Registration Dossier

Administrative data

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.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 August 2013 - 17 October 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study is GLP compliant and follow the OECD 422 guideline. Acceptable with no restrictions.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in Section 13.
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
- Name of test material: Nonene, branched
- CAS No.:97280-95-0
- Substance type: UVCB
- Physical state: Clear colorless liquid
- Analytical purity: 100%
- Lot/batch No.: TQ-12-2003-23042013
- Data received: 29 April 2013
- Label: Nonene Sampling Date Apr 22.2013
- Expiration date of the lot/batch: 23 April2014
Species:
rat
Strain:
other: Wistar Han™:RccHan™:WIST strain rats
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd., Blackthorn, Bicester, Oxon, UK.
- Age at study initiation: 12 weeks old
- Weight at study initiation: (P) Males: 311 to 375 g; Females: 194 to 222 g.
- Housing: Pre-mating: groups of four animals were housed in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding (Datesand Ltd., Cheshire, UK). Pairing phase: polypropylene grid floor cages suspended over trays lined with absorbent paper on a one male: one female basis within each dose group. Post mating: the males were returned to their original cages. Mated females were housed individually during gestation and lactation in solid floor polypropylene cages with stainless steel mesh lids and softwood flakes.
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): A pelleted diet (Rodent 2018C Teklad Global Certified Diet, Harlan Laboratories U.K. Ltd., Oxon, UK.)
- Water (e.g. ad libitum): free access to food and water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/-2°C
- Humidity (%): 55 =/- 15%
- Air changes (per hr): at least 15 air changes per hour. The low intensity fluorescent lighting was controlled to give twelve hours continuous light
- Photoperiod (hrs dark / hrs light): 12 hr dark and 12 hr light

The study was performed between 10 June 2013 and 10 June 2014. The in-life phase of the study was conducted between 22 August 2013 (first day of treatment) and 17 October 2013 (final day of necropsy).



Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Arachis oil BP
- Storage temperature of food: 4 C

VEHICLE
- Amount of vehicle (if gavage): 4 ml/kg
- Concentration in vehicle:
- Control: 0 ml/kg
- Low: 25 mg/ml
- Intermediate: 75 mg/ml
- High: 250 mg/ml
- Lot/batch no. (if required): 2018C-020713MA
- The volume of the test and control item administrated to each animal was based on the most recent scheduled body weight and was adjusted at weekly intervals.
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation:15 days
- Proof of pregnancy referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged individually during gestation and lactation in solid floor polypropylene cages.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6 weeks
Frequency of treatment:
The test item was administrated daily by gavage using a stainless cannula attached to a disposable plastic syringe. Control animals were treated in an identical manner with 4 ml/kg of Arachis oil BP.
Details on study schedule:
i. Groups of twelve male and twelve female animals were treated daily at the appropriate dose level throughout the study (except for females during parturition where applicable). The first day of dosing was designated as Day 1 of the study.
ii. Prior to the start of treatment and once weekly thereafter, all animals were observed for signs of functional/behavioral toxicity.
iii. On Day 15, animals were paired on a 1 male: 1 female basis within each dose group for a maximum of fourteen days.
iv. Following evidence of mating (designated as Day 0 post coitum) the males were returned to their original cages and females were transferred to individual cages.
v. On completion of the pairing phase (during Week 6), five selected males per dose group were evaluated for functional/sensory responses to various stimuli.
vi. Pregnant females were allowed to give birth and maintain their offspring until Day 5 post partum. Litter size, offspring weight and sex, surface righting and clinical signs were also recorded during this period.
vii. At Day 4 post partum, five selected females per dose group were evaluated for functional/sensory responses to various stimuli.
viii. Blood samples were taken from five males from each dose group for hematological and blood chemical assessments on Day 42. The male dose groups were killed and examined macroscopically on Day 43.
ix. Blood samples were taken from five randomly selected females from each dose group for hematological and blood chemical assessment on Day 4 post partum. At Day 5 post partum, all females and surviving offspring were killed and examined macroscopically. Any female which did not produce a pregnancy was also killed and examined macroscopically.
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:

Basis: actual ingested 100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:

Basis: actual ingested 300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:

Basis: actual ingested 1000 mg/kg bw/day
No. of animals per sex per dose:
Three groups, each of twelve males and twelve females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose selected during the Range-finding experiment - Study Number 41301414

Parental animals: Observations and examinations:
Clinical Observations:
Signs of toxicity, ill-health and behavioural change immediately before dosing, soon after dosing, and one hour after dosing throughout the treatment period.

Functional Observations:
All animals were observed for signs of functional/behavioural toxicity prior to the start of treatment and at weekly intervals thereafter.
Functional performance tests were also performed on five selected males and females from each dose level, prior to termination, together with an assessment of sensory reactivity to various stimuli.
- behavioural assessment
- functional Performance Tests
- Sensory Reactivity

Body Weight:
Individual body weights: Day 1 (prior to dosing), weekly for surviving males until termination and weekly for females until mating was evident.
Female: Days 0, 7, 14 and 20 post coitum, and on Days 1, 4 post partum and terminal kill.

Food Consumption:
Pre-pairing period and after (male): weekly
Females showing evidence of mating: post coitum Days 0-7, 7-14 and 14-20.
Females with live litters: Days 1 and 4 post partum.

Food efficiency:
Males (throughout the study period-with the exception of the mating phase, and females during the pre-pairing phase

Water Consumption:
Daily- visual inspection of the water bottles

Reproductive Performance:
Presence of ejected copulation plugs and each female was examined for the presence of a copulation plug in the vagina.
A vaginal smear was prepared for each female and the stage of oestrus or the presence of sperm was recorded.
The presence of sperm within the vaginal smear and/or vaginal plug in situ was taken as positive evidence of mating (Day 0 of gestation).

Pregnancy and Parturition:
Pregnant females: observations at approximately 0830, 1230 and 1630 hours and around the period of expected parturition (08.30 and 12.30 hr at weekends and public holidays)

Female data collections:

i. Date of pairing
ii. Date of mating
iii. Date and time of observed start of parturition
iv. Date and time of observed completion of parturition

Laboratory Investigations:
- Haematology
- Blood Chemistry
Litter observations:
Number of live and dead offspring
For each litter the following was recorded:
i. Number of offspring born
ii.Number of offspring alive recorded daily and reported on Days 1 and 4 post partum
iii. Sex of offspring on Days 1 and 4 post partum
iv. Clinical condition of offspring from birth to Day 5 post partum
v. Individual offspring weights on Days 1 and 4 post partum (litter weights were calculated retrospectively from this data)

All live offspring were assessed for surface righting reflex on Day 1 post partum.
Postmortem examinations (parental animals):
Pathology Females: Uterus (for signs of implantation and the number of uterine implantations in each horn), the corpora lutea. All adult animals and offspring: full external and internal examination. All macroscopic abnormalities were recorded.
- Organ Weights- Histopathology: Tissues from 5 selected male and female animals/group were preserved. Histopathological examination was undertaken on tissues from control and high dost animals.
To clarify possible treatment-related changes, histopathological examination was extended to include similarly prepared sections of the liver, kidneys (males only), stomach, thyroid and pituitary from animals in the low and intermediate groups. In addition, male kidney tissue was subject to immunohistochemical examination to confirm the presence of alph-2-microglobulin.
Postmortem examinations (offspring):
All adult animals and offspring, including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
Statistics:
Where considered appropriate, quantitative data was subjected to statistical analysis to detect the significance of intergroup differences from control; statistical significance was achieved at a level of p<0.05.
Where appropriate, data transformations were performed using the most suitable method: Bartlett’s test, ANOVA, or if required, ANCOVA, Williams Test, Shirley Test, Dunnett’s (parametric) or Steel (non-parametric) test, Student t-test (parametric) or the MannWhitney U test (non-parametric).
Reproductive indices:
- Pre-coital Interval
- Fertility Indices
- Gestation length
- Parturition Index

Offspring viability indices:
- Implantation Losses (%)
- Live Birth and Viability Indices
- Sex Ratio (% males)
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1000 and 300 mg/kg bw/day: Increasing salivation in males and females. No effects in animals of either sex treated with 100 mg/kg bw/day.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day (males): statistically significant reduction in weeks 1 and 3.
300 mg/kg bw/day (female): statistically significant increase in cumulative body weight gain during the final week of gestation. This is not considered an adverse effect.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day (males): statistically significant reduction in weeks 1 and 3.
300 mg/kg bw/day (female): statistically significant increase in cumulative body weight gain during the final week of gestation. This is not considered an adverse effect.
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Liver: hepatocyte hypertrophy was evident in animals of either sex treated with 1000 and 300 mg/kg bw/day and in males treated with 100 mg/kg bw/day. No such effects were detected in females treated with 100 mg/kg bw/day.

Kidneys: proximal tubular basophilia and hyaline droplets were evident in males from all treatment groups. Tubular degeneration/debris was evident in males treated with 1000 and 300 mg/kg bw/day.
These findings were demonstrated by immunohistochemical staining to be due to alpha-2-microglobulin nephropathy. No such effects were detected in any treated female.

Stomach: epithelial hyperplasia was evident in the fore stomach of animals of either sex treated with 1000 mg/kg bw/day and in males treated with 300 mg/kg bw/day. No such effects weredetected in females treated with 300 mg/kg bw/day or animals of either sex treated with 100 mg/kg bw/day.

Thyroid: follicular cell hypertrophy and hyperplasia was evident in animals of either sex treated with 1000 and 300 mg/kg bw/day and in males treated with 100 mg/kg bw/day. No such effects were detected in females treated with 100 mg/kg bw/day.

Pituitary: increased incidence and severity of hypertrophic/vacuolated cells in pars anterior was evident in males treated with 1000 and 300 mg/kg bw/day. No such effects were detected in any treated female or in males treated with 100 mg/kg bw/day.
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No unscheduled deaths
1000 and 300 mg/kg bw/day: Increasing salivation in males and females. No effects in animals of either sex treated with 100 mg/kg bw/day.

FUNCTIONALE OBSERVATIONS: No treatment-related effects

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
1000 mg/kg bw/day (males): statistically significant reduction in weeks 1 and 3.
300 mg/kg bw/day (female): statistically significant increase in cumulative body weight gain during the final week of gestation. This is not considered an adverse effect.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No adverse effect on food consumption or food efficiency.

WATER CONSUMPTION (PARENTAL ANIMALS)
1000 mg/kg bw/day: marked increase in water consumption in males
300 or 100 mg/kg: slight increase in males during the treatment period.
Females from all treatment groups: increased water consumption throughout the treatment period with statistical significance being achieved throughout gestation and lactation at 1000 mg/kg bw/day.

REPRODUCTIVE FUNCTION: MATING (PARENTAL ANIMALS)
No treatment-related effects on mating performance.

REPRODUCTIVE FUNCTION: FERTILITY (PARENTAL ANIMALS)
No treatment-related effects on fertility performance.

REPRODUCTIVE PERFORMANCE: GESTATION LENGHT (PARENTAL ANIMALS)
No differences in gestation length.

BLOOD CHEMISTRY: No toxicologically significant effects.

NECROPSY
1000 mg/kg bw/day: Nine males had enlarged kidneys, eight of which had pale kidneys; four showed a mottled appearance to the kidneys and five of these males also had a dark liver at necropsy.
300 mg/kg bw/day: one male had enlarged kidneys.
100 mg/kg bw: no findings

Females of any dose levels: no findings

100 mg/kg bw/day: one make had small testes and epididymides.
300 mg/kg bw/day: one female had reddened lungs
100 mg/kg bw/day: two female had reddened lungs

Histopathological examination of these tissues did reveal associated microscopic findings to the macroscopic abnormalities however they were considered to be of no toxicological importance.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Increase in absolute and relative liver weight: males and females treated with 1000 and 300 mg/kg bw/day and females treated with 100 mg/kg bw/day
Increase in kidney weight both absolute and relative to terminal body weight: Males treated with 1000 mg/kg bw/day
Increase in absolute and relative thyroid weight: males from all treatment groups
Reduction in absolute and relative thyroid weight: females treated with 1000 mg/kg bw/day
The microscopic thyroid changes observed in thyroid weights cannot be excluded as an effect of treatment.
Reduction in pituitary weight and an increase in kidney weight both absolute and relative to terminal body weight: females treated with 1000 mg/kg bw/day. Fot the changes detected in the kidneys or pituitary of females the intergroup differences were considered not to be of toxicological importance.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Liver: hepatocyte hypertrophy was evident in animals of either sex treated with 1000 and 300 mg/kg bw/day and in males treated with 100 mg/kg bw/day. No such effects were detected in females treated with 100 mg/kg bw/day.

Kidneys: proximal tubular basophilia and hyaline droplets were evident in males from all treatment groups. Tubular degeneration/debris was evident in males treated with 1000 and 300 mg/kg bw/day.
These findings were demonstrated by immunohistochemical staining to be due to alpha-2-microglobulin nephropathy. No such effects were detected in any treated female.

Stomach: epithelial hyperplasia was evident in the fore stomach of animals of either sex treated with 1000 mg/kg bw/day and in males treated with 300 mg/kg bw/day. No such effects weredetected in females treated with 300 mg/kg bw/day or animals of either sex treated with 100 mg/kg bw/day.

Thyroid: follicular cell hypertrophy and hyperplasia was evident in animals of either sex treated with 1000 and 300 mg/kg bw/day and in males treated with 100 mg/kg bw/day. No such effects were detected in females treated with 100 mg/kg bw/day.

Pituitary: increased incidence and severity of hypertrophic/vacuolated cells in pars anterior was evident in males treated with 1000 and 300 mg/kg bw/day. No such effects were detected in any treated female or in males treated with 100 mg/kg bw/day.

Dose descriptor:
LOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on hepatocellular and thyroid follicular cell hypertrophy and kidney effects (mediated by alpha-2-microglobulin).
Dose descriptor:
LOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on hepatocellular and thyroid follicular cell hypertrophy.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on adaptive findings in liver, thyroid and pituitary – not considered toxicologically significant. Also male rat specific kidney findings that are not relevant for human health
Dose descriptor:
NOEL
Remarks:
(reproductive toxicity)
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on post-natal effects on offspring viability, litter size and weight at 1000 mg/kg/day
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
VIABILITY (OFFSPRING): No toxicological significant effects detected. Offspring viability on Day 4 post partum was statistically significantly reduced in these litters. A total litter loss was also observed for one female treated with 1000 mg/kg bw/day. No such effects were
detected in litters from females treated with 300 or 100 mg/kg bw/day.

CLINICAL SIGNS (OFFSPRING): No toxicological significant effects detected. The incidental clinical signs detected in the control and treated groups (small size, cold, weak, pale, no milk in stomach, physical injury, found dead or missing) were considered unrelated to test item toxicity.

PATHOLOGY: No treatment-related macroscopic abnormalities were detected.


Dose descriptor:
NOEL
Generation:
F1
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: reduced post natal offspring viability, offspring body weight gain and litter size at 1000 mg/kg bw/day.
Reproductive effects observed:
yes
Lowest effective dose / conc.:
300 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
Oral administration of Nonene, branched to rats for 8 weeks, at levels of 100, 300 and 1000 mgk/kg/day, resulted in treatment related effects in both sexes and at all treatment levels. The LOEL for both males and females was 100 mg/kg/day. The effects seen were however either adaptive in nature or were not considered toxicologically relevant for man. The No Observed Adverse Effect Level (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day.

The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 300 mg/kg bw/day based on reduced offspring viability, offspring body weight gain, litter size and litter weigh at 1000 mg/kg bw/day.
Executive summary:

The test material Nonene, branched with CAS no. 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 female). Treatment related effects were reported in animals of either sex from all treatment groups, therefore a No Observed Effect Level (NOEL) was not established. The LOEL was therefore 100 mg/kg/day.

The results showed stomach changes in animals treated with 1000 mg/kg bw/day and the reduction in body weight gain in males. 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) can be therefore be established at 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, a No Observed Adverse Effect Level (NOAEL) can be established at 1000 mg/kg bw/day for males.

The ‘No Observed Effect Level’ (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.
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.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11 February 2015 - 26 March 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to OECD 414 Guideline and GLP conditions. Fully adequate for assessment.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in Section 13.
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries Testing guidelines for Toxicology studies, 12 NohSan No 8147, (24 November 2000)
Qualifier:
according to
Guideline:
other: Commission Regulation (EC) No 440/2008 of 30 May 2008 test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
- Test Material: Octadecene
- CAS Number: CAS 27070-58-2
- Physical State/Appearance : Clear colorless liquid
- Molecular Formula: C18 Isomerized Olefin
- Purity: 94.1%
- Batch Number: 747273
- Label: C18 Isomerised Olefin Lot 747273
- Date Received: 3 March 2014
- Storage Conditions: Room temperature, in the dark and under nitrogen (after opening the container)
- Expiry Date: 10 February 2016

Species:
rat
Strain:
other: Sprague-Dawley Crl:CD (SD) IGS BR strain
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent
- Age at study initiation: not specified
- Weight at study initiation: 180 to 284g.
- Housing: solid-floor polypropylene cages with stainless steel mesh lids furnished with softwood flakes
- Diet (e.g. ad libitum): A pelleted diet (Rodent 2018C Teklad Global Certified Diet, Harlan UK, Oxon, UK) - free access
- Water (e.g. ad libitum): freely available


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 50 ± 20%
- Air changes (per hr): 15 air changes per hr
- Photoperiod (hrs dark / hrs light): 12 hr light/12 hr dark

Experimental Starting Date: 11 February 2015
Experimental Completion Date: 26 March 2015

Justification for specie selection: the selected species is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.


IN-LIFE DATES: From 11 February 2015 to 26 March 2015
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Formulations were prepared once.
- Mixing appropriate amounts with (Type of food): The appropriate concentrations were prepared in Arachis oil solutions.
- Storage temperature of food: Stored at approximately +4 °C in the dark.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability and homogeneity of the test item formulations were previously determined by Harlan Laboratories Ltd., Shardlow, UK Analytical Services (Project Number 41301656 - Octadecene CAS 27070-58-2: Ninety Day Repeated Dose Oral (Gavage) Toxicity Study in Rats). The results indicate that the prepared formulations were within 90-103% of the nominal concentration confirming the accuracy of the formulation procedure.
Details on mating procedure:
Female animals were delivered in two batches prior to Day 3 of gestation. The day that positive evidence of mating was observed was designated Day 0 of gestation.
Duration of treatment / exposure:
From Day 5 to Day 19 of gestation, by gavage
Frequency of treatment:
Daily
Duration of test:
From Day 5 to Day 19 of gestation
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
24 Females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected based on available toxicity data including a dose range finding study (Harlan Laboratories Ltd report number 41403655)
Maternal examinations:
CAGE SIDE OBSERVATIONS:
Once daily during the gestation period. During the dosing period, observations were recorded immediately before and soon after dosing and one hour post dosing.

BODY WEIGHT:
Individual body weights were recorded on Day 3 (prior to dosing) and on Days 5, 6, 7, 8, 11, 14 and 17 of gestation of gestation, including for surviving animals at terminal kill (Day 20).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Food consumption was recorded for each surviving individual animal at Day 3, 5, 8, 11, 14, 17 and 20 of gestation.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):
Daily by visual inspection of the water bottles for any overt changes.

POST-MORTEM EXAMINATIONS: Yes
- Full external and internal examination ( any macroscopic abnormalities were recorded).

Ovaries and uterine content:
Ovaries and uteri examinations:
i) Number of corpora lutea
ii) Number, position and type of intrauterine implantation
iii) Fetal sex
iv) External fetal appearance
v) Fetal weight
vi) Placental weight
vii) Gravid uterus weight
Fetal examinations:
- Fetal external findings
- Visceral findings
- Skeletal findings and skeletal development

- Number of implantations
- Embryofetal survival
- Litter size
- Sex ratio
- Mean fetal litter and placental weights


Statistics:
- Shapiro Wilk normality test and Bartlett’s test for homogeneity of variance
- Dunnett’s test
- Kruskal-Wallis nonparametric analysis of variance
- Mann-Whitney ‘U’ test
Indices:
Percentage pre-implantation loss
Percentage post-implantation loss
Sex ratio
Clinical signs:
no effects observed
Mortality:
no mortality observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No maternal toxicity
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No embryotoxic/teratogenic effects
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Developmental Toxicity
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
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 is considered to be 1000 mg/kg bw/day.
Executive summary:

The test material Octadecene CAS no. 27070 -58 -2 was administrated 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 adverse 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.

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.