Alcohols, C12-14

Repeated dose toxicity: other routes

Administrative data

Endpoint:

sub-chronic toxicity: other route

Type of information:

other: published data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1966

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Method: other: See Examinations

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hexan-1-ol

EC Number:

203-852-3

EC Name:

Hexan-1-ol

Cas Number:

111-27-3

IUPAC Name:

hexan-1-ol

Details on test material:

- Name of test material (as cited in study report): Alfol 6 (tradename)- 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:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ORGANISMS
- Age: 5 months
- Weight at study initiation: M4.77-8.97 kg; F4.31-7.95 kg
- Number of animals: 2M+2F treated; 4M+5F controls

Administration / exposure

Route of administration:

other: dietary at 0.5 & 1% (low & mid dose), high dose 1000 mg/kg/day by capsule

Vehicle:

unchanged (no vehicle)

Details on exposure:

ADMINISTRATION / EXPOSURE
- Duration of test/exposure: 13 weeks
- Type of exposure: 0.5% and 1% in the diet (low and mid dose) daily, 1000 mg/kg/day as a gelatin capsule 6 days/week (high dose, dietary high dose was unpalatable).
- Post exposure period: None
- Vehicle: Diet, none for top dose level(gelatin capsule).
- Doses: 0.5 and 1% in diet, 1000 mg/kg by gelatin capsules.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

tdaily for dietary administration, 6 days/week via capsules.

Doses / concentrations

Remarks:

Doses / Concentrations:
00.5, 1.0% w/w and 1000 mg/kg/day

No. of animals per sex per dose:

Number of animals: 2M+2F treated; 4M+5F controls

Control animals:

yes, concurrent no treatment

Details on study design:

Post-exposure period: none

Examinations

Observations and examinations performed and frequency:

ADMINISTRATION / EXPOSURE
- Duration of test/exposure: 13 weeks
- Type of exposure: 0.5% and 1% in the diet (low and mid dose) daily, 1000 mg/kg/day as a gelatin capsule 6 days/week (high dose, dietary high dose was unpalatable).
- Post exposure period: None
- Vehicle: Diet, none for top dose level(gelatin capsule).
- Doses: 0.5 and 1% in diet, 1000 mg/kg by gelatin capsules.

CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: Daily 5 days/week. Complete physical examination, body temperature, pulse rate, reflexes, mucous membranes, auscultation pretreatment, 3, 6 & 13 weeks. ECG pretreatment, 3 and 13 weeks.
- Mortality: Daily (5 days/week?)
- Body weight: weekly
- Food consumption: weekly
- Water consumption: Not recorded.
- Ophthalmoscopic examination: Not recorded.
- Haematology: Total & differential leucocyte counts, Hb, haematocrit, erythrocyte sedimentation rate, prothrombin time measured pretreatment, 3, 6 and 13 weeks.
- Biochemistry: Plasma levels of glucose, total protein & albumin, albumin/globulin ratios, urea nitrogen measured pretreatment, 3, 6 and 13 weeks. Liver function assessed by BSP retention, alkaline phosphatase & ASAT at same time periods.
- Urinalysis: albumin, glucose, bilirubin, pH, vol. , specific gravity, microscopic examination of sediment, total nitrogen. Carried out pretreatemnt & at 3, 6 & 13 weeks.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
- Macroscopic: complete, organ weights determined for brain, thyroid, heart, liver, kidneys, adrenals, spleen, gonads.
- Microscopic: Brain, pituitary, sub-maxillary salivary gland, thyroid, parathyroid, heart, lung, liver, spleen, stomach (fundic & pyloric), small intestine (3 levels), large intestine, pancreas, gall bladder, kidney, urinary bladder, adrenal, gonads, lymph node (cervical & mesenteric), bone, bone marrow, muscle (striated). All fixed. Tissues from controls & high dose animals examined microscopically. Stomach & intestinal tissues from mid dose animals also examined plus any abnormal tissues identified at necropsy.

Other examinations:

ECG's showed no differences between the initial pattern recorded and those seen at 3 or 13 weeks.

Statistics:

No statistical analysis reported in the original report. For the HPV program the results were analysed using Tukey's Test.

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:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX
0.5% M 199 F 190 mg/kg/day
1% M 370 F 435 mg/kg/day
Top dose 1000 mg/kg/day

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
- Mortality and time to death: 1000 mg/kg both males died day 23 & 38. Both females died day 1 & day 38. Another female was
included which survived the 13 week exposure period. All control, lower & mid dose animals survived the exposure period.

- Clinical signs: 1000 mg/kd/day signs seen in all dogs, at some stage during the dosing period, were salivation, emesis, mild excitation, ataxia,
slight tremors and varying stages of anaesthesia (which preceded death in all animals which died). No specific clinical signs in lower dose or control animals.

- Body weight gain: No difference from control values for the low & mid dose groups.

- Food consumption: No difference from control values for the low & mid dose groups.

- Ophthalmoscopic examination: Not done
- Clinical chemistry, Haematology, Urinalysis: No apparent differences between treated and control groups.

- Organ weights: No difference from control values for the low & mid dose groups.

- Gross pathology: Lymph node hyperplasia in both control & treated animals considered due to roundworm infestation (despite routine deworming throughout the study). In all animals which died there was evidence that the dogs may have aspirated vomit while anaesthetised (as a result of exposure to Alfol 6), death resulting from respiratory crisis. There was evidence of food particles in the trachea and the respiratory system smelled of the test substance.

- Histopathology: In top dose (1000 mg/kg/day) animals and to a lesser extent in animals of the intermediate dose level there was evidence of gastro-intestinal irritation (mucosal hyperemia without ulceration or acute inflammatory reaction).
The 2 high dose males (both died) showed testicular atrophy while one high dose female which died showed decreased oogenesis, the ovaries of the female which surived exposure to the high dose level appeared within normal limits. Other than gastro-intestinal irritation in mid dose animals there were no other treatment related hisptopathological changes in dogs receiving 0.5 or 1% Alfol 6 in the diet.

- Other: ECG's showed no differences between the initial pattern recorded and those seen at 3 or 13 weeks.

STATISTICAL RESULTS: Analysis not carried out. Subsequent analysis of the data using Tukeys Test indicates no significant differences in organ weight data.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

>= 370 - <= 435 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

2

Dose descriptor:

LOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX

 0.5% M 199 F 190 mg/kg/day

 1% M 370 F 435 mg/kg/day

 Top dose 1000 mg/kg/day

 

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:

- Mortality and time to death: 1000 mg/kg both males died day 23 & 38. Both females died day 1 & day 38. Another female was included which survived the 13 week exposure period. All control, lower & mid dose animals survived the exposure period.

 

- Clinical signs: 1000 mg/kd/day signs seen in all dogs, at some stage during the dosing period, were salivation, emesis, mild excitation, ataxia, slight tremors and varying stages of anaesthesia (which preceded death in all animals which died). No specific clinical signs in lower dose or control animals.

 

 - Body weight gain: No difference from control values for the low & mid dose groups.

 

 - Food consumption: No difference from control values for the low & mid dose groups.

 

 - Ophthalmoscopic examination: Not done

 - Clinical chemistry, Haematology, Urinalysis: No apparent differences between treated and control groups.

 

- Organ weights: No difference from control values for the low & mid dose groups.

 

 - Gross pathology: Lymph node hyperplasia in both control & treated animals considered due to roundworm infestation (despite routine deworming throughout the study). In all animals which died there was evidence that the dogs may have aspirated vomit while anaesthetised (as a result of exposure to Alfol 6), death resulting from respiratory crisis. There was evidence of food particles in the trachea and the respiratory system smelled of the test substance.

 

- Histopathology: In top dose (1000 mg/kg/day) animals and to a lesser extent in animals of the intermediate dose level there was evidence of gastro-intestinal irritation (mucosal  hyperemia without ulceration or acute inflammatory reaction).

 The 2 high dose males (both died) showed testicular atrophy while one high dose female which died showed decreased oogenesis, the ovaries of the female which surived exposure to the high dose level appeared within normal limits. Other than gastro-intestinal irritation in mid dose animals there were no other treatment related hisptopathological changes in dogs receiving 0.5 or 1% Alfol 6 in the diet.

 

- Other: ECG's showed no differences between the initial pattern recorded and those seen at 3 or 13 weeks.

 

STATISTICAL RESULTS: Analysis not carried out. Subsequent analysis of the data using Tukeys Test indicates no significant differences in organ weight data.

Applicant's summary and conclusion

Conclusions:

The NOAEL for Alfol 6 is considered to be 370 mg/kg day for male dogs and 435 mg/kg/day for females (dietary administration). The treshold for irritation of the gastrointestinal tract was 190 mg/kg/day. High dose animals showed evidence of testicular atrophy 2/2 or decreased oogenesis 1/2. These animals died during the study and the effects are attributed to the acute lethality of the test substance adminstered at 1000 mg/kg by capsule. There were no adverse effects on the gonads at the lower dose levels. The value of this study is limited by the small numbers of test animals and the toxicity of the high dose level.


Reported in Iuclid 2000.