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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 November 2014 - 20 November 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according the OECD 408 guideline and GLP compliance. 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.
Cross-reference
Reason / purpose:
read-across: supporting information
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
13 November 2014 - 20 November 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according the OECD 408 guideline and GLP compliance. 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 source
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
other: Commission Regulation (EC) No 440/2008 of 30 May 2008, laying down 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).
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
Identification : Oct-1-ene (#2) CAS 111-66-0
Physical State/Appearance : clear colorless liquid
Purity : 99.9%
Lot Number : 748027
Label : Alpha Olefin C8 (1-Octene) 5L Lot 748027
Date Received : 03 March 2014
Storage Conditions : Room temperature in the dark under nitrogen
Expiry Date : 17 February 2015

Oct-1-ene, CAS# 111-66-0 used in this study was a typical production sample, according to the details included in the boundary composition in IUCLID section 1.2. Oct-1-ene was chosen in the Higher Olefins category testing strategy because it represents a substance with high alpha olefin content (category range 0 - 98%). Please see the testing strategy attached in section 13 for further details.
Species:
rat
Strain:
other: Wistar Han™:RccHan™:WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd., Oxon, UK
- Age at study initiation: six to eight weeks old
- Weight at study initiation: Males: 200 to 242g, Females: 161 to 193g
- Housing: The animals were housed in groups of three or four by sex in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding
- Diet (e.g. ad libitum): A pelleted diet (Rodent 2014C Teklad Global Certified Diet, Harlan Laboratories U.K. Ltd., Oxon, UK - free access
- Water (e.g. ad libitum): free access
- Acclimation period: 7 days

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

Experimental Starting Date: 13 November 2014
Experimental Completition Date: 20 November 2015

Justification for specie selection: The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.

Route of administration:
oral: gavage
Vehicle:
other: arachis oil BP
Details on oral exposure:
The test item was administered daily, for ninety consecutive days, by gavage using a stainless steel cannula attached to a disposable plastic syringe. Control animals were treated in an identical manner with 4 mL/kg of Arachis oil BP.

The volume of test and control item administered to each animal was based on the most recent scheduled body weight and was adjusted at weekly intervals.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test item was prepared in Arachis oil BP solution. The stability and homogeneity of the test item formulations were determined by Harlan Laboratories Ltd., Shardlow, UK, Analytical Services. The results of the analytical determination showed that the formulations were stable for at least 20 days. Formulations were prepared and stored at approximately 4 °C in the dark.
The results indicate that the prepared formulations were in the range between 96% and 102% of the nominal concentration confirming the suitability and accuracy of the formulation procedure.
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on a fourteen day dose range finding study in the rat (Harlan Study Number: 41301411). In this study, a high dosage of 1000 mg/kg bw/day was well tolerated, therefore, the dose 0 (Control), 100, 300 and 1000 mg/kg bw/day have been selected for the OECD 408 study.

Observations and examinations performed and frequency:
Clinical Observations:
- Signs of toxicity
- Ill-health or behavioural change immediately before dosing

Functional Observations:
- Prior to the start of treatment and at weekly intervals thereafter

Behavioural Assessment
- Functional Performance Tests: Motor Activity, Forelimb/Hindlimb Grip Strength
- Sensory Reactivity

Body Weight
- Individual body weights were recorded on Day 1 (prior to dosing), at weekly intervals thereafter and at terminal kill

Food Consumption
- Weekly intervals throughout the study

Water Consumption
- Daily by visual inspection of the water bottles

Ophthalmoscopic Examination
- Pre-treatment and before termination of treatment (during Week 12)

Laboratory Investigations
- End of the study
- Haematology
- Blood Chemistry

Sacrifice and pathology:
Sacrifice: All animals were terminated by intravenous overdose of a suitable barbiturate agent followed by exsanguination.
Pathology
- Necropsy: all animals were subjected to a full external and internal examination.
- Organ Weights (Adrenals, Ovaries, Brain Spleen, Epididymides, Testes, Heart, Thymus, Kidneys, Uterus, Liver)
- Histopathology: Samples of selected tissues were removed from all animals and preserved. All tissues from control and 1000 mg/kg group animals were examined microscopically.
Stomach, lungs and kidney (males only) from 100 and 300 mg/kg groups were examined to clarify potential treatment related findings. In addition the kidneys form male animals were subject to immunohistochemical examination to confirm the presence of alpha-2-microglobulin.
Statistics:
Bartlett’s test
ANOVA
ANCOVA
Williams Test
Student t-test (parametric)
MannWhitney U test
Shirley Test
Dunnett’s
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Animals of either sex treated with 1000 and 300 mg/kg bw/day showed episodes of increased salivation during the treatment period. One male treated with 1000 mg/kg bw/day showed incidences of noisy respiration and one female from this treatment group had noisy respiration, decreased respiratory rate and hunched posture on Day 68. No such effects were detected in animals of either sex treated with 100 mg/kg bw/day.
Mortality:
no mortality observed
Description (incidence):
There were no unscheduled deaths on the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There was no effect of treatment on body weight performance for either sex at 100, 300 or 1000 mg/kg bw/day.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no treatment-related effects on food consumption at dosages of 100, 300 or 1000 mg/kg bw/day.
Food efficiency:
no effects observed
Description (incidence and severity):
There were no treatment-related effects on food conversion efficiency at dosages of 100, 300 or 1000 mg/kg bw/day.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
There was no treatment-related effect detected on water consumption for either sex at dosages of 100, 300 or 1000 mg/kg bw/day.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related ocular effects detected.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
There were no toxicologically significant effects detected in the hematological parameters examined.

Males from all treatment groups showed a statistically significant increase in mean corpuscular hemoglobin concentration (p<0.05). The majority of individual values were within the normal background range and in the absence of a true dose related response the intergroup differences were considered to be of no toxicological significance.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
There were no toxicologically significant effects detected in the blood chemical parameters examined.

Males treated with 1000 mg/kg bw/day showed a statistically significant increase in alanine aminotransferase and females from this treatment group showed a statistically significant increase in urea (p<0.01). The majority of individual values for these parameters were within the normal background ranges and in the absence of any associated histopathological correlates the intergroup differences were considered to be of no toxicological significance.

Males from all treatment groups showed statistically significant reductions in sodium concentration (p<0.05), potassium concentration (p<0.05) and chloride concentration (p<0.05) and a statistically significant increase in inorganic phosphorus (p<0.05). Males treated with 100 mg/kg bw/day also showed a statistically significant increase in bilirubin (p<0.01). Females treated with 1000 and 300 mg/kg bw/day showed a statistically significant increase in glucose (p<0.05). The majority of individual values for these parameters were within the normal background ranges and in the absence of true dose related responses the intergroup differences were considered to be of no toxicological significance.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Behavioral Assessment
There were no treatment-related changes in behavioral parameters measured at dosages of 100, 300 or 1000 mg/kg bw/day.

Functional Performance Tests
There were no toxicologically significant changes in functional performance at dosages of 100, 300 or 1000 mg/kg bw/day.

Males from all treatment groups and females treated with 1000 and 300 mg/kg bw/day showed a statistically significant reduction in overall activity when compared with controls (p<0.05-0.01). Females treated with 1000 and 300 mg/kg bw/day also showed a statistically significant reduction in activity during the final 20% period of observation (p<0.05). In the absence of a true dose related response and/orany supporting clinical observations to suggest an effect of neurotoxicity, the intergroup differences were considered to be of no toxicological significance.

Males treated with 1000 mg/kg bw/day showed a statistically significant reduction (p<0.05) in the first fore limb and hind limb grip strength test and a statistically significant increase in the final hind limb grip strength test. In the absence of a consistent effect or any supporting clinical observations to suggest an effect of neurotoxicity, the intergroup differences were considered to be of no toxicological significance.

Sensory Reactivity Assessments
There were no treatment-related changes in sensory reactivity at dosages of 100, 300 or 1000 mg/kg bw/day.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
There were no toxicologically significant effects detected in the organ weights measured.

Males treated 1000 mg/kg bw/day and females from all treatment groups showed a statistically significant increase in liver weight both absoluteand relative to terminal body weight (p<0.01; males, p<0.05; females). Although a number of the individual values were outside of the normal background range, no true dose related response for females was evident. In the absence of any associated histopathological correlates, the intergroup differences were therefore considered of no toxicological importance.

Males treated with 1000 mg/kg bw/day showed a statistically significant reduction in epididymides weight both absolute and relative to terminal body weight (p<0.05). All of the individual values were within the normal background range and in the absence of any associated histopathological correlates the intergroup difference was considered to be of no toxicological significance.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
There were no toxicologically significant macroscopic abnormalities detected.

A mass surrounding the heart and lungs and a fluid filled vagina was found in one female treated with 1000 mg/kg bw due to an abscess in the heart, granuloma in the lungs and a dilated lumen in the uterus. One control female, one female treated with 100 mg/kg bw/day, two females and one male treated with 300 mg/kg bw/day and four females treated with 1000 mg/kg bw/day had reddened lungs at necropsy. At microscopic examination, the treated animals were shown to have congestion in the lungs. Although there was an increased incidence/severity of congestion in the lungs the intergroup differences were considered to be within the normal range of background alterations that are seen in untreated animals of this age and strain and therefore was considered an incidental finding, not related to the treatments.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The following treatment related microscopic abnormalities were detected:

Kidneys:increased incidence and severity of hyaline droplets and granular casts (consistent with alpha-2u-globulin nephropathy) were evident in males from all treatment groups. Although the findings of granular casts in the male kidney may be considered to represent an adverse effect of the test item, immunohistochemical staining demonstrated that these changes were correlated to accumulation of alpha 2u-globulin and formation of hyaline droplets, 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 effects in humans.

Granular casts may be considered to represent an adverse effect of the test item, however immunohistochemical staining demonstrated that these changes within the kidneys was correlated to the same condition as hyaline droplets therefore the kidney changes were considered to be of limited toxicological significance.

Stomach: Acanthosis, hyperkeratosis, ulceration and submucosal inflammation was evident in the forestomach of animals of either sex treated with 1000 and 300 mg/kg bw/day. The stomach changes identified in 1000 and 300 mg/kg bw/day animals were considered to be a result of local irritation of the test item rather than a true effect of systemic toxicity.

Lungs:increased incidence and severity of alveolar macrophages were evident in animals of either sex treated with 1000 mg/kg bw/day and in females treated with 100 mg/kg bw/day. This observation is considered to be a result of local irritation following inhalation of microdroplets of the test compound as the gavage catheter was withdrawn. The absence of the finding at 300 mg/kg bw/day is further evidence that this is a procedure-related finding and as such, it is of limited toxicological significance.
Histopathological findings: neoplastic:
not specified
Details on results:
Necropsy and Gross Pathological Findings:
A mass surrounding the heart and lungs and a fluid filled vagina was found in one female treated with 1000 mg/kg bw due to an abscess in the heart, granuloma in the lungs and a dilated lumen in the uterus. One control female, one female treated with 100 mg/kg bw/day, two females and one male treated with 300 mg/kg bw/day and four females treated with 1000 mg/kg bw/day had reddened lungs at necropsy. At microscopic examination, the treated animals were shown to have congestion in the lungs. Although there was an increased incidence/severity of congestion in the lungs the intergroup differences were considered to be within the normal range of background alterations that are seen in untreated animals of this age and strain and therefore was considered an incidental finding, not related to the treatments.

Histopathology:
The following treatment related microscopic abnormalities were detected:

Kidneys:increased incidence and severity of hyaline droplets and granular casts (consistent with alpha-2u-globulin nephropathy) were evident in males from all treatment groups. Although the findings of granular casts in the male kidney may be considered to represent an adverse effect of the test item, immunohistochemical staining demonstrated that these changes were correlated to accumulation of alpha 2u-globulin and formation of hyaline droplets, 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 effects in humans.

Granular casts may be considered to represent an adverse effect of the test item, however immunohistochemical staining demonstrated that these changes within the kidneys was correlated to the same condition as hyaline droplets therefore the kidney changes were considered to be of limited toxicological significance.

Stomach: Acanthosis, hyperkeratosis, ulceration and submucosal inflammation was evident in the forestomach of animals of either sex treated with 1000 and 300 mg/kg bw/day. The stomach changes identified in 1000 and 300 mg/kg bw/day animals were considered to be a result of local irritation of the test item rather than a true effect of systemic toxicity.

Lungs:increased incidence and severity of alveolar macrophages were evident in animals of either sex treated with 1000 mg/kg bw/day and in females treated with 100 mg/kg bw/day. This observation is considered to be a result of local irritation following inhalation of microdroplets of the test compound as the gavage catheter was withdrawn. The absence of the finding at 300 mg/kg bw/day is further evidence that this is a procedure-related finding and as such, it is of limited toxicological significance.

Organ Weights:
Males treated 1000 mg/kg bw/day and females from all treatment groups showed a statistically significant increase in liver weight both absoluteand relative to terminal body weight (p<0.01; males, p<0.05; females). Although a number of the individual values were outside of the normal background range, no true dose related response for females was evident. In the absence of any associated histopathological correlates, the intergroup differences were therefore considered of no toxicological importance.

Males treated with 1000 mg/kg bw/day showed a statistically significant reduction in epididymides weight both absolute and relative to terminal body weight (p<0.05). All of the individual values were within the normal backgroundrange and in the absence of any associated histopathological correlates the intergroup difference was considered to be of no toxicological significance.

Clinical Biochemistry:
There were no toxicologically significant effects detected in the blood chemical parameters examined.

Males treated with 1000 mg/kg bw/day showed a statistically significant increase in alanine aminotransferase and females from this treatment group showed a statistically significant increase in urea (p<0.01). The majority of individual values
for these parameters were within the normal background ranges and in the absence of any associated histopathological correlates the intergroup differences were considered to be of no toxicological significance.

Males from all treatment groups showed statistically significant reductions in sodium concentration (p<0.05), potassium concentration (p<0.05) and chloride concentration (p<0.05) and a statistically significant increase in inorganic phosphorus
(p<0.05). Males treated with 100 mg/kg bw/day also showed a statistically significant increase in bilirubin (p<0.01). Females treated with 1000 and 300 mg/kg bw/day showed a statistically significantincrease in glucose (p<0.05). The majority of individual values for these parameters were within the normal background ranges and in the absence of true doserelated responses the intergroup differences were considered to be of no toxicological significance.

Hematology:
Males from all treatment groups showed a statistically significant increase in mean corpuscular hemoglobin concentration (p<0.05). The majority of individual values were within the normal background range and in the absence of a true dose related responsethe intergroup differences were considered to be of no toxicological significance.

Functional Performance Tests:
There were no toxicologically significant changes in functional performance at dosages of 100, 300 or 1000 mg/kg bw/day.

Males from all treatment groups and females treated with 1000 and 300 mg/kg bw/day showed a statistically significant reduction in overall activity when compared with controls (p<0.05-0.01). Females treated with 1000 and 300 mg/kg bw/day also showed a statistically significant reduction in activity during the final 20% period of observation (p<0.05). In the absence of a true dose related response and/orany supporting clinical observations to suggest an effect of neurotoxicity, the intergroup differences were considered to be of no toxicological significance.

Males treated with 1000 mg/kg bw/day showed a statistically significant reduction (p<0.05) in the first fore limb and hind limb grip strength test and a statistically significant increase in the final hind limb grip strength test. In the absence of a consistent effect or any supporting clinical observations to suggest an effect of neurotoxicity, the intergroup differences were considered to be of no toxicological significance.
Key result
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on treatment related effects in males from all treatment groups and in females treated with 1000 and 300 mg/kg bw/day. The No Observed Effect Level (NOEL) was not established for males.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the fact that the findings in lungs and stomach were not considered to reflect true systemic toxicity. The kidney findings in males are species and sex specific and are not relevant for human health.
Key result
Critical effects observed:
no

Table 1. Group Mean Functional Performance Test Values - Males

Group

(sex)

 

Test 1 Forelimb

(g)

Test 1 Hindlimb

(g)

Test 2 Forelimb

(g)

Test 2 Hindlimb

(g)

Test 3 Forelimb

(g)

Test 3 Hindlimb

(g)

Overall

Activity

Overall Mobile

Last 20%

Activity

Last 20% Mobile

1 (M)

Mean

1234.3

432.8

1157.1

406.0

1022.3

347.1

1093.8

1.8

137.7

0.2n

S.D.

240.7

107.7

285.2

62.1

162.9

99.5

300.2

1.9

118.4

0.4

N

10

10

10

10

10

10

10

10

10

10

 

2 (M)

Mean

1067.0

385.9

1093.5

377.3

1060.0

425.2

797.6**

0.4

49.2

0.0n

S.D.

276.5

116.5

300.8

98.2

243.1

95.1

225.2

0.5

62.4

0.0

N

10

10

10

10

10

10

10

10

10

10

 

3 (M)

Mean

1217.5

425.3

1084.0

422.4

1069.8

405.6

862.5**

1.1

87.7

0.0n

S.D.

237.5

104.6

276.5

134.2

195.5

74.4

149.0

1.6

81.4

0.0

N

10

10

10

10

10

10

10

10

10

10

 

4 (M)

Mean

943.8*

325.8*

1101.5

446.0

990.0

442.2*

820.7*

1.0

72.4

0.0n

S.D.

186.3

84.6

198.7

128.5

178.7

127.1

248.2

2.2

58.5

0.0

N

10

10

10

10

10

10

10

10

10

10

General Footnote: Unit = Time (seconds) for Motor Activity Assessments

Dose Levels: Group 1 - 0(Control); Group 2 - 100 mg/kg bw/day; Group 3 - 300 mg/kg bw/day; Group 4 - 1000 mg/kg bw/day

 

Table 2. Group Mean Functional Performance Test Values - Females

Group

(sex)

 

Test 1 Forelimb

(g)

Test 1 Hindlimb

(g)

Test 2 Forelimb

(g)

Test 2 Hindlimb

(g)

Test 3 Forelimb

(g)

Test 3 Hindlimb

(g)

Overall

Activity

Overall Mobile

Last 20%

Activity

Last 20% Mobile

1 (F)

Mean

966.3

309.4

866.0

293.4

904.5

291.9

803.1

5.3

122.1

1.2

S.D.

255.2

73.7

185.3

97.7

174.1

66.4

266.0

9.9

113.4

2.6

N

10

10

10

10

10

10

10

10

10

10

 

2 (F)

Mean

992.2

238.8

1004.0

232.4

963.2

308.4

724.2

6.2

89.7

2.0

S.D.

224.9

68.5

191.6

95.7

174.6

124.4

619.7

17.9

168.6

6.3

N

10

10

10

10

10

10

10

10

10

10

 

3 (F)

Mean

985.6

242.3

1011.2

288.3

857.3

255.6

498.4*

1.3

33.3*

0.1

S.D.

147.0

93.5

182.1

74.4

183.1

115.0

256.0

2.1

50.5

0.3

N

10

10

10

10

10

10

10

10

10

10

 

4 (F)

Mean

1024.5

302.9

936.2

296.9

1040.8

288.9

544.5*

1.8

22.0*

0.2

S.D.

175.2

108.5

258.3

109.4

293.8

89.6

201.7

1.3

33.7

0.6

N

10

10

10

10

10

10

10

10

10

10

General Footnote: Unit = Time (seconds) for Motor Activity Assessments

Dose Levels: Group 1 - 0(Control); Group 2 - 100 mg/kg bw/day; Group 3 - 300 mg/kg bw/day; Group 4 - 1000 mg/kg bw/day

Table 3. Group Mean Hematological Values - Males

Group (sex)

 

MCHC (g/dL)

Group 1 (0 – Control)

Mean

33.83

S.D.

0.18

N

10

 

Group 2 (100 mg/Kg bw/day)

Mean

34.38*

S.D.

0.46

N

10

 

Group 3 (300 mg/Kg bw/day)

Mean

34.02*

S.D.

0.28

N

10

 

Group 4 (1000 mg/Kg bw/day)

Mean

34.23*

S.D.

0.4

N

10

Table 4. Group Mean Blood Chemical Values - Males

Group

(sex)

 

Na+

mmol/L

K+

mmol/L

Cl-

mmol/L

P

mmol/L

ALAT

IU/L

Bili

mg/dL

Group 1

(0 – Control)

Mean

150.7

4.713

102.6

1.70

55.5

0.090

S.D.

2.1

0.291

1.4

0.19

10.7

0.012

N

10

10

10

10

10

10

 

Group 2

(100 mg/Kg bw/day)

Mean

147.6*

4.410*

100.6*

1.95*

58.6

0.165**

S.D.

1.7

0.264

1.3

0.15

10.3

0.063

N

10

10

10

10

10

10

 

Group 3

(300 mg/Kg bw/day)

Mean

148.6*

4.489*

101.4*

1.91*

92.7

0.099

S.D.

3.9

0.373

1.9

0.17

111.6

0.014

N

10

10

10

10

10

10

 

Group 4

(1000 mg/Kg bw/day)

Mean

148.7*

4.429*

101.4*

1.91*

66.7*

0.092

S.D.

1.5

0.196

1.3

0.24

8.9

0.008

N

10

10

10

10

10

10

 

Table 5. Group Mean Blood Chemical Values - Females

Group (sex)

 

Urea (mg/dL)

Glucose (mg/dL)

Group 1

(0 – Control)

Mean

38.1

123.7

S.D.

5.7

18.4

N

10

10

 

Group 2

(100 mg/Kg bw/day)

Mean

40.9

121.9

S.D.

7.3

15.8

N

10

10

 

Group 3

(300 mg/Kg bw/day)

Mean

39.6

145.4*

S.D.

6.1

17.2

N

10

10

 

Group 4

(1000 mg/Kg bw/day)

Mean

47.3**

137.0*

S.D.

4.7

17.0

N

10

10

Table 6. Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Weights

 

 

Males

Females

0

Control

100

mg/Kg bw/day

300

mg/Kg bw/day

1000

mg/Kg bw/day

0

Control

100

mg/Kg bw/day

300

mg/Kg bw/day

1000

mg/Kg bw/day

Epididymides

Mean (g)

1.73769

1.66163

1.64448

1.60713*

 

 

 

 

S.D.

0.16852

0.16045

0.10688

0.12939

 

 

 

 

N

10

10

10

10

 

 

 

 

 

 

 

 

 

 

 

 

 

Mean (%)

0.430

0.395

0.392

0.387*

 

 

 

 

S.D.

0.037

0.067

0.027

0.035

 

 

 

 

N

10

10

10

10

 

 

 

 

 

Liver

Mean (g)

12.6953

13.8934

14.0717

15.1921**

8.37888

8.68144*

8.55061*

8.88699*

S.D.

2.20822

2.07704

0.84560

1.33677

0.65274

0.87496

0.77236

0.95142

N

10

10

10

10

10

10

10

10

 

 

 

 

 

 

 

 

 

Mean (%)

3.120

3.246

3.347

3.652**

3.345

3.605*

3.468*

3.591*

S.D.

0.314

0.244

0.102

0.298

0.286

0.080

0.224

0.214

N

10

10

10

10

10

10

10

10

 

Table 7. Summary Incidence of Necropsy Findings - Males

 

Males

0

Control

100

mg/Kg bw/day

300

mg/Kg bw/day

1000

mg/Kg bw/day

Number of animals examined

10

10

10

10

Lungs (With Bronchi)

 

Submitted

(10)

(10)

(10)

(10)

No Visible Lesions

10

10

9

10

Reddened

0

0

1

0

 

Table 8. Summary Incidence of Necropsy Findings - Females

 

Females

0

Control

100

mg/Kg bw/day

300

mg/Kg bw/day

1000

mg/Kg bw/day

Number of animals examined

10

10

10

10

Heart

 

Submitted

(10)

(10)

(10)

(10)

No Visible Lesions

10

10

10

9

Mass

0

0

0

1

 

Lungs (With Bronchi)

 

Submitted

(10)

(10)

(10)

(10)

No Visible Lesions

9

9

8

5

Discolouration; Red

1

0

2

4

Reddened

0

1

0

0

Mass

0

0

0

1

 

Vagina

 

Submitted

(10)

(10)

(10)

(10)

No Visible Lesions

10

10

10

9

Fluid Filled

0

0

0

1

Conclusions:
Based on the results of the study, the No Observed Effect Level (NOEL) was considered to be 100 mg/kg bw/day for females and was not established for males. The No Observed Adverse Effect Level (NOAEL) was established at 1000 mg/kg bw/day for females and males because the findings were either not considered to reflect true systemic toxicity or were not relevant for human health.
Executive summary:

The test material Oct-1-ene CAS 111-66-0 was administrated orally to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day for 90 consecutive days. The results showed treatment - related effects in males of all dose groups and females treated with 1000 and 300 mg/kg bw.

Pathology examination showed increased incidence and severity of hyaline droplets and granular casts (consistent with alpha-2u-globulin nephropathy) in kidneys of males from all treatment groups. The presence of alpha-2-microglobulin was confirmed histochemically. This finding is species and sex specific and is not considered relevant for human health. Acanthosis, hyperkeratosis and submucosal inflammation was evident in the forestomach of animals of either sex treated with 1000 and 300 mg/kg bw/day. This finding is a result of local irritation. Alveolar macrophages were observed in animals of either sex treated with 1000 mg/kg bw/day and in females treated with 300 mg/kg bw/day. This finding is considered to be a result of local irritation following inhalation of micro droplets of the test compound (gavage route exposure) and, therefore, are not considered related to the treatment.

Based on the results of the study, the No Observed Effect Level (NOEL) was considered to be 100 mg/kg bw/day for females and was not established for males. The No Observed Adverse Effect Level (NOAEL) was established at 1000 mg/kg bw/day for females and males because the findings were either not evidence of true systemic toxicity or were not relevant for human health.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report Date:
2015

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
other: Commission Regulation (EC) No 440/2008 of 30 May 2008, laying down 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).
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Clear colourless liquid
Details on test material:
- Test Material : Oct-1-ene
- CAS Number: 111-66-0
- Physical State/Appearance : Clear colourless liquid
- Purity : 99.9%
- Lot Number : 748027
- Label: Alpha Olefin C8 (1-Octene) 5L Lot 748027
- Date Received : 03 March 2014
- Storage Conditions : Ambient temperature, in the dark and under nitrogen
- Expiry Date : 17 Feb 2016
Specific details on test material used for the study:
Identification : Oct-1-ene (#2) CAS 111-66-0
Physical State/Appearance : clear colorless liquid
Purity : 99.9%
Lot Number : 748027
Label : Alpha Olefin C8 (1-Octene) 5L Lot 748027
Date Received : 03 March 2014
Storage Conditions : Room temperature in the dark under nitrogen
Expiry Date : 17 February 2015

Oct-1-ene, CAS# 111-66-0 used in this study was a typical production sample, according to the details included in the boundary composition in IUCLID section 1.2. Oct-1-ene was chosen in the Higher Olefins category testing strategy because it represents a substance with high alpha olefin content (category range 0 - 98%). Please see the testing strategy attached in section 13 for further details.

Test animals

Species:
rat
Strain:
other: Wistar Han™:RccHan™:WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd., Oxon, UK
- Age at study initiation: six to eight weeks old
- Weight at study initiation: Males: 200 to 242g, Females: 161 to 193g
- Housing: The animals were housed in groups of three or four by sex in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding
- Diet (e.g. ad libitum): A pelleted diet (Rodent 2014C Teklad Global Certified Diet, Harlan Laboratories U.K. Ltd., Oxon, UK - free access
- Water (e.g. ad libitum): free access
- Acclimation period: 7 days

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

Experimental Starting Date: 13 November 2014
Experimental Completition Date: 20 November 2015

Justification for specie selection: The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: arachis oil BP
Details on oral exposure:
The test item was administered daily, for ninety consecutive days, by gavage using a stainless steel cannula attached to a disposable plastic syringe. Control animals were treated in an identical manner with 4 mL/kg of Arachis oil BP.

The volume of test and control item administered to each animal was based on the most recent scheduled body weight and was adjusted at weekly intervals.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test item was prepared in Arachis oil BP solution. The stability and homogeneity of the test item formulations were determined by Harlan Laboratories Ltd., Shardlow, UK, Analytical Services. The results of the analytical determination showed that the formulations were stable for at least 20 days. Formulations were prepared and stored at approximately 4 °C in the dark.
The results indicate that the prepared formulations were in the range between 96% and 102% of the nominal concentration confirming the suitability and accuracy of the formulation procedure.
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on a fourteen day dose range finding study in the rat (Harlan Study Number: 41301411). In this study, a high dosage of 1000 mg/kg bw/day was well tolerated, therefore, the dose 0 (Control), 100, 300 and 1000 mg/kg bw/day have been selected for the OECD 408 study.

Examinations

Observations and examinations performed and frequency:
Clinical Observations:
- Signs of toxicity
- Ill-health or behavioural change immediately before dosing

Functional Observations:
- Prior to the start of treatment and at weekly intervals thereafter

Behavioural Assessment
- Functional Performance Tests: Motor Activity, Forelimb/Hindlimb Grip Strength
- Sensory Reactivity

Body Weight
- Individual body weights were recorded on Day 1 (prior to dosing), at weekly intervals thereafter and at terminal kill

Food Consumption
- Weekly intervals throughout the study

Water Consumption
- Daily by visual inspection of the water bottles

Ophthalmoscopic Examination
- Pre-treatment and before termination of treatment (during Week 12)

Laboratory Investigations
- End of the study
- Haematology
- Blood Chemistry

Sacrifice and pathology:
Sacrifice: All animals were terminated by intravenous overdose of a suitable barbiturate agent followed by exsanguination.
Pathology
- Necropsy: all animals were subjected to a full external and internal examination.
- Organ Weights (Adrenals, Ovaries, Brain Spleen, Epididymides, Testes, Heart, Thymus, Kidneys, Uterus, Liver)
- Histopathology: Samples of selected tissues were removed from all animals and preserved. All tissues from control and 1000 mg/kg group animals were examined microscopically.
Stomach, lungs and kidney (males only) from 100 and 300 mg/kg groups were examined to clarify potential treatment related findings. In addition the kidneys form male animals were subject to immunohistochemical examination to confirm the presence of alpha-2-microglobulin.
Statistics:
Bartlett’s test
ANOVA
ANCOVA
Williams Test
Student t-test (parametric)
MannWhitney U test
Shirley Test
Dunnett’s

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Animals of either sex treated with 1000 and 300 mg/kg bw/day showed episodes of increased salivation during the treatment period. One male treated with 1000 mg/kg bw/day showed incidences of noisy respiration and one female from this treatment group had noisy respiration, decreased respiratory rate and hunched posture on Day 68. No such effects were detected in animals of either sex treated with 100 mg/kg bw/day.
Mortality:
no mortality observed
Description (incidence):
There were no unscheduled deaths on the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There was no effect of treatment on body weight performance for either sex at 100, 300 or 1000 mg/kg bw/day.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no treatment-related effects on food consumption at dosages of 100, 300 or 1000 mg/kg bw/day.
Food efficiency:
no effects observed
Description (incidence and severity):
There were no treatment-related effects on food conversion efficiency at dosages of 100, 300 or 1000 mg/kg bw/day.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
There was no treatment-related effect detected on water consumption for either sex at dosages of 100, 300 or 1000 mg/kg bw/day.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related ocular effects detected.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
There were no toxicologically significant effects detected in the hematological parameters examined.

Males from all treatment groups showed a statistically significant increase in mean corpuscular hemoglobin concentration (p<0.05). The majority of individual values were within the normal background range and in the absence of a true dose related response the intergroup differences were considered to be of no toxicological significance.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
There were no toxicologically significant effects detected in the blood chemical parameters examined.

Males treated with 1000 mg/kg bw/day showed a statistically significant increase in alanine aminotransferase and females from this treatment group showed a statistically significant increase in urea (p<0.01). The majority of individual values for these parameters were within the normal background ranges and in the absence of any associated histopathological correlates the intergroup differences were considered to be of no toxicological significance.

Males from all treatment groups showed statistically significant reductions in sodium concentration (p<0.05), potassium concentration (p<0.05) and chloride concentration (p<0.05) and a statistically significant increase in inorganic phosphorus (p<0.05). Males treated with 100 mg/kg bw/day also showed a statistically significant increase in bilirubin (p<0.01). Females treated with 1000 and 300 mg/kg bw/day showed a statistically significant increase in glucose (p<0.05). The majority of individual values for these parameters were within the normal background ranges and in the absence of true dose related responses the intergroup differences were considered to be of no toxicological significance.
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Behavioral Assessment
There were no treatment-related changes in behavioral parameters measured at dosages of 100, 300 or 1000 mg/kg bw/day.

Functional Performance Tests
There were no toxicologically significant changes in functional performance at dosages of 100, 300 or 1000 mg/kg bw/day.

Males from all treatment groups and females treated with 1000 and 300 mg/kg bw/day showed a statistically significant reduction in overall activity when compared with controls (p<0.05-0.01). Females treated with 1000 and 300 mg/kg bw/day also showed a statistically significant reduction in activity during the final 20% period of observation (p<0.05). In the absence of a true dose related response and/orany supporting clinical observations to suggest an effect of neurotoxicity, the intergroup differences were considered to be of no toxicological significance.

Males treated with 1000 mg/kg bw/day showed a statistically significant reduction (p<0.05) in the first fore limb and hind limb grip strength test and a statistically significant increase in the final hind limb grip strength test. In the absence of a consistent effect or any supporting clinical observations to suggest an effect of neurotoxicity, the intergroup differences were considered to be of no toxicological significance.

Sensory Reactivity Assessments
There were no treatment-related changes in sensory reactivity at dosages of 100, 300 or 1000 mg/kg bw/day.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
There were no toxicologically significant effects detected in the organ weights measured.

Males treated 1000 mg/kg bw/day and females from all treatment groups showed a statistically significant increase in liver weight both absolute and relative to terminal body weight (p<0.01; males, p<0.05; females). Although a number of the individual values were outside of the normal background range, no true dose related response for females was evident. In the absence of any associated histopathological correlates, the intergroup differences were therefore considered of no toxicological importance.

Males treated with 1000 mg/kg bw/day showed a statistically significant reduction in epididymides weight both absolute and relative to terminal body weight (p<0.05). All of the individual values were within the normal background range and in the absence of any associated histopathological correlates the intergroup difference was considered to be of no toxicological significance.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
There were no toxicologically significant macroscopic abnormalities detected.

A mass surrounding the heart and lungs and a fluid filled vagina was found in one female treated with 1000 mg/kg bw due to an abscess in the heart, granuloma in the lungs and a dilated lumen in the uterus. One control female, one female treated with 100 mg/kg bw/day, two females and one male treated with 300 mg/kg bw/day and four females treated with 1000 mg/kg bw/day had reddened lungs at necropsy. At microscopic examination, the treated animals were shown to have congestion in the lungs. Although there was an increased incidence/severity of congestion in the lungs the intergroup differences were considered to be within the normal range of background alterations that are seen in untreated animals of this age and strain and therefore was considered an incidental finding, not related to the treatments.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The following treatment related microscopic abnormalities were detected:

Kidneys:increased incidence and severity of hyaline droplets and granular casts (consistent with alpha-2u-globulin nephropathy) were evident in males from all treatment groups. Although the findings of granular casts in the male kidney may be considered to represent an adverse effect of the test item, immunohistochemical staining demonstrated that these changes were correlated to accumulation of alpha 2u-globulin and formation of hyaline droplets, 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 effects in humans.

Granular casts may be considered to represent an adverse effect of the test item, however immunohistochemical staining demonstrated that these changes within the kidneys was correlated to the same condition as hyaline droplets therefore the kidney changes were considered to be of limited toxicological significance.

Stomach: Acanthosis, hyperkeratosis, ulceration and submucosal inflammation was evident in the forestomach of animals of either sex treated with 1000 and 300 mg/kg bw/day. The stomach changes identified in 1000 and 300 mg/kg bw/day animals were considered to be a result of local irritation of the test item rather than a true effect of systemic toxicity.

Lungs:increased incidence and severity of alveolar macrophages were evident in animals of either sex treated with 1000 mg/kg bw/day and in females treated with 100 mg/kg bw/day. This observation is considered to be a result of local irritation following inhalation of microdroplets of the test compound as the gavage catheter was withdrawn. The absence of the finding at 300 mg/kg bw/day is further evidence that this is a procedure-related finding and as such, it is of limited toxicological significance.
Histopathological findings: neoplastic:
not specified
Details on results:
Necropsy and Gross Pathological Findings:
A mass surrounding the heart and lungs and a fluid filled vagina was found in one female treated with 1000 mg/kg bw due to an abscess in the heart, granuloma in the lungs and a dilated lumen in the uterus. One control female, one female treated with 100 mg/kg bw/day, two females and one male treated with 300 mg/kg bw/day and four females treated with 1000 mg/kg bw/day had reddened lungs at necropsy. At microscopic examination, the treated animals were shown to have congestion in the lungs. Although there was an increased incidence/severity of congestion in the lungs the intergroup differences were considered to be within the normal range of background alterations that are seen in untreated animals of this age and strain and therefore was considered an incidental finding, not related to the treatments.

Histopathology:
The following treatment related microscopic abnormalities were detected:

Kidneys:increased incidence and severity of hyaline droplets and granular casts (consistent with alpha-2u-globulin nephropathy) were evident in males from all treatment groups. Although the findings of granular casts in the male kidney may be considered to represent an adverse effect of the test item, immunohistochemical staining demonstrated that these changes were correlated to accumulation of alpha 2u-globulin and formation of hyaline droplets, 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 effects in humans.

Granular casts may be considered to represent an adverse effect of the test item, however immunohistochemical staining demonstrated that these changes within the kidneys was correlated to the same condition as hyaline droplets therefore the kidney changes were considered to be of limited toxicological significance.

Stomach: Acanthosis, hyperkeratosis, ulceration and submucosal inflammation was evident in the forestomach of animals of either sex treated with 1000 and 300 mg/kg bw/day. The stomach changes identified in 1000 and 300 mg/kg bw/day animals were considered to be a result of local irritation of the test item rather than a true effect of systemic toxicity.

Lungs:increased incidence and severity of alveolar macrophages were evident in animals of either sex treated with 1000 mg/kg bw/day and in females treated with 100 mg/kg bw/day. This observation is considered to be a result of local irritation following inhalation of microdroplets of the test compound as the gavage catheter was withdrawn. The absence of the finding at 300 mg/kg bw/day is further evidence that this is a procedure-related finding and as such, it is of limited toxicological significance.

Organ Weights:
Males treated 1000 mg/kg bw/day and females from all treatment groups showed a statistically significant increase in liver weight both absolute and relative to terminal body weight (p<0.01; males, p<0.05; females). Although a number of the individual values were outside of the normal background range, no true dose related response for females was evident. In the absence of any associated histopathological correlates, the intergroup differences were therefore considered of no toxicological importance.

Males treated with 1000 mg/kg bw/day showed a statistically significant reduction in epididymides weight both absolute and relative to terminal body weight (p<0.05). All of the individual values were within the normal backgroundrange and in the absence of any associated histopathological correlates the intergroup difference was considered to be of no toxicological significance.

Clinical Biochemistry:
There were no toxicologically significant effects detected in the blood chemical parameters examined.

Males treated with 1000 mg/kg bw/day showed a statistically significant increase in alanine aminotransferase and females from this treatment group showed a statistically significant increase in urea (p<0.01). The majority of individual values
for these parameters were within the normal background ranges and in the absence of any associated histopathological correlates the intergroup differences were considered to be of no toxicological significance.

Males from all treatment groups showed statistically significant reductions in sodium concentration (p<0.05), potassium concentration (p<0.05) and chloride concentration (p<0.05) and a statistically significant increase in inorganic phosphorus
(p<0.05). Males treated with 100 mg/kg bw/day also showed a statistically significant increase in bilirubin (p<0.01). Females treated with 1000 and 300 mg/kg bw/day showed a statistically significantincrease in glucose (p<0.05). The majority of individual values for these parameters were within the normal background ranges and in the absence of true doserelated responses the intergroup differences were considered to be of no toxicological significance.

Hematology:
Males from all treatment groups showed a statistically significant increase in mean corpuscular hemoglobin concentration (p<0.05). The majority of individual values were within the normal background range and in the absence of a true dose related responsethe intergroup differences were considered to be of no toxicological significance.

Functional Performance Tests:
There were no toxicologically significant changes in functional performance at dosages of 100, 300 or 1000 mg/kg bw/day.

Males from all treatment groups and females treated with 1000 and 300 mg/kg bw/day showed a statistically significant reduction in overall activity when compared with controls (p<0.05-0.01). Females treated with 1000 and 300 mg/kg bw/day also showed a statistically significant reduction in activity during the final 20% period of observation (p<0.05). In the absence of a true dose related response and/orany supporting clinical observations to suggest an effect of neurotoxicity, the intergroup differences were considered to be of no toxicological significance.

Males treated with 1000 mg/kg bw/day showed a statistically significant reduction (p<0.05) in the first fore limb and hind limb grip strength test and a statistically significant increase in the final hind limb grip strength test. In the absence of a consistent effect or any supporting clinical observations to suggest an effect of neurotoxicity, the intergroup differences were considered to be of no toxicological significance.

Effect levels

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on treatment related effects in males from all treatment groups and in females treated with 1000 and 300 mg/kg bw/day. The No Observed Effect Level (NOEL) was not established for males.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the fact that the findings in lungs and stomach were not considered to reflect true systemic toxicity. The kidney findings in males are species and sex specific and are not relevant for human health.

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Table 1. Group Mean Functional Performance Test Values - Males

Group

(sex)

 

Test 1 Forelimb

(g)

Test 1 Hindlimb

(g)

Test 2 Forelimb

(g)

Test 2 Hindlimb

(g)

Test 3 Forelimb

(g)

Test 3 Hindlimb

(g)

Overall

Activity

Overall Mobile

Last 20%

Activity

Last 20% Mobile

1 (M)

Mean

1234.3

432.8

1157.1

406.0

1022.3

347.1

1093.8

1.8

137.7

0.2n

S.D.

240.7

107.7

285.2

62.1

162.9

99.5

300.2

1.9

118.4

0.4

N

10

10

10

10

10

10

10

10

10

10

 

2 (M)

Mean

1067.0

385.9

1093.5

377.3

1060.0

425.2

797.6**

0.4

49.2

0.0n

S.D.

276.5

116.5

300.8

98.2

243.1

95.1

225.2

0.5

62.4

0.0

N

10

10

10

10

10

10

10

10

10

10

 

3 (M)

Mean

1217.5

425.3

1084.0

422.4

1069.8

405.6

862.5**

1.1

87.7

0.0n

S.D.

237.5

104.6

276.5

134.2

195.5

74.4

149.0

1.6

81.4

0.0

N

10

10

10

10

10

10

10

10

10

10

 

4 (M)

Mean

943.8*

325.8*

1101.5

446.0

990.0

442.2*

820.7*

1.0

72.4

0.0n

S.D.

186.3

84.6

198.7

128.5

178.7

127.1

248.2

2.2

58.5

0.0

N

10

10

10

10

10

10

10

10

10

10

General Footnote: Unit = Time (seconds) for Motor Activity Assessments

Dose Levels: Group 1 - 0(Control); Group 2 - 100 mg/kg bw/day; Group 3 - 300 mg/kg bw/day; Group 4 - 1000 mg/kg bw/day

 

Table 2. Group Mean Functional Performance Test Values - Females

Group

(sex)

 

Test 1 Forelimb

(g)

Test 1 Hindlimb

(g)

Test 2 Forelimb

(g)

Test 2 Hindlimb

(g)

Test 3 Forelimb

(g)

Test 3 Hindlimb

(g)

Overall

Activity

Overall Mobile

Last 20%

Activity

Last 20% Mobile

1 (F)

Mean

966.3

309.4

866.0

293.4

904.5

291.9

803.1

5.3

122.1

1.2

S.D.

255.2

73.7

185.3

97.7

174.1

66.4

266.0

9.9

113.4

2.6

N

10

10

10

10

10

10

10

10

10

10

 

2 (F)

Mean

992.2

238.8

1004.0

232.4

963.2

308.4

724.2

6.2

89.7

2.0

S.D.

224.9

68.5

191.6

95.7

174.6

124.4

619.7

17.9

168.6

6.3

N

10

10

10

10

10

10

10

10

10

10

 

3 (F)

Mean

985.6

242.3

1011.2

288.3

857.3

255.6

498.4*

1.3

33.3*

0.1

S.D.

147.0

93.5

182.1

74.4

183.1

115.0

256.0

2.1

50.5

0.3

N

10

10

10

10

10

10

10

10

10

10

 

4 (F)

Mean

1024.5

302.9

936.2

296.9

1040.8

288.9

544.5*

1.8

22.0*

0.2

S.D.

175.2

108.5

258.3

109.4

293.8

89.6

201.7

1.3

33.7

0.6

N

10

10

10

10

10

10

10

10

10

10

General Footnote: Unit = Time (seconds) for Motor Activity Assessments

Dose Levels: Group 1 - 0(Control); Group 2 - 100 mg/kg bw/day; Group 3 - 300 mg/kg bw/day; Group 4 - 1000 mg/kg bw/day

Table 3. Group Mean Hematological Values - Males

Group (sex)

 

MCHC (g/dL)

Group 1 (0 – Control)

Mean

33.83

S.D.

0.18

N

10

 

Group 2 (100 mg/Kg bw/day)

Mean

34.38*

S.D.

0.46

N

10

 

Group 3 (300 mg/Kg bw/day)

Mean

34.02*

S.D.

0.28

N

10

 

Group 4 (1000 mg/Kg bw/day)

Mean

34.23*

S.D.

0.4

N

10

Table 4. Group Mean Blood Chemical Values - Males

Group

(sex)

 

Na+

mmol/L

K+

mmol/L

Cl-

mmol/L

P

mmol/L

ALAT

IU/L

Bili

mg/dL

Group 1

(0 – Control)

Mean

150.7

4.713

102.6

1.70

55.5

0.090

S.D.

2.1

0.291

1.4

0.19

10.7

0.012

N

10

10

10

10

10

10

 

Group 2

(100 mg/Kg bw/day)

Mean

147.6*

4.410*

100.6*

1.95*

58.6

0.165**

S.D.

1.7

0.264

1.3

0.15

10.3

0.063

N

10

10

10

10

10

10

 

Group 3

(300 mg/Kg bw/day)

Mean

148.6*

4.489*

101.4*

1.91*

92.7

0.099

S.D.

3.9

0.373

1.9

0.17

111.6

0.014

N

10

10

10

10

10

10

 

Group 4

(1000 mg/Kg bw/day)

Mean

148.7*

4.429*

101.4*

1.91*

66.7*

0.092

S.D.

1.5

0.196

1.3

0.24

8.9

0.008

N

10

10

10

10

10

10

 

Table 5. Group Mean Blood Chemical Values - Females

Group (sex)

 

Urea (mg/dL)

Glucose (mg/dL)

Group 1

(0 – Control)

Mean

38.1

123.7

S.D.

5.7

18.4

N

10

10

 

Group 2

(100 mg/Kg bw/day)

Mean

40.9

121.9

S.D.

7.3

15.8

N

10

10

 

Group 3

(300 mg/Kg bw/day)

Mean

39.6

145.4*

S.D.

6.1

17.2

N

10

10

 

Group 4

(1000 mg/Kg bw/day)

Mean

47.3**

137.0*

S.D.

4.7

17.0

N

10

10

Table 6. Group Mean Organ Weights with Corresponding Relative (% of Body Weight) Organ Weights

 

 

Males

Females

0

Control

100

mg/Kg bw/day

300

mg/Kg bw/day

1000

mg/Kg bw/day

0

Control

100

mg/Kg bw/day

300

mg/Kg bw/day

1000

mg/Kg bw/day

Epididymides

Mean (g)

1.73769

1.66163

1.64448

1.60713*

 

 

 

 

S.D.

0.16852

0.16045

0.10688

0.12939

 

 

 

 

N

10

10

10

10

 

 

 

 

 

 

 

 

 

 

 

 

 

Mean (%)

0.430

0.395

0.392

0.387*

 

 

 

 

S.D.

0.037

0.067

0.027

0.035

 

 

 

 

N

10

10

10

10

 

 

 

 

 

Liver

Mean (g)

12.6953

13.8934

14.0717

15.1921**

8.37888

8.68144*

8.55061*

8.88699*

S.D.

2.20822

2.07704

0.84560

1.33677

0.65274

0.87496

0.77236

0.95142

N

10

10

10

10

10

10

10

10

 

 

 

 

 

 

 

 

 

Mean (%)

3.120

3.246

3.347

3.652**

3.345

3.605*

3.468*

3.591*

S.D.

0.314

0.244

0.102

0.298

0.286

0.080

0.224

0.214

N

10

10

10

10

10

10

10

10

 

Table 7. Summary Incidence of Necropsy Findings - Males

 

Males

0

Control

100

mg/Kg bw/day

300

mg/Kg bw/day

1000

mg/Kg bw/day

Number of animals examined

10

10

10

10

Lungs (With Bronchi)

 

Submitted

(10)

(10)

(10)

(10)

No Visible Lesions

10

10

9

10

Reddened

0

0

1

0

 

Table 8. Summary Incidence of Necropsy Findings - Females

 

Females

0

Control

100

mg/Kg bw/day

300

mg/Kg bw/day

1000

mg/Kg bw/day

Number of animals examined

10

10

10

10

Heart

 

Submitted

(10)

(10)

(10)

(10)

No Visible Lesions

10

10

10

9

Mass

0

0

0

1

 

Lungs (With Bronchi)

 

Submitted

(10)

(10)

(10)

(10)

No Visible Lesions

9

9

8

5

Discolouration; Red

1

0

2

4

Reddened

0

1

0

0

Mass

0

0

0

1

 

Vagina

 

Submitted

(10)

(10)

(10)

(10)

No Visible Lesions

10

10

10

9

Fluid Filled

0

0

0

1

Applicant's summary and conclusion

Conclusions:
Based on the results of the study, the No Observed Effect Level (NOEL) was considered to be 100 mg/kg bw/day for females and was not established for males. The No Observed Adverse Effect Level (NOAEL) was established at 1000 mg/kg bw/day for females and males because the findings were either not considered to reflect true systemic toxicity or were not relevant for human health.
Executive summary:

The test material Oct-1-ene CAS 111-66-0 was administrated orally to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day for 90 consecutive days. The results showed treatment - related effects in males of all dose groups and females treated with 1000 and 300 mg/kg bw.

Pathology examination showed increased incidence and severity of hyaline droplets and granular casts (consistent with alpha-2u-globulin nephropathy) in kidneys of males from all treatment groups. The presence of alpha-2-microglobulin was confirmed histochemically. This finding is species and sex specific and is not considered relevant for human health. Acanthosis, hyperkeratosis and submucosal inflammation was evident in the forestomach of animals of either sex treated with 1000 and 300 mg/kg bw/day. This finding is a result of local irritation. Alveolar macrophages were observed in animals of either sex treated with 1000 mg/kg bw/day and in females treated with 300 mg/kg bw/day. This finding is considered to be a result of local irritation following inhalation of micro droplets of the test compound (gavage route exposure) and, therefore, are not considered related to the treatment.

Based on the results of the study, the No Observed Effect Level (NOEL) was considered to be 100 mg/kg bw/day for females and was not established for males. The No Observed Adverse Effect Level (NOAEL) was established at 1000 mg/kg bw/day for females and males because the findings were either not evidence of true systemic toxicity or were not relevant for human health.