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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
29 May 1998 to 26 June 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study. The original study was reliability 1. Read across to the registered substance is considered scientifically justified and reliabiltiy 2.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
(no functional observations; limited pathological examination)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
Alcohols, C10-16
EC Number:
267-019-6
EC Name:
Alcohols, C10-16
Cas Number:
67762-41-8
IUPAC Name:
tetradecan-1-ol
Details on test material:
- Name of test material (as cited in study report): Compound 33A (Safol 23). Equivalent to Alcohols, C12-13-branched and linear (CAS 740817-83-8).
- Substance type: technical product
- Physical state: colourless liquid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: mixture of C12-C13 alcohols
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: KPT/SAS/DA/2/98
- Expiration date of the lot/batch: no data
- Stability under test conditions: stable in the vehicle (corn oil) when stored at 2-10oC for 7 days
- Storage condition of test material: in refrigerator

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 5 weeks
- Weight at study initiation: males, 144.2-171.6 g (mean 159.3 g); females, 114.4-134.8 g (124.7 g)
- Fasting period before study: no data
- Housing: in groups of 5 in stainless steel cages with mesh floors
- Diet (e.g. ad libitum): conventional, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5-25.0
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 29-May-1998 To: 26-Jun-1998

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: prepared in corn oil; concentration adjusted to give a constant dosing volume of 5 ml/kg bw. Twice per week the dose volumes were adjusted to the latest body weight of each individual animal. Fresh dosing solutions were prepared weekly.

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 0, 20, 60 or 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of the test material in corn oil were analysed using a Perkin Elmer 8700 gas chromatograph with flame ionisation detection on day of preparation and after 7 days storage in a refrigerator.
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily (7 days/week)
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300 or 1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on a 7-day range-finding study
- Rationale for animal assignment (if not random): animals were weighed of first day of treatment and allocated to the various groups proportionally to weight class by a computer randomization program
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (once daily at weekends)
- Cage side observations included: all abnormalities, signs of ill health and reactions to treatment

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 4, 11, 14, 18, 21, 25, 27 and 28

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination on day 28
- Anaesthetic used for blood collection: Yes, ether
- Animals fasted: Yes
- How many animals: all groups
- Parameters examined: haemoglobin, packed cell volume, red blood cell count, reticulocytes, total white blood cell count, differential white blood cell count, prothrombin time, thrombocyte count. Mean corpuscular volume, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration were calculated.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination on day 28
- Animals fasted: Yes
- How many animals: all groups
- Parameters examined: alkaline phosphatase (ALP), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma glutamyl transferase (GGT), total protein, albumin , albumin/globulin ratio, urea, creatinine, fasting glucose, bilirubin, cholesterol, triglycerides, phospholipids, calcium, sodium, chloride, inorganic phosphate

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Full necropsy performed. Due to some difficulties during dosing it was decided to remove, examine and sample the oesophagus from all animals. However these samples were not processed for histopathological examination.
- Organ weights: adrenals, brain, kidneys, liver, spleen, testes

HISTOPATHOLOGY: Yes. Adrenals, heart, kidneys, liver, spleen, testes and gross lesions from all control and high dose animals.
Statistics:
Body weights: one-way analysis of covariance (covariate body wt day 0)  followed by Dunnetts multiple comparision tests
Food consumption: no statistics
Haematological parameters: one-way analysis of covariance (ANOVA) followed by Dunnetts multiple comparision tests. 
Differential WBC:  Kruskal-Wallis non-parametric ANOVA followed by Mann-Whitney U-tests.
Histopathology: Fishers exact probability test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
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):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
At the high-dose most males (80%) and all females showed thinly haired areas of skin (probably due to hair nibbling). 3/5 high-dose males showed weakness, thin appearance and respiratory disorders, one of these died on day 27, probably due to faulty dosing. High-dose animals in particular showed some resistance to dosing. A few rats regurgitated the test material immediately after dosing. No other clinical signs were attributed to the test material.

BODY WEIGHT AND WEIGHT GAIN
The high-dose males showed a reduction in mean body weight which reached statistical significance in the first and last weeks of the study (p<0.05). On day 27 the mean body weight of the control males was 269 g while the mean body weight of the high-dose males was 232 g.

FOOD CONSUMPTION AND COMPOUND INTAKE
Food consumption was decreased in the high-dose males compared to the controls [control 17.3 g/rat per day; high-dose 14.4 g/rat per day].

FOOD EFFICIENCY
Food efficiency was decreased in the high-dose males compared to the controls [control mean 0.23 g wt gain/g food consumed; high-dose 0.17 g wt gain/g food consumed, the value for week 4 in the high-dose group was -0.01 g wt gain/g food consumed].

HAEMATOLOGY
High-dose females: thrombocyte count was significantly reduced [control 1185 x 10E9/l; high-dose 1066 x 10E9/l (p<0.01)] and the absolute number of monocytes was increased [control 0 x 10E9/l; treated 0.04 x 10E9/l (p<0.05)].
Mid-dose males: mean corpuscular haemoglobin was significantly reduced [control 1.34 fmol; test 1.26 fmol (p<0.05)]. [The investigators considered this to be "fortuitous" presumably because of the lack of effect at the high dose.]
No other changes were evident.

CLINICAL CHEMISTRY
Significant increases in high-dose females for plasma ALP [control mean 101 U/l; high dose 150 U/l p<0.05], ALAT [control mean 27 U/l; high-dose mean 39 U/l (p<0.05)] and cholesterol [control mean 1.73 mmol/l; high-dose mean 2.21 mmol/l (p<0.01)]. A reduction in the albumin/globulin ratio was seen in high dose males [control mean ratio 1.05, high-dose mean ratio 0.88 (p<0.05)]. There were no other differences between the groups for the parameters analysed.

ORGAN WEIGHTS
There was a dose-related statistically significant increase in relative kidney weight in mid- and high-dose males [controls 6.80 g/kg bw; low-dose 7.15 g/kg bw; mid-dose 7.31 g/kg bw (p<0.05); high-dose 7.80 g/kg bw (p<0.01)]. Absolute kidney weights showed no significant change from controls. There were no other significant changes in absolute or relative organ weights.

GROSS PATHOLOGY
Pathological changes in two high-dose males (hydrothorax & spotted lungs in the animal which died) and a grossly abnormal thoracic cavity filled with fibrin in another male were considered by the investigators to have been associated with the dosing procedure .

HISTOPATHOLOGY: NON-NEOPLASTIC
Pleuritis and severe haemorrhage of the lungs were present in the rat that died before study termination, suggesting that the test material had come into contact with the lungs during dosing. In the two other high-dose males showing clinical signs of distress, there was evidence of pericarditis in one animal and pericarditis with myocarditis and inflammation of the thoracic wall muscles was observed in the other. These changes were attributed to the administration procedure. There were no other treatment-related histopathological changes.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: kidney weight increased in males at 300 and 1000 mg/kg bw/day, but no accompanying clinical chemistry or pathological findings

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a reliable study, conducted to OECD guideline 407, an NOAEL of 300 mg/kg bw/day was established for Compound 33A (a mixture of C12-C13 alcohols). The study was performed in compliance with GLP.