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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:
weight of evidence
Study period:
not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study (draft guideline) with acceptable restrictions, on a related material
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1992

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Draft OECD 422 Combined Repeat dose and Reproductive/Developmental Toxicity Screening Test.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Moellegard breeding centre
- Age at study initiation: F 8 weeks, M 7 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 2/cage, steel wire cages type 3 (for males and for females up to day 20 of gestation); macrolon cages type 3 (for females from day 20 of gestation)
- Diet (e.g. ad libitum): IT chow 101, presumably ad libitum
- Water (e.g. ad libitum): acidified tapwater, ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2
- Humidity (%): 55 +- 10
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

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): no data
- Mixing appropriate amounts with (Type of food): IT chow 101
- Storage temperature of food:no data
- Preparation procedure: Diet preparation involved first mixing an aqueous dodecanol solution with the barley component, which varied for each dose level.  The other components of the diet were then added.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Males 41-45 days; Females approx. 54 days
Frequency of treatment:
continuous in the diet
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1500, 7500 & 30,000 ppm (approx 100, 500, 2000 mg/kg bw/day)
Basis:
nominal in diet
No. of animals per sex per dose:
12
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: preliminary test via a dermal route
- Rationale for animal assignment (if not random): 2 days prior to the start of dosing, animals randomised into four groups with same mean body weight
- Post-exposure recovery period: none
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Mortality, daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: males once per week; females premating once per week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Yes, once per week
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/week: Yes
- Compound intake calculated from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Food consumption in g body weight gain/kg food per week calculated from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: males after 37 days of dosing
- Anaesthetic used for blood collection: Yes (identity - no data)
- Animals fasted: No data
- How many animals: all males
- Parameters examined: haematocrit, heamoglobin, total erythrocyte and total leukocyte count, leukocyte differential count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: males after 37 days of dosing
- Animals fasted: No data
- How many animals: all males
- Parameters examined: protein, alkaline phosphatase, alanine aminotransferase, glucose, urea, creatinine, total and free cholesterol, triglycerides

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: animals mated for reproductive and developmental toxicity studies
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, full necropsy on all animals
ORGAN WEIGHT: males - liver, kidneys, thymus, testes, epididymides; females - liver, kidneys, thymus
ORGANS FIXED IN FORMALIN: males - liver, kidneys, adrenals, brain, heart, spleen, thymus, organs with pathological changes, testes and epididymides fixed in Bouin's solution; females - liver, kidneys, adrenals, brain, heart, spleen, ovaries, thymus, other organs with observed pathological changes
HISTOPATHOLOGY: Yes, control and top dose group, all fixed organs except thymus
Other examinations:
Foetal examinations and reproductive parameters (reported elsewhere)
Statistics:
Using the SAS-stat program; analysis of variance; all statistically significant findings further evaluated by Dunnett's t-test

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:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
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
- Mortality and time to death: None
- Clinical signs: None reported

BODY WEIGHT AND WEIGHT GAIN
- Body weight gain: No differences between treated and controls of either sex.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
FOOD EFFICIENCY
- Food consumption/food efficiency: No differences between treated and controls of both sexes.
- Dietary concentrations of 1500, 7500 and 30000 ppm provided nominal dose levels of 100, 500 and 2000 mg/kg bw/day; measured dose levels were 82-122, 425-642 and 1616-2646 mg/kg bw/day respectively for males and 125-136, 639-676 and 2503-3058 mg/kg bw/day respectively for females premating.

HAEMATOLOGY (see table 1)
- Haematology: (males only investigated) A dose related reduction in total WBC was observed which reached statistical significance in top and mid 
dose males, there were no differences in the differential white cell count that explained these observations. 

CLINICAL CHEMISTRY (see table 1)
- Clinical chemistry (males only investigated): There was a significant reduction in plasma triglyceride (TG) at the top dose level and a significant 
reduction in plasma free cholesterol (F-chol) at the intermediate dose level. The reduced cholesterol level was re-analysed after removing 2 outlying
values when the statistical significance was lost. These results may have been confounded by the difference in dietary composition between 
groups.        

ORGAN WEIGHTS (see table 2)
- Organ weights: There were no dose related changes in organ weights. In males only there was a reduction in relative and absolute liver weights at
the low dose level and a reduction in relative liver weight at the mid dose, the top dose was comparable to controls.       

GROSS PATHOLOGY
- Gross pathology: There were no changes attributable to exposure to the test compound.

HISTOPATHOLOGY
- Histopathology: There were no treatment related histopathological changes.

HISTORICAL CONTROL DATA (if applicable): none

OTHER FINDINGS
- ACTUAL DOSE RECEIVED BY DOSE LEVEL BY SEX
Males: 102.4, 530.8 and 2046.4 mg/kg bw/day (mean of values reported for 2 weeks prior to mating and 3 weeks after mating)
Females: 130.5, 657.5 and 2870.5 mg/kg bw/day (mean of values reported 2 weeks prior to mating)

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
NOEL
Effect level:
< 100 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: Haematology: dose-dependent reduction in white blood cell count, statistically significant at 500 and 2000 mg/kg bw/day [Dietary concentrations of 1500, 7500 and 30000 ppm provided nominal dose levels of 100, 500 and 2000 mg/kg bw/day]

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1: Selected haematology and clinical chemistry findings

Doses (mg/kg bw/day (nominal))

0

100

500

2000

male (mean and standard deviation)

Number of animals/group

12

12

12

12

Haematology (day 37)

 

 

 

 

- WBC (mmol/l)

[sic, presumably x 109/l]

 7.0 ± 1.8

5.9 ± 1.3

4.3*** ± 1.4

4.7** ± 1.2 

Blood chemistry (day 37)

 

 

 

 

- total cholesterol (mmol/l)

 1.60 ± 0.27

1.74 ± 0.36 

1.64 ± 0.30 

1.75 ± 0.22 

- free cholesterol (mmol/l)

 0.18 ± 0.07

0.16 ± 0.05 

0.11* ± 0.06 

0.15 ± 0.05 

- triglyceride (mmol/l)

 0.58 ± 0.32

0.42 ± 0.11 

0.45 ± 0.17 

0.31** ± 0.06 

* p<0.05   ** p<0.01  *** p<0.001

Table 2: Absolute and relative organ weights

 

Males (mean and standard deviation)

DAILY DOSE
(mg/kg bw (nominal))

0

100

500

2000

NUMBER OF ANIMALS

12

12

12

12 

BODY WEIGHT (g)a

 370 ± 26.9

366 ± 20.4 

383 ± 20.6 

367 ± 16.7 

LIVER

 

 

 

 

AbsoluteWeighta

g

12.27 ± 1.2 

11.20* ± 0.8 

11.76 ± 1.0 

11.98 ± 0.9 

Per BodyWeighta

%

3.3 ± 0.19 

3.1* ± 0.21 

3.1* ± 0.24 

3.3 ± 0.21 

aGroup means at terminal necropsy are shown.

* p<0.05

 

 

Applicant's summary and conclusion

Conclusions:
In a reliable study conducted to the draft OECD guideline 422, an NOAEL for systemic toxicity of 2000 mg/kg bw/day (highest dose tested) was determined in male rats in the absence of toxicologically significant effects at any dose level. . The study was performed in compliance with GLP.
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 Undecanol linear and branched.]