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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 from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Robust summary of study published in official document (Test Plan for fatty acid dimers and trimer) submitted to US EPA. There the study was classified as Klimisch 1. The study was GLP compliant and performed according to OECD guideline 408. As the robust study summary is taken from a secondary source the reliability was downgraded.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
concentration of 5% in the diet = approximate dose of 5000 mg/kg day
Basis:
other: standard conversion factors (WHO 1990)
Remarks:
Doses / Concentrations:
concentration of 1% in the diet = approximate dose of 1000 mg/kg day
Basis:
other: standard conversion factors (WHO 1990)
Remarks:
Doses / Concentrations:
concentration of 0.1% in the diet = approximate dose of 100 mg/kg day
Basis:
other: standard conversion factors (WHO 1990)
No. of animals per sex per dose:
20
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
Parameters evaluated included clinical signs, body weight, food and water consumption, ophthalmoscopy, hematology, clinical chemistry, gross pathology, organ weights (brain, heart, liver, kidneys, spleen, testes, adrenal glands), and microscopic pathology (adrenal glands, brain, colon, femur and stifle joint, ileum, larynx, lymph nodes, muscle, ovaries and fallopian tubes, pituitary, sciatic nerve, sternum, thyroid and parathyroids, uterus, aorta, cecum, duodenum, head, jejunum, liver, esophagus, pancreas, prostate, spinal cord, stomach, tongue, bladder, cervix, heart, kidneys, lungs, mammary glands, rectum, spleen, thumus, trachea, epididymides, skin, salivary glands, testes, seminal vesicles, vagina, eyes/harderian glands).

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):
effects observed, treatment-related
Description (incidence and severity):
A statistically significantly decrease in food consumption occurred in the 5% males and females during the first four weeks of study.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Slight changes in hemoglobin (increased in males at 5000 mg/kg/day) and prothrombin time (increased in females at 1000 mg/kg/day and in males and females at 5000 mg/kg/day) were considered not to be toxicologically significant.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
see details on results
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
see details on results
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see details on results
Details on results:
Treatment-related clinical chemistry changes included statistically significant increases in alkaline phosphatase (in males and females at concentrations of 1 and 5% ) and ALT (in males and females at 5% ), and statistically significant decreases in total cholesterol (in males and females at concentrations of 1 and 5% ), triglycerides (at 1% in males and at 5% in males and females), total serum protein and albumin (in males and females at 5% ), and beta-globulin fraction (at 1 and 5% in males). At necropsy, the mesenteric lymph nodes were slightly to moderately enlarged in all dimer treatment groups and the incidence of uterine fluid distension was increased at a concentration of 5%.
Absolute and relative spleen (in males at 1 and 5%) and liver (in males and/or females at 1 and 5%) weights were statistically significantly decreased. In addition, absolute kidney weight was significantly decreased in females at a concentration of 5% and absolute and relative liver weights were significantly decreased in females at 0.1%. The relevance of these decreases in organ weights is not known, since they did not correlate to any microscopic changes.
Histopathology revealed treatment-related findings in the following organs:
mesenteric lymph nodes (aggregation of macrophages in both sexes at 0.1% and higher); spleen (macrophages with brown pigment in both sexes at 1 and 5% and in the females at 0.1%); liver (bile duct proliferation and bile duct sclerosis in males at 5%); adrenals (cortical vacuolation in females at 1 and 5%); and thyroids (follicular epithelial hypertrophy in females at 5%).

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on increases in clinical chemistry parameters and histopathological findings at the higher doses

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Although a NOEL was not identified in this study, 0.1% (approximately 100 mg/kg/day) can be considered as NOAEL based on increases in clinical chemistry parameters and histopathological findings at the higher doses.
Executive summary:

Dimer (CAS #61788-89-4) was administered to CD Sprague-Dawley rats (n = 20/sex/group) in the diet at concentrations of 0, 0.1, 1, or 5% for 13 weeks. The approximate doses were 0, 100, 1,000, or 5,000 mg/kg/day, based on standard conversion factors (WHO 1990). Parameters evaluated included clinical signs, body weight, food and water consumption, ophthalmoscopy, hematology, clinical chemistry, gross pathology, organ weights, and microscopic pathology.

 

No deaths occurred and no treatment-related effects on clinical signs, body weight, body weight gain, water intake, or ophthalmoscopy were noted.

Although a NOEL was not identified in this study, 0.1% (approximately 100 mg/kg/day) can be considered as NOAEL based on increases in clinical chemistry parameters and histopathological findings at the higher doses.