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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:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study reasonably well documented, meets generally accepted scientific principles, acceptable for assessment of the limited parameters assessed, on a related material

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1966
Report Date:
1966

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Rats treated via the diet for 90 days with limited evaluation
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Alfol 6 (tradename)
- Molecular formula (if other than submission substance): C6-H14-O
- Molecular weight (if other than submission substance): 102.176
- Smiles notation (if other than submission substance): C(CCC)CCO
- InChl (if other than submission substance): 1/C6H14O/c1-2-3-4-5-6-7/h7H,2-6H2,1H3
- Structural formula attached as image file (if other than submission substance): see Fig 1.
- Substance type: colourless liquid with "viscosity of fine household oil"
- Physical state: liquid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: 601-6544 and 601-6545 from Continental Oil Company, USA
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other:
- Specific gravity: 0.823

Test animals

Species:
rat
Strain:
other: albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: no data but "young"
- Weight at study initiation: males 103.6 g, females 90.5 g
- Fasting period before study: no data
- Housing: individually in suspended wire-mesh cages
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data but "controlled within narrow limits"
- Humidity (%): no data but "controlled within narrow limits"
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): basal laboratory diet (Purina Laboratory Chow)
- Storage temperature of food: no data
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
continuous in diet
Doses / concentrations
Remarks:
Doses / Concentrations:
0.25%, 0.50%, 1.0-6.0%
Basis:
nominal in diet
No. of animals per sex per dose:
10 (treated), 20 (controls)
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: no satellite groups
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 5 days/week
- Cage side observations included: general physical appearance, gross signs of systemic toxicity and/or pharmacological effect, behaviour, mortality

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: days 30 and 90
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5/sex per group
- Parameters examined: microhaematocrit, haemoglobin, total and differential leukocyte count

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for collection of urine: days 30 and 90
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- How many animals: 5/sex per group (samples pooled)
- Parameters examined: albumin, acetone, bilirubin, colour, occult blood, sugar, pH, appearance, microscopic examination of sediment

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: brain, thyroid, heart, liver, spleen, kidneys, adrenals, gonads (testes or ovaries)

HISTOPATHOLOGY: Yes
- brain, thyroid, parathyroid, heart, lung, liver, spleen, stomach, small intestine, large intestine, pancreas, kidney, urinary bladder, adrenal, gonad, lymph node, bone, bone marrow
- all listed tissues from 5/sex from high dose and controls examined
Other examinations:
none
Statistics:
Chi-squared test for comparing relative organ weights (but see 'Any other information on materials and methods')

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
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:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- one male in low dose group died during week 9; cause of death was said to be unrelated to treatment
- occasional bloody encrustations of the eyes and nose
- otherwise no effects

BODY WEIGHT
- no effects

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- food consumption 87.8% of controls in females in high dose group during week 13
- otherwise no effects

FOOD EFFICIENCY
- not examined

WATER CONSUMPTION
- not examined

OPHTHALMOSCOPIC EXAMINATION
- not examined

HAEMATOLOGY
- no effects other than "occasional aberrant value"

CLINICAL CHEMISTRY
- not examined

URINALYSIS
- high albumin, positive findings for occult blood; but no differences between treated and control groups

NEUROBEHAVIOUR
- not examined

ORGAN WEIGHTS
- some statistically significant effects (but see 'Remarks on results')

GROSS PATHOLOGY
- no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
- no effects

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- no effects

HISTORICAL CONTROL DATA (if applicable)
- no data

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 127 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
1 243 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX (means calculated from individual weekly dietary intake data)
0.25% M 182 mg/kg/day; F 216 mg/kg/day
0.5% M 374 mg/kg/day; F 427 mg/kg/day
1% M 1127 mg/kg/day; F 1243 mg/kg/day

Organ weights: The original report indicates that there were significant differences in some relative organ weights from treated groups compared 

to controls. These were reanalysed by the Weinberg Group using the Tukey test which indicated that only the increased heart weight in mid dose 

males remained significant. The significant changes found in  the original report together with the results of the Weinberg analysis are summarisedbelow.

Organ Sex Orig sig. Weinberg report
Heart M   mid-dose  Significant
Spleen M high dose   Not significant
  F    high dose  Not significant
  F     low dose   Not significant
Gonads M all levels    Not significant

Additionally Weinberg reanalysed the organ weight data for the liver, kidney, adrenal, brain and thyroid none of which showed significant changes in

the original statistical analysis. There were no significant changes except in the thyroid weight which showed a significant increase in top dose 

males according to the Weinberg analysis.

Statistical results are not reported in detail, while individual animal data are reported means are not given. Using this data to calculate the mean 

and SD for the organ weight changes originally reported as  significant (see table above) the magnitude of the changes is a follows:

Spleen weight mean relative:

  Control Low Mid High
Males 0.185 0.175  0.19  0.199*
SD  0.044 0.008 0.028 0.047
Females 0.189 0.223* 0.189 0.217*
SD 0.018 0.036 0.01 0.02

Gonad weight mean relative: 

Control Low Mid High
Males 0.793 0.809* 0.814* 0.804*
SD 0.062 0.007 0.079  0.075


Heart weight mean relative: 

  Control Low Mid High
Males 0.296 0.268 0.331*+ 0.328
SD 0.005 0.002 0.074 0.041


*Significant using Chi square test as reported in original report.  +Significant in Tukey test.

STATISTICAL RESULTS: Original organ weight analyses using the Chi square  test were supplemented by Tukey tests carried out by the Weinberg 

group.


Applicant's summary and conclusion

Conclusions:
In a reliable study, the NOAEL for Alfol 6 in rats following 13 weeks dietary exposure was 1127 mg/kg bw/day for males and 1243 mg/kg bw/day for females (highest doses tested).
Executive summary:

[In view of the structural and chemical similarities, it is considered that the results of this study can be used for read-across to Alcohols C9 -11 linear and branched.]