurological behavior appeared normal in all treatment animals when compared to the controls. Ophthalmological and morphological assessments revealed no significant differences between treatment and control animals. Mean platelet counts were found to be higher than the control group in the 1000 mg/Kg bw/day male rats. Mean packed cell volume (male and female), haemoglobin (males only), and red blood cell (RBC) count (females only) were observed to be lower in animals that received the test material at 1000 mg/Kg bw/day. These changes, although statistically significant, were not considered to be toxicologically significant. Mean glucose levels in male rats exposed at 1000 mg/Kg bw/day were observed to be higher than the corresponding controls. These isolated changes were reversible at the end of the 4-week recovery period and were therefore not considered to be treatment-related. Group mean liver weights in the 1000 mg/Kg bw/day female rats were higher (statistically significant) than the control group, as were the mean adrenal weights in the 1000 mg/Kg bw/day male and 500 and 1000 mg/Kg bw/day female rats.  Histopathological analysis suggested that these weight changes were associated with centrilobular hepatocyte hypertrophy and adrenal cortical hypertrophy, indicative of an adaptive rather than adverse response to the test material. The toxicological significance of these findings was considered to be doubtful.  Based on a lack of toxicologically relevant or significant findings at the highest concentration tested, a NOAEL of 1000 mg/Kg bw/day was determined for C20-C24, alkenes, branched and linear.

 

Supporting data are available from a sub-acute oral toxicity study. In this study (Dunster, 2008) the short-term toxicity potential of alkenes C20-24 was evaluated in Sprague-Dawley rats (40/sex/dose). The test material was administered via gavage at dose levels of 0, 30, 300, and 1000 mg/Kg/day for a period of 28 days.  No treatment-related systemic toxicity effects were observed. The NOEL was 1000 mg/Kg/day.

In conclusion, substances from the higher olefin category, covering C6 to C20-24, appear to have limited potential to cause systemic toxicity following repeated oral exposure. While available sub-chronic toxicity data on hex-1-ene, tetradec-1-ene, and octadec-1-ene appear to suggest some potential for systemic toxicity in rats, only minor effects were observed and at dose levels greater than 100 mg/Kg bw/day. Repeated oral exposure to the other substances in the category did not result in any systemic toxicity in rats at doses as high as 1000 mg/Kg bw/day.

Repeat Dose Inhalation Toxicity

In a repeat dose inhalation toxicity study (Bennick et al., 1984), 1-hexene was administered to Fischer 344 rats (40/sex/concentration) by whole body exposure at concentrations of 0, 300, 1000, or 3000 parts per million (corresponding to 0; 1033; 3442; or 10,326 mg/m3), 6 hours a day, 5 days a week, for a period of 13 weeks. Ten rats/ sex/ concentration were used for neuromuscular testing, ten rats/ sex/ concentration were sacrificed after 7 weeks of exposure, and 20 rats/ 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 weights were observed in the 3000 ppm females (statistically significant) and males (statistically significant only sporadically). Decreased absolute liver and kidney weights were observed in 3000 ppm females; however, in the absence of histopathological findings in these organs, these findings were considered secondary to reduced body weight. 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 the test material at concentrations of 1000 and 3000 ppm. The toxicological significance of these findings is doubtful. The NOAEC was determined to be 3000 ppm (10,326 mg/m3) based on the lack of toxicologically relevant findings at the highest concentration tested.

Supporting data are available from two sub-acute inhalation toxicity studies conducted in rats.

In one study (Gordon, T., 1983), administration of hex-1-ene to Fischer 344 rats (10/sex/concentration) by whole body exposure at concentrations of 0; 1000; or 10,000 parts per million, 6 hours per day, for a total of 9 days did not result in any adverse treatment-related effects. The NOAEC was reported to be >10,000 ppm.

In the second study, (Mailey et al., 1983), exposure to Hex-1-ene at concentrations of 0, 300, 1000, 3000, or 8000 ppm, 6 hours per day, 5 days/week, for a period of 2 weeks resulted in treatment-related body weight effects in females from the highest dose group (8000 ppm). The LOAEC was therefore determined to be 8000 ppm while the NOAEC was determined to be 3000 ppm.

Repeat Dose Dermal Toxicity

Only supporting data are available from two studies that investigated the sub-acute dermal toxicity potential of oct-1-ene and C12-C16, alpha olefins in rabbits and rats, respectively.

In a sub-acute dermal toxicity study (Monrose, 1973), oct-1-ene was applied to the shaved skin of six New Zealand white rabbits (3 intact and 3 abraded) at a dose level of 0.2 mL, 5 days/week during a 28-day period. The skin reactions were ranked using a graded system 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 could be identified. Additionally, the study tested only one dose level and systemic toxicity was not evaluated. This data is therefore considered to be of limited use.

In a 9-day dermal toxicity study (Zellers, 1983), the test material (C12-16, alpha olefins) was applied to the shaved skin of 5 Fischer 344 rats per sex per dose at dose levels of 0, 1000, or 2000 mg/Kg bw/day, 6 hours per day on 9 non-consecutive days during a 2 week study period.

Body weight gains were reduced in the 2000 mg/Kg group with the effect more notable in males. Severe dermal reactions occurred in the 2000 mg/kg group starting after the second treatment and continuing throughout the study period. This consisted of severe erythema (i.e. beet redness), slight to moderate eschar formation, very slight to slight edema, and slight to moderate desquamation. Slight to moderate hair loss occurred in nearly all animals after the 8th treatment and fissuring occurred in 4 of the 5 treated females after the 6th treatment. Slight erythema occurred in 3 of the 10 animals exposed to1000 mg/Kg after 6 or 7 treatments, with one animal exhibiting a pinpoint spot of eschar. These changes were histopathologically confirmed. No effects were observed in hematology or clinical chemistry. There were several significant changes in organ weights in the 2000 mg/Kg bw/day group that were related to the decreased body weights. Histopathology findings were only observed in the skin. No NOAEL or LOAEL was reported in the study.

The above study did not conform to guideline recommendations and hence these data are considered to be of limited use.


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 in rats have been conducted for 14 members of the higher olefin category, covering C6 to C20-24. The majority of substances in this category appear to possess limited potential to cause systemic toxicity following repeated oral exposure. While available sub-chronic toxicity data for hex-1-ene, tetradec-1-ene, and octadec-1-ene suggest some potential for systemic toxicity in rats, the effects observed were either minor or adaptive in nature and occurred at dose levels greater than 100 mg/Kg bw/day. Repeated oral exposure to the other substances in the category did not result in any systemic toxicity in rats at doses as high as 1000 mg/Kg bw/day. Therefore, based on the weight of evidence, substances in this category do not warrant classification for repeat dose oral toxicity under the current CLP regulation.   

Repeat dose inhalation toxicity data available from studies conducted using hex-1-ene indicate a NOAEC of 3000 ppm (10,326 mg/m3) in rats. Therefore, substances in this category do not warrant classification for repeat dose inhalation toxicity under the current CLP regulation.  

Limited data are available on the repeated dose dermal toxicity potential of higher olefin category substances. The physicochemical and toxicological properties of higher olefins (linear alpha; isomerised; alpha, internal, linear and branched – single and multiple carbon numbers) do not suggest potential to readily penetrate the skin or to be absorbed at a significant rate through the skin. Additionally, results from acute oral and dermal toxicity studies in animals affirm that these substances are not toxic by either route. Repeated oral administration of higher olefins for up to 90 days has not been associated with significant or long-lasting effects. Based on the weight of evidence provided by the physicochemical data, and acute as well as repeat dose toxicity data, substances in this category do not warrant classification for repeat dose dermal toxicity under the current CLP regulation.