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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (OECD)

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes
Remarks:
Dept. of Toxicology, BASF AG

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1,6-Hexandiol
- Test substance number: 93/230
- Physical state: solid - liquid/colorless
- Analytical purity: 97,0 %
- Purity test date: analytical report fromFebruary 9, 1994
- Lot/batch No.: Tank 19
- Date of production : Dec . 17 - 21, 1993
- Storage condition of test material: room temperature; in a closed container due to the hygroscopic properties of the test substance

OTHER:
- Food analyses:
The food used in the study was assayed for chemical and microbiological contaminants.

- Drinking water analyses:
The drinking water is regularly assayed for chemical contaminants by the municipal authorities of Frankenthal and the Technical Services of BASF Aktiengesellschaft as well as for the presence of microorganisms by a contract laboratory.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach/Riss, Germany
- Identification: ear tattoo
- Age at study initiation: 42 d
- Weight at study initiation: mean 183 g (male), 147 g (female)
- Housing: singly in type DK III stainless steel wire mesh cages supplied by Becker & Co., Castrop-Rauxel, FRG (floor area about 800 cm2). Underneath the cages, waste trays were fixed containing absorbent material (typ 3/4 dustfree embedding, supplied by SSNIFF, Soest, Germany)
- Diet (e.g. ad libitum): ad lbitum, ground Kliba maintenance diet rat/mouse/hamster, 343 meal, supplied by Klingentalmühle AG, Kaiseraugst, Switzerland
- Water (e.g. ad libitum): ad libitum, drinking water (from water bottles)
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 -70
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
To prepare the solution, 1,6-Hexandiol was heated up to 50°C and weighed depending on the dose group. Then doubly distilled water was added and the mixture was subsequently dissolved with a magnetic stirrer for at least 5 minutes. The test substance preparations were prepared in intervals, for which the stability was demonstrated (the preparations were not stored for longer than 4 hours).

VEHICLE
- Concentration in vehicle: 1, 4, 10%
- Amount of vehicle (if gavage): 10 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- The analyses of the test substance and its preparations were carried out at the Analytical Department of BASF AG (Dr. P. Schmidt responsible)
- Before the beginning of the study, the stability of the test substance in the vehicle for a period of 4 hours at room temperature was checked in study 32M0015/924088 (BASF AG).
- Due to the fact, that the test substance preparations were true solutions, it was not necessary to verify the homogeneous distribution by analysis.
- At the start of the study, one sample of each concentration was sent to the analytical laboratory for determination of the correctness of the concentration of the test substance preparations.
.
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 400, 1000 mg/kg/d
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The oral LD50 value, rat, is determined as >3,000 mg/kg body weight (BUA Stoffbericht 107, Oct .1992). Alos, the neurotoxicological potential of 1, 6-Hexandiol was investigated in comparison to 2,5-Hexandion and/or 2,5-Hexandiol by repeated administration to rats as 0.5% solution in drinking water over 12 weeks and by administration of 414 mg/kg body weight/day ip over 5 weeks, respectively. No signs of neurotoxicity occurred (BUA Stoffbericht 107, Oct. 1992).

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day from Mondays to Fridays and once a day on Saturdays, Sundays and public holidays.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly


BODY WEIGHT: Yes
- Time schedule for examinations: before start of administration; day 0 (start of the administration period) and thereafter in weekly intervals


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
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


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: No


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


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: in the morning
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: 5
- Parameters checked in table were examined: differential blood count (leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets) clotting analysis


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: in the morning
- Animals fasted: No
- How many animals: 5
- Parameters checked in table were examined: Enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase,serum-y-glutamyltransferase), Blood chemistry (sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, magnesium)


URINALYSIS: Yes
- Time schedule for collection of urine: overnight
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters checked in table were examined: volume, color, turbidity, nitrite, pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, specific gravity, sediment


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
- Clinical examinations, clinical chemistry and hematology:
For all values, excepting the differential blood count, and body weight data a non-parametric one-way analysis was performed using the KRUSKAL-WALLIS test. If the resulting p-values were equal or less than 0 .05, a pairwise comparison of each dose group with the control group
was carried out . This comparison was performed via the MANN-WHITNEY U-test [1) for hypothesis of equal medians. If the results of this test were significant, labels (* for p<0.05, ** for p<0.02, ***for p<0.002) were printed together with the group means in the tables. Both tests were performed two-sided.

- Urinalyses:
With the exception of volume, color, turbidity, specific gravity and pH, the scale for the urine parameters is divided into 4 sections (0, 1, 2, 3). For the parameter "Nitrite" only a division in two sections (0, 1) is made. The parameters were sorted into 2 classes. This was done for the statistical analysis. A pairwise comparison of each dose group with the control was carried out using FISHER'S exact test for the hypotheses of equal proportions . If the results of this test are significant, labels (* for p<=0.5, ** for p<= 0.01) were printed in the tables.

Results and discussion

Effect levels

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

There were no substantial substance-related effects
concerning food consumption, body weight, body weight
change, clinical, clinicochemical, gross pathological and
histopathological observations.
The observed statistical significances for the values of
body weight (-13% at 400 mg/kg/d) and body weight gain (-31
and -25%, respectively, at the 400 and 1000 mg/kg/d dose
level) toward the end of the study in female rats are
regarded as incidental, because of missing dose-response
relationship. In parallel, the values for food consumption
were also reduced, but without showing statistical
significance. Furthermore, all these changes were within
ranges of historical controls.

Thus, under the study conditions, the test substance at
doses of 100, 400 or 1000 mg/kg/d caused no
substance-related effects in rats.

Applicant's summary and conclusion

Conclusions:
No classification required.