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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)

Data source

Reference
Reference Type:
other: study report
Title:
Toxicity Testing Reports of Environmental Chemicals
Author:
MHLW, Japan
Year:
1998
Bibliographic source:
OECD SIDS ; Ministry of Health, Labour and Welfare (MHLW, former MHW), Japan (1998), Toxicity Testing Reports of Environmental Chemicals 6, 236-246.

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
OECD Test Guideline 422 (Combined Repeat Dose and Reproductive/ Developmental Toxicity Screening Test)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Docosanoic acid
- Substance type: Organic
- Physical state: Solid
- Analytical purity:85.9 %
- Impurities (identity and concentrations):(C14-C20) fatty acids (10.9 %) and C 24 fatty acid (2.3%)
- Storage condition of test material:Kept at room temperature until use

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: NOF CORPORATION
- Age at study initiation: 8 weeks old

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Exposure period: Males: 42 days; Females: from 14 days prior to mating to day 3 of lactation

VEHICLE
- Justification for use and choice of vehicle (if other than water):Corn oil
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: 43 days; Females: from 14 days prior to mating to day 4 of lactation
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0(vehicle), 100, 300, 1,000 mg/kg/day.
Basis:

No. of animals per sex per dose:
100 mg/kg/day: 13 males and 13 females
300 mg/kg/day: 13 males and 13 females
1000 mg/kg/day: 13 males and 13 females
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Observed at least once a day.

BODY WEIGHT: Yes
- Time schedule for examinations: Basically determined once a week.

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
- Time schedule for examinations: measured nearly once a week except for mating period.

HAEMATOLOGY: Yes
Parameters checked as follows:(only for males) :
1) Red blood cell count (RBC)
2) white blood cell count (WBC)
3) Platelet count
4) Hemoglobin (Hb)
5) Hematocrit (Ht)
6) Mean corpuscular volume(MCV),
7) Mean corpuscular hemoglobin (MCH)
8) Mean corpuscular hemoglobin concentration (MCHC)
9) Differentiation of leukocytes

CLINICAL CHEMISTRY: Yes
Blood chemical examinations : (only for males)
Following parameters were checked : 1) total protein
2) albumin, A/G,
3) blood urea nitrogen (BUN),
4) creatinine,glucose,
5) total cholesterol,
6) total bilirubin,
7) triglyceride, sodium (Na), potassium (K), chloride (Cl),
calcium (Ca), inorganic phosphorus (IP), alkaline phosphatase (ALP), GPT, GOT

OPHTHALMOSCOPIC EXAMINATION: Not examined
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Organs examined at necropsy:organ weights: heart, liver, kidneys, thymus, testes,epididymides

HISTOPATHOLOGY: Yes
all animals in control and 1,000 mg/kg, and any organs which have histopathological changes at the higher doses: brain, heart, liver,spleen, thymus, kidney, adrenal, testis, epididymis, urinary bladder, ovary (only for females which were non pregnant or not copulated).
Statistics:
Dunnett’s or Scheffe’s test for continuous numerical data, Chi square test for copulated index and fertility index, and Mann-Whitney U test or Fisher’s test for histopathological examination data.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related abnormalities.
Mortality:
no mortality observed
Description (incidence):
No treatment-related abnormalities.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related abnormalities.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No treatment-related abnormalities.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No treatment-related abnormalities.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Decrease of MCHC at 300 and 1,000 mg/kg (p<0.01). However, this change in both groups was concluded as a casual one, because the degree of the change in both groups was very slight (the same 2.3 % decrease) and no other haematological changes were noted.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Decrease of serum ALP in treated groups (p<0.05) and decrease of glucose at 1,000 mg/kg (p<0.05). However, these changes were considered to be toxicologically meaningless ones since they were slight.
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No statistically significant differences from controls in any organs.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related abnormalities.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related abnormalities.
Histopathological findings: neoplastic:
not specified
Details on results:
– Body weight: No treatment-related abnormalities.
– Food/water consumption: No treatment-related abnormalities.
– Clinical signs: No treatment-related abnormalities.
– Haematology:
Males: Decrease of MCHC at 300 and 1,000 mg/kg (p<0.01). However, this change in both groups was concluded as a casual one, because the degree of the
change in both groups was very slight (the same 2.3 % decrease) and no other haematological changes were noted.

Biochem:
Males: Decrease of serum ALP in treated groups (p<0.05) and decrease of glucose at 1,000 mg/kg (p<0.05). However, these changes were considered to
be toxicologically meaningless ones since they were slight and related histopathological findings were not observed.
– Ophthalmologic findings: Not examined.
– Mortality and time to death: None
– Gross pathology incidence and severity: No treatment-related abnormalities.
– Organ weight changes: No statistically significant differences from controls in any organs.
– Histopathology:
Males: No treatment-related abnormalities in heart, liver, spleen, kidneys,adrenals and epididymides. In testes, atrophy of seminiferous tube was recognized in two of thirteen at 1,000 mg/kg group, but they were considered not to be treatment related specific findings, because they were slight and sometimes observed in historical control data in the laboratory conducting this study. No abnormalities detected in brain, thymus and urinary bladder.
Females: No treatment-related abnormalities in brain, liver, spleen, thymus,kidneys and adrenals. No abnormalities detected in heart, urinary bladder and ovaries.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: There were no treatment-related adverse effects though some slight changes in blood biochemistry and histopathology in testes.
Dose descriptor:
LOAEL
Effect level:
> 1 000 other: mg/kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Some slight changes in blood biochemistry and histopathology in testes was observed.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No treatment related adverse effects were found in either dose group 0, 100, 300 or 1000 mg/kg/day. Thus, NOAEL is considered to be 1000 mg/kg/day and LOAELis considered to be >1000 mg/kg/day for repeated dose toxicity study of docosanoic acid.
Executive summary:

The study was conducted to investigate the repeated dose toxicity of the test substance Docosanoic acid (behenic acid),andcomplies with the recommendations of the OECD Guidelines 422 "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test".The test material was administered by oral to dose groups, each of thirteen male and thirteen female Crj:CD (SD) strain rats,upto forty-three days at dose levels of 0, 100, 300or1,000 mg/kg/day. A control group of thirteen males and thirteen females was dosed with vehicle alone (corn oil).

Clinical signs , Body weight, Food consumption, Water consumption, Haematology, Blood chemistry, Organ weights, Gross pathologyandHistopathology were examined.No treatment related adverse effects were found in either dose group 0, 100, 300or1000 mg/kg/day,though some slight changeswere observedin blood biochemistry and histopathology in testes.

Thus, on the basis of overall discussion of the study,the 'No Observed Adverse Effect Level' (NOAEL) and lowest observed adverse effect level (LOAEL) for repeated dose toxicity by oral route was considered to be 1000 mg/kg/day and >1000 mg/kg/day respectively.

NOAEL : 1,000 mg/kg/day

LOAEL : >1,000 mg/kg/day