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Key value for chemical safety assessment

Effects on fertility

Description of key information

Guideline (OECD 421 and 422) reproductive toxicity screening studies have been conducted in rats, for nine members of the higher olefin category, covering C6 to C18. These investigations have all used oral (gavage) exposure.

Oral toxicity data is supported by results from a 90-day sub-chronic inhalation study in rats with a C8 olefin.

Except for one study with Nonene, branched, where the NOAEL for reproductive toxicity was considered to be 300 mg/Kg bw/day based on reduced post-natal offspring viability, offspring body weight gain, and litter size at 1000 mg/Kg bw/day, no effects on reproduction were observed in any other study at oral dose levels up to 1000 mg/Kg bw/day. Inhalation exposure up to 10,326 mg/m3 did not reveal any effects on reproductive organs.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
In total, nine good quality screening studies are available on nine category members, covering C6 to C18 higher olefins. The study on nonene, branched, in common with all other studies, showed no effects on fertility at levels up tp 1000 mg/Kg. There was however, a slight effect on post-natal pup viability, litter size and weight at 1000 mg/Kg, with a clear NOAEL of 300 mg/Kg. This study was selected as being the 'worst case', although it should be recognized that none of the other eight studies showed any reproductive effects on post-natal pup viability.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Effects on Fertility

Reproductive toxicity screening studies are available for the following members of the higher olefin Category:

Test substance identity

Testing for Reproductive Effects

Hex-1-ene

OECD 421

Alkenes, C6

OECD 422

Oct-1-ene

OECD 422

Nonene

Branched

OECD 422

Decene

OECD 422

Tetradec-1-ene

OECD 422

Hexadecene

OECD 422

Octadec-1-ene

OECD 422

Octadecene

OECD 421

Information is available from multiple guideline (OECD 421 and 422) studies that investigated the reproductive toxicity potential in rats, for members of the higher olefin category. Studies covered substances in the range C6 to C18, following oral exposure.

C6 members of the category

 

In an OECD 422 study (Thorsud, 2003), C6 alkenes dissolved in corn oil were administered via oral gavage to F0 male and female Sprague-Dawley rats at dose levels of 100, 500 and 1000 mg/Kg/day for at least 4 weeks. For the reproduction phase of the study, males and females were mated after 14 days of treatment. Mating was allowed to continue for 14 days if no evidence of pregnancy was seen.Treatment continued until sacrifice with males sacrificed on day 37 and females sacrificed on lactation day 4.

There was no mortality observed in either sex at any of the doses tested. Besides post-dosing salivation at 1000 mg/kg, no signs of clinical toxicity were observed.Functional observational evaluations revealed no significant differences between the treatment and control animals. Mean body weight, body weight gain, food consumption, haematology and clinical chemistry parameters were comparable to controls at all dose levels. Organ weight and gross necropsy evaluations revealed no significant adverse effects. F0 mating, fertility indices, mean gestation lengths, mean number of pups delivered, F1 live birth index, F1 viability index, F1 pups per litter, and F1 pup sex ratios were comparable between control and treatment groups.

Gross necropsy o f F0 females and F1 pups revealed no significant treatment-related findings. Based on the lack of significant adverse clinical effects, the systemic toxicity and reproductive toxicity NOAEL for C6 alkenes is 1000 mg/Kg/day.

In an OECD 421 reproductive/developmental toxicity screening study (Daniel, 1995), hex-1-ene 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 to lactation day 4.

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. This effect showed no dose response relationship., there were no microscopic effects and no effect on fertility and is therefore, 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 not considered relevant to humans. There was no LOAEL for this study.

 

The NOAEL for systemic, reproductive, and developmental toxicity was 1000 mg/Kg/day, which excluded the hydrocarbon nephropathy in males.

C8 members of the category

 

A guideline Oral (Gavage) Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test in the Rat (OECD 422) was performed on 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 differences between treated and control animal were detected in body weight development and food consumption. In contrast, 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.

 

In view of these results, the NOAEL ‘for systemic toxicity was considered to be 1000 mg/Kg bw/day, and the ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 1000 mg/Kg bw/day.

C9 members of the category

 

In an OECD 422 study (Harlan Laboratories, 2014), Nonene, branched (CAS # 97280-95-0) was administrated by gavage, at dose levels of 100, 300, 1000 mg/Kg bw/day for 8 weeks (pre-pairing, gestation and early lactation for females). Treatment-related effects were reported in animals of either sex from all treatment groups, therefore a NOEL was not established. The LOEL was therefore 100 mg/Kg/day.

 

Results showed stomach changes in male animals treated with 1000 mg/Kg bw/day and a reduction in body weight gain. These effects are considered to be a result of local irritation of the test item rather than a true effect of systemic toxicity. The organ weight changes detected in all female treated groups and microscopic liver and thyroid changes in females at 1000 and 300 mg/Kg bw/day were considered to be an adaptive response to treatment, of no toxicological significance. The No Observed Adverse Effect Level (NOAEL) was therefore determined to be 1000 mg/Kg bw/day for females.

The organ weight changes in all male treatment groups and the microscopic liver, thyroid and pituitary changes in treated males were also considered to be an adaptive response to treatment. The male kidney findings were considered to be associated with alpha-2-microglobulin mediated male rat nephropathy, a species and sex specific effect which is not relevant for human health. Therefore, the NOAEL was determined to be 1000 mg/Kg bw/day for males.

 

The NOEL for reproductive toxicity was considered to be 300 mg/Kg bw/day due to the reduced post-natal offspring viability, offspring body weight gain and litter size at 1000 mg/Kg bw/day.

C10 members of the category

 

An OECD 422 screening study (Harlan Laboratories, 2014) was conducted using 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.

 

The results of the screening study showed no adverse effect with regard the clinical signs, body weight, and food and water consumption. Microscopic stomach changes were observed in one male at 300 mg/kg bw/day and 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 has limited relevance to human toxicity. There were no effects on reproductive performance, therefore the No Observed Effect Level (NOEL) for reproduction, including the survival, growth and development of the offspring, is considered to be 1000 mg/Kg bw/day.

 

C14 members of the category

In a screening for reproductive/developmental toxicity study (Daniel, 1995), 1-tetradecene was administered via gavage to twelve Sprague-Dawley Crl:CDBR VAF/Plus rats/sex/dose at doses of 0, 100, 500, or 1000 mg/Kg/day in corn oil. Males were treated for 43 to 47 days beginning 28 days prior to mating and females were treated for 42 to 51 days beginning 14 days prior to mating through to lactation day 4.

 

No reproductive or developmental toxicity effects were observed. There were clinical signs of toxicity observed in females dosed at 500 and 1000 mg/Kg/day, but they were unrelated to reproduction. There was no LOEL for this study. The NOEL for reproductive and developmental toxicity was determined to be 1000 mg/Kg/day.

C16 members of the category

 

In an OECD 422 study (Harlan Laboratories, 2014), the test material, Hexadecene (CAS # 26952-14-7) was administered via gavage at dosages of 100, 300 and 1000 mg/Kg bw/day for approximately six weeks.

 

No mortality occurred during 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 true systemic toxicity.

 

The dose level of 1000 mg/Kg bw/day represents the No Observed Effect Level (NOEL) for adult toxicity. The No Observed Effect Level (NOEL) for reproduction, including the survival, growth and development of the offspring, is also considered to be 1000 mg/Kg bw/day.

 

C18 members of the category

In a guideline (OECD 422) reproductive toxicity study (Harlan Laboratories, 2014), Octadec-1-ene UVCB was administered by gavage, at dose levels of 100, 300, 1000 mg/Kg bw day for 8 weeks (pre-pairing, gestation and early lactation for female).

 

Gross and histopathology examinations showed microscopic mesenteric lymph node changes in animals of either sex treated with 1000 and 300 mg/Kg bw day and microscopic spleen changes in animals (both male and female) treated with 1000 mg/Kg bw day and in females treated with 300mg/Kg bw day.

Based on these findings, the NOEL for systemic toxicity was considered to be 100 mg/Kg bw day for males and females. No effects were detected on reproductive function and therefore the NOEL for reproductive toxicity was 1000 mg/Kg bw day.

 

In an OECD 421 reproduction/developmental screening study (Thorsud, 2003), octadecene (CAS# 27070-58-2), 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.

 

There was no mortality observed in animals in the control, 100, 500, or 1000 mg/Kg/day dose groups. No treatment-related or dose-dependent signs of clinical toxicity were noted in rats at any dose level. Mean body weight, body weight change and food consumption was observed to be normal in all treatment animals when compared with the controls. Parent female mating, fertility, and mean gestation lengths were observed to be comparable with controls as were the mean number of pups delivered and live birth and viability indices. Mean live pups/litter and sex ratio/litter were also found to be normal and comparable to those observed in control animals.

Gross necropsy revealed no remarkable differences between octadecene treated and control animals. There were no microscopic lesions observed in male or female rats treated with octadecene and no statistically significant differences in absolute or relative epididymides weight were noted in treated males when compared with control males. There were no statistically significant differences observed in pup weights on lactation days 1 and 4 and gross necropsy on lactation day 4 revealed no treatment-related effects.

 

Based on the lack of adverse effects observed in the study, the developmental/reproductive toxicity NOAEL for octadecene was reported to be 1000 mg/Kg/day.

 

Supporting Inhalation Toxicity Data

Supporting information is also available from a sub-chronic repeat dose inhalation toxicity study (Bennick et al., 1984) where 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 reproductive or testicular effects in rats. 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.

Justification for selection of Effect on fertility via oral route:
Oral screening level information, supported by results from a 90-day sub-chronic inhalation study, is available on the potential of 4 members of this category covering C6 to C18 to affect reproduction and fertility. No effects were observed in male or female rats receiving oral treatments at dose levels up to 1000 mg/kg bw/day, or inhalation exposures up to 10,326 mg/m3.

Effects on developmental toxicity

Description of key information
         
    
    

Guideline (OECD 414) developmental toxicity studies in rats have been conducted for five members of the higher olefins category, covering C6 to C12 -30. Nine reproductive toxicity screening studies have also been conducted on nine category members. These investigations have all used oral (gavage) exposure.

No effects on the development of the off-spring were observed in any study at dose levels up to 1000 mg/Kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
In total, fourteen good quality guideline and screening studies are available for ten category members, covering C6 to C30 higher olefins. The study on Octadecene is one of five good quality, guideline reproductive toxicity studies conducted on members of the higher olefins category. In addition, nine supporting toxicity screening studies are available for category members. None of the studies showed any evidence of effects on development of the rat foetus at levels up to 1000 mg/Kg.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental Toxicity

 

Guideline (OECD 414, 421 and 422) developmental toxicity studies are available for the following members of the higher olefin Category:

Test substance identity

Testing for Developmental Effects

Hex-1-ene

OECD 414 & OECD 421

Alkenes, C6

OECD 422

Oct-1-ene

OECD 422

Nonene

Branched

OECD 414 & OECD 422

Decene

OECD 422

Tetradec-1-ene

OECD 422

Hexadecene

OECD 422

Octadec-1-ene

OECD 414 & OECD 422

Octadecene

OECD 414 & OECD 421

Hydrocarbons, C12-30 Olefin rich

OECD 414

Information is available from multiple guideline (OECD 414, 421 AND 422) studies that investigated the developmental toxicity potential in rats, for members of the higher olefin category. Studies covered substances in the range C6 to C12-30, following oral exposure.

C6 members of the category

In a guideline (OECD 414) pre-natal developmental toxicity study (Envigo Research Ltd., 2016), Hex-1-ene (CAS # 592-41-6) was administered to pregnant rats by oral gavage during gestation at dose levels of 100, 300 and 1000 mg/Kg bw/day.

 

No treatment-related effects were observed through the study period. Therefore, the ‘No Observed Effect Level’ (NOEL) for the pregnant female was considered to be 1000 mg/Kg bw/day. No treatment-related changes were detected in the offspring parameters measured. The ‘No Observed Effect Level’ (NOEL) for developmental toxicity was therefore considered to be 1000 mg/Kg bw/day.

 

In an OECD 422 reproductive/developmental toxicity screening study, (Thorsud, 2003), Alkenes, C6 dissolved in corn oil was administered via oral gavage to F0 male and female Sprague-Dawley rats at dose levels of 0, 100, 500 and 1000 mg/Kg/day for at least 4 weeks. 

 

There were no adverse signs of toxicity observed at any dose level and the mean number of pups delivered, F1 live birth index, F1 viability index, F1 pups per litter, and F1 pup sex ratios were comparable between control and treatment groups.

 

Based on the lack of significant adverse clinical effects, the developmental toxicity NOAEL for Alkenes, C6 was 1000 mg/Kg/day.

 

Additionally, in an OECD 421 screening study, (Daniel, 1995), Hex-1-ene 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.

 

No developmental effects were observed. Therefore, the NOAEL for developmental toxicity was 1000 mg/Kg/day.

C8 member of the category

 

In an Oral (Gavage) Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test in the Rat (OECD 422), the test material Oct-1-ene (CAS # 111-66-0) was administered to male and female rats. No treatment-related effects were observed on reproductive or developmental parameters. The ‘No Observed Effect Level’ (NOEL) for reproductive and developmental toxicity was considered to be 1000 mg/Kg bw/day.

C9 members of the category

 

In an OECD 414 toxicity study (Harlan Laboratories, 2015), the test material Nonene, branched (CAS # 97280-95-0) was administered to pregnant female rats (from Day 3 to day 19 of gestation) by gavage at dose levels of 100, 300 and 1000 mg/Kg/day.

 

A transient decrease in body weight gain and food intake was recorded in females dosed at 1000 mg/Kg bw/day between Days 3 and 8 of gestation. This finding was not considered to represent an adverse effect of treatment. Incidences of increased post-dosing salivation only during the final two weeks of treatment were observed. No adverse effects of maternal treatment on litter data as assessed by mean number of implantations, early and late embryonic/foetal deaths and live foetuses or sex ratio, as assessed by percentage male foetuses were recorded. No treatment-related effects were detected on foetal external findings, skeletal development or in the type and incidence of skeletal or visceral findings.

 

Based on the result of the study, the ‘No Observed Adverse Effect Level' (NOAEL) for the pregnant female and the ‘No Observed Effect Level' (NOEL) for developmental toxicity are considered to be 1000 mg/Kg bw/day.

 

In an OECD 422 study (Harlan Laboratories, 2014), Nonene, branched (CAS # 97280-95-0) was administered by gavage, at dose levels of 100, 300, 1000 mg/Kg bw/day for 8 weeks (pre-pairing, gestation and early lactation for females).

 

There were no pre-natal developmental effects observed. The NOEL for reproductive toxicity was considered to be 300 mg/Kg bw/day due to the reduced post-natal offspring viability, offspring body weight gain and litter size at 1000 mg/Kg bw/day.

C10 members of the category

 

In an OECD 422 screening study (Harlan Laboratories, 2014), the test material Decene (CAS # 25993-53-1) was administered to male and female rats via gavage at doses of 100, 300 and 1000 mg/Kg bw/day for approximately six weeks. There were no effects on reproductive performance or developmental parameters and therefore, the No Observed Effect Level (NOEL) for reproduction, including the survival, growth and development of the offspring, was considered to be 1000 mg/Kg bw/day.

C14 members of the category

 

In a screening for reproductive/developmental toxicity study (Daniel, 1995), 1-tetradecene was administered via gavage to twelve Sprague-Dawley Crl:CDBR VAF/Plus rats/sex/dose at doses of 0, 100, 500, or 1000 mg/Kg/day (5 mL/kg. Males were treated for 43 to 47 days beginning 28 days prior to mating and females were treated for 42 to 51 days beginning 14 days prior to mating through lactation day 4.

 

No reproductive or developmental effects were observed. There were clinical signs noted in 500 and 1000 mg/kg/day females, but they were unrelated to reproduction. There was no systemic LOEL for this study.

 

The NOEL for reproductive and developmental toxicity was 1000 mg/Kg/day.

C16 members of the category

 

In an OECD 422 reproductive/developmental toxicity screening study (Harlan Laboratories, 2014), the test material Hexadecene (CAS # 26952-14-7) was administered via gavage at dosages of 100, 300 and 1000 mg/Kg bw/day for approximately six weeks. The No Observed Effect Level (NOEL) for reproduction, including the survival, growth and development of the offspring, was considered to be 1000 mg/Kg bw/day.

C18 members of the category

 

In a guideline (OECD 414), pre-natal developmental toxicity study (Harlan Laboratories, 2015), the test material, Octadecene (CAS# 27070-58-2) was administered to female pregnant rats from Day 5 to day 19 of gestation by gavage at dose levels of 100, 300 and 1000 mg/Kg/day.

The results did not show any maternal or foetal effects.

 

Based on the result of this study, the ‘No Observed Effect Level' (NOEL) for the pregnant female and the ‘No Observed Effect Level' (NOEL) for developmental toxicity are considered to be 1000 mg/Kg bw/day.

 

In another OECD 414 study, the test material (Octadec-1-ene, CAS # 112-88-9) was administered to female pregnant rats from Day 3 to day 19 of gestation by gavage at dose levels of 100, 300 and 1000 mg/Kg/day. The results did not show any maternal or foetal effects. Based on the result of this study, the ‘No Observed Effect Level' (NOEL) for the pregnant female and the ‘No Observed Effect Level' (NOEL) for developmental toxicity are considered to be 1000 mg/Kg bw/day.

 

In an OECD 422 study (Harlan Laboratories, 2014), the test material Octadec-1-ene UVCB was administered 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 effects were detected on reproductive function or on the development of the off-spring. Therefore, the NOEL for reproductive and developmental toxicity was 1000 mg/Kg bw day.

 

In an additional guideline (OECD 421) screening study (Thorsud, 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.

 

Mean live pups/litter and sex ratio/litter were also found to be normal and comparable to those observed in control animals. Gross necropsy revealed no remarkable differences between octadecene-treated and control animals. There were no statistically significant differences observed in pup weights on lactation days 1 and 4 and gross necropsy of the pups on lactation day 4 revealed no treatment-related effects.

 

Based on the lack of adverse systemic effects observed in the study, the developmental toxicity NOAEL for octadecene was 1000 mg/Kg/day.

C12-30 members of the category

 

In a guideline (OECD 414) toxicity study (Envigo Research Ltd., 2016), the test material, Hydrocarbons, C12-30, olefin-rich, ethylene polymn by product (CAS # 68911-05-7) was administered to female pregnant rats from Day 5 to day 19 of gestation by oral gavage at dose levels of 100, 300 and 1000 mg/Kg/day.

 

The results did not show any maternal or foetal adverse effects. Based on the result of the study, the ‘No Observed Effect Level' (NOEL) for the pregnant female and the ‘No Observed Effect Level' (NOEL) for developmental toxicity are considered to be 1000 mg/Kg bw/day.


Justification for selection of Effect on developmental toxicity: via oral route:
Oral screening level information is available on the potential of 4 members of this category covering C6 to C18 to cause developmental toxicity. No developmental effects were observed in female rats treated for the duration of pregnancy at dose levels up to 1000 mg/kg bw/day.

Justification for classification or non-classification

Guideline screening reproductive toxicity (OECD 421 and 422) and developmental toxicity (OECD 414) studies have been conducted for members of the Higher Olefins category covering C6 to C18.

 

The weight of evidence from oral reproductive and developmental toxicity studies, accompanied with data from oral and inhalation sub-chronic toxicity studies in rats indicate that category members have little or no potential to be considered reproductive/developmental toxicants.

 

Therefore, no classification is considered necessary under the current CLP regulation.