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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1993-12-09 to 1994-07-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was conducted according to OECD 422 and was GLP compliant.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Blended from equal amounts of Neodene 14 alpha olefin, alpha olefin C14 1-tetradecene, and 1-tetradecene Gulftene 14
- Substance type: C14 alpha olefin
- Physical state: Clear colourless liquid
- Analytical purity: 99.0% to 99.98%
- Lot/batch No.: Neodene 14 alpha olefin 20202-45-1050, alpha olefin C14 1-tetradecene 300-954, and 1-tetradecene Gulftene 14 CBN0048
- Expiration date of the lot/batch: Only provided for Neodene 14 alpha olefin, 1994-12
- Storage condition of test material: Room temperature under nitrogen

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Portage, Michigan
- Age at study initiation: Males were 6 weeks old and females were 8 weeks old.
- Weight at study initiation: Males: 159 to 220 grams; satellite females: 184 to 242; breeding females: 158 to 215
- Fasting period before study: None
- Housing: Individually except during cohabitation; males were housed 2-3 per cage during the first 4 days of acclimation
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 11 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 to 25 °C
- Humidity (%): 21 to 79%
- Air changes (per hr): 10 to 12
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light


IN-LIFE DATES: From:1994-03-17 To: 1994-05-03

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: After stirring the blended test material for 15 minutes, a specified amount of test material was added to a flask with half of the corn oil. The flasks were capped and inverted several times, then the remaining corn oil was added and the procedure repeated. The solution was then stirred for 15 minutes. Preparations were kept for a maximum of 28 days.

VEHICLE
- Concentration in vehicle: 0, 20, 100, or 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): APR0695A, OCT0494A, and DEC2194A
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Top, middle, and bottom samples of a 20 and 200 mg/mL dose formulation were tested to determine homogeneity. All samples were within 6% of the nominal concentration indicating that the dose formulations were homogeneous. Stability was tested on the 20 and 200 mg/mL dose formulation stored in the refrigerator and sampled at 3, 8, 15, and 29 days. The dose formulations were found to be stable under these conditions with all samples within 7% of the nominal value. All dose formulations were tested during weeks 1, 3, and 7 and were all found to be within 4% of the nominal concentration.
Duration of treatment / exposure:
Males: 43 to 47 days; female satellite group: 46 to 47 days; female breeding group: 42 to 51 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 500, 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
12 males per dose; 12 females in the breeding group per dose; 8 satellite females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were selected based on a range-finding study
- Rationale for selecting satellite groups: Satellite females were selected so that the study could be used as a short-term repeated dose study as well as a reproductive/developmental screening study.
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once daily except mortality which was checked twice a day.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly and in pregnant rats on day 0, 7, 14, and 20 of gestation and day 1 and 4 of lactation

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: On day 46 or 47
- Anaesthetic used for blood collection: Yes, light isoflurane
- Animals fasted: Yes
- How many animals: All males and satellite females
- Parameters checked in table 2 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On day 46 or 47
- Animals fasted: Yes
- How many animals: All males and satellite females
- Parameters checked in table 3 were examined.

URINALYSIS: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 4)
Other examinations:
Neurotoxicity and reproduction and development were also tested and are presented as separate study records. The liver, kidneys, testis/ovaries, adrenal glands, thymus, spleen, brain, and heart were weighed.
Statistics:
All continuous parameters were analyzed with a one-way ANOVA followed by either the Dunnett's test or a modified Dunnett's test. Count data were analyzed using a Chi-square test. All tests were two-tailed with a p<0.05.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: Clinical signs that were related to treatment included urine stains in all male treatment groups and mid- and high-dose females, post-dosing salivation and urine staining occurred in mid-dose males and breeding females and high-dose males and females. Salivation immediately prior to dosing was observed in high-dose breeding females.


BODY WEIGHT AND WEIGHT GAIN: There were no effects on body weight in any of the groups.


FOOD CONSUMPTION: There were no effects on food consumption.


HAEMATOLOGY:. Haematological changes possible related to treatment include a dose-related decrease in mean red blood cell count and haematocrit in =100 mg/kg/day females and decreased haemoglobin and MCV values in 1000 mg/kg/day females. Similar findings were observed in males; however, they were not statistically significant (Table 5).


CLINICAL CHEMISTRY:Minor but statistically significant clinical chemistry findings included increased ALT levels in =500 mg/kg/day males; decreased sodium levels in =100 mg/kg/day females; and increased cholesterol levels in =500mg/kg/day females (Table 6). The changes in ALT were minimal and would not be considered toxicologically significant except that changes in liver weight and histopathology were also observed, which could indicate a minor effect on the liver.


NEUROBEHAVIOUR: There were no effects on neurobehaviour.


ORGAN WEIGHTS: Increased absolute liver weights were observed in =500mg/kg/day males and females. Increased liver weights relative to brain weights were observed in =500mg/kg/day males and 1000 mg/kg/day females. In females there appears to be a dose-related increase in both absolute and relative to brain liver weights (Table 7).


GROSS PATHOLOGY:Pitted kidneys were observed in one mid-dose and one high-dose male.


HISTOPATHOLOGY: Hydrocarbon nephropathy evident by increased eosinophilic hyaline droplets in the proximal tubules was observed in ll male groups (=100 mg/kg/day). Microscopic examination of the liver revealed minimal to moderate hepatocellular vaculation in =500 mg/kg/day males and females (Table 8).



Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Clinical signs, haematology, clinical chemistry, organ weights, and histopathology
Dose descriptor:
other: No NOEL identified
Sex:
male
Basis for effect level:
other: Hydrocarbon nephropathy was observed at all dose levels. A systemic toxicity NOAEL and/or LOAEL could not be determined because the effect of hydrocarbon nephropathy may interfere with the outcome of other endpoint
Remarks on result:
not measured/tested
Remarks:
Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 Table 5. Haematology data

Summary of Haematology Data (mean ± s.d.)

 

Males - mg/kg/day (n)

0 (8)

100 (8)

500 (8)

1000 (8)

Erythrocytes (106/CMM)

8.588±0.4291

8.400±0.4899

8.400±0.3117

8.113±0.5939

Haemoglobin (g/dL)

16.24±0.447

16.01±0.804

15.74±0.737

15.69±1.346

Haematocrit (%)

46.64±1.014

45.34±2.523

44.33±2.180

43.86±3.609

MCV (FL)

54.40±1.943

54.00±1.108

52.76±1.752

54.06±1.122

 

Females - mg/kg/day (n)

0 (8)

100 (8)

500 (8)

1000 (8)

Erythrocytes (106/CMM)

8.663±0.2504

8.113±0.4190 *

8.063±0.5290 *

7.925±0.3536 #

Haemoglobin (g/dL)

16.38±0.271

15.70±0.719

15.36±1.004

15.11±0.511 #

Haematocrit (%)

46.73±0.855

44.10±1.831 *

42.91±2.606 *

41.24±1.687 #

MCV (FL)

53.98±1.334

54.38±1.053

53.23±0.833

52.05±1.244 *

Significantly different from the control *=p<0.05; **=p<0.01; # =p<0.001

 

Table 6 Clinical Chemistry Data

Summary of Clinical Chemistry Data (mean ± s.d.)

 

Males - mg/kg/day (n)

0 (8)

100 (8)

500 (8)

1000 (8)

ALT (IU/L)

27.9±2.22

30.7±5.18

41.2±6.60 **

39.1±7.65 *

Sodium (MEQ/L)

142.5±2.90

140.9±1.27

140.6±2.04

141.3±1.76

Cholesterol (mg/dL)

42.6±6.60

40.1±6.28

50.6±11.27

44.6±9.73

 

Females - mg/kg/day (n)

0 (8)

100 (8)

500 (8)

1000 (8)

ALT (IU/L)

44.7±25.60

39.6±30.68

34.6±9.70

43.9±8.51

Sodium (MEQ/L)

143.9±2.79

140.2±2.21 *

140.4±1.21 *

140.1±1.71 *

Cholesterol (mg/dL)

36.5±10.04

39.1±7.22

49.1±9.05 *

71.5±9.59 #

Significantly different from the control *=p<0.05; **=p<0.01; # =p<0.001

 

Table 7. Liver Weight Data

Summary of Liver Weight Data (mean ± s.d.)

 

Males - mg/kg/day (n)

0 (8)

100 (8)

500 (8)

1000 (8)

Absolute liver weight

15.70±2.159

16.98±2.043

18.44±2.017 *

18.29±0.756 *

Liver to brain weight

697.55±69.952

746.03±71.448

800.84±82.540 *

788.87±56.956 *

 

Females - mg/kg/day (n)

0 (8)

100 (8)

500 (8)

1000 (8)

Absolute liver weight

9.93±0.913

10.76±1.208

11.83±1.312 *

12.90±1.491 **

Liver to brain weight

474.17±51.143

504.49±55.374

542.45±60.928

596.20±73.855 **

Significantly different from the control *=p<0.05; **=p<0.01; # =p<0.001

Table 8. Histopathology

 

Histopathology Incidence

 

Males - mg/kg/day

0

100

500

1000

Kidney- hyaline droplets in the proximal convoluted tubules

1/8

4/8

3/8

4/8

Liver- hepatocyte vacuolation, multifocal

1/8

1/8

3/8

3/8

 

Females - mg/kg/day

0

100

500

1000

Kidney- hyaline droplets in the proximal convoluted tubules

0/8

0/8

0/8

0/8

Liver- hepatocyte vacuolation, multifocal

0/8

1/8

2/8

4/8

 

Applicant's summary and conclusion

Conclusions:
A systemic toxicity LOEL of 500 mg/kg/day was established for the satellite females based on clinical signs, haematology, clinical chemistry, organ weight, and histopathology changes in the liver. A NOEL of 100 mg/kg/day was established for satellite females. The presence of large hyaline drops noted in the kidneys of paternal males at all dose levels suggests hydrocarbon nephropathy, which is a toxicological effect specific to male rats and is not considered a biologically relevant endpoint in humans. Therefore, a systemic toxicity NOEL and/or LOEL in males could not be determined because the effect of hydrocarbon nephropathy was observed at all dose levels.
Executive summary:

A screening study examining the systemic, reproductive, developmental, and neurotoxicity of 1-tetradecene was conducted with male and female rats. The test material, blended from equal amounts of Neodene 14 alpha olefin, alpha olefin C14 1 -tetradecene, and 1 -tetradecene Gulftene 14, was administered via gavage to Sprague-Dawley Crl:CDBR VAF/Plus rats (12 males and 20 females) at doses of 0, 100, 500, or 1000 mg/kg/day (administered at 5 mL/kg of a 0, 20, 100, or 200 mg/mL concentration). The females were separated into asatellite group of females used to determine systemic toxicity and neurotoxicity without breeding, while a separate group of breeding females was used to determine reproductive and developmental toxicity.   

 

With regard to systemic toxicity, increased salvation and urine staining were observed in =500mg/kg/day males and breeding females and in 1000 mg/kg/day satellite females.  Haematological changes included decreased mean red blood cell count and haematocrit in =100 mg/kg/day females and decreased haemoglobin and MCV values in 1000 mg/kg/day females. Similar findings were observed in males; however, they were not statistically significant. Minor but statistically significant clinical chemistry findings included increased ALT levels in =500 mg/kg/day males; decreased sodium levels in =100 mg/kg/day females; and increased cholesterol levels in =500mg/kg/day females. Hydrocarbon nephropathy was evident by pitted kidneys (=500 mg/kg/day) and increased eosinophilic hyaline droplets in the proximal tubules (=100 mg/kg/day) in all male treatment groups. Increased absolute liver weights were observed in =500mg/kg/day males and females. Increased liver weights relative to brain weights were observed in =500mg/kg/day males and 1000 mg/kg/day females.  Microscopic examination of the liver revealed minimal to moderate hepatocellular vaculation in =500 mg/kg/day males and females.Results indicate possible minimal effects on the blood and liver.

 

There were no neurotoxicity findings in either sex. Females used for the reproductive and developmental study showed increased urine staining and salivation at =500 mg/kg/day. There was no evidence of reproductive/developmental toxicity in males used for breeding, dams, or pups.

 

A systemic toxicity LOEL of 500 mg/kg/day was established for the satellite females based on clinical signs, haematology, clinical chemistry, organ weight, and histopathology changes in the liver. A NOEL of 100 mg/kg/day was established for satellite females. The presence of large hyaline drops noted in the kidneys of paternal males at all dose levels suggests hydrocarbon nephropathy, which is a toxicological effect specific to male rats and is not considered a biologically relevant endpoint in humans. Therefore, a systemic toxicity NOEL and/or LOEL in males could not be determined because the effect of hydrocarbon nephropathy was observed at all dose levels.

 

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was conducted according to OECD 422 guidelines and was GLP compliant.