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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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (no data on test substance purity).
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
(analytical purity of test substance not given)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sorbitan monooctadecanoate
- Physical state: light yellow crystalline pellet
- Analytical purity: no data
- Storage condition of test material: stored in a sealed box under the room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Yokohama, Japan
- Age at study initiation: 10 weeks
- Weight at study initiation: males (g): 385.3 ± 18.2 - 386.6 ± 16.8, females (g): 220.4 ± 9.6 - 224.8 ± 7.8
- Housing: metal wire mesh cages (220x270x190 mm)
- Diet (ad libitum): CE-2, Clea Japan
- Water (ad libitum): tap water
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.0 - 24.5
- Humidity (%): 55.0 - 65.5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: serial dilutions in water were prepared
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to the main study, analytical measurements were performed (GC).
Duration of treatment / exposure:
females: 2 weeks before mating until day 4 of lactation ~42 days
males: 42 days
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
40, 200, 1000 mg/kg bw/d
Basis:
nominal in water
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: preliminary range-finding study (pilot project number: R-04-004) 0, 500, 1000 and 2000 mg/kg bw/d
- Post-exposure recovery period in satellite groups: 14 days

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 1 time daily during the breeding and recovery period and twice daily during the treatment period before and after administration

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: day 7, 14, 21, 28, 35, 42 during treatment and day 7, 14 during recovery
[position, posture, spontaneous movement, noise, tremor, ease of retrieval, ease of handling, heart beat, body temperature, fur, skin, visible mucous membranes, tearing, bulging eyes, pupil diameter, Postural position, exploratory behavior, grooming, vocalizations, straub tail reaction, walking, stereotypic behavior, bizarre behavior, tremors, piloerection, eye fissure]

BODY WEIGHT: Yes
- Time schedule for examinations:
males: 1, 7, 14, 21, 28, 35, 42 during treatment and 1, 7, 14, 15 during recovery
pregnant females: 1, 7, 14, 21, 28 before the copulation, 0, 7, 14, 20 after the copulation and 0, 4, 5 after delivery,
females in satellite group: 1, 7, 14, 21, 28, 35, 42 during treatment and 1, 7, 14, 15 during recovery

FOOD CONSUMPTION:
males and satellite fimales: between days 1-2, 7-8, 14-15, 29-30, 35-36, 41-42 during treatment and 6-7, 13-14 during recovery
females: between days 1-2, 7-8, 14-15 before pregnancy, 0-1, 7-8, 14-15, 20-21 during pregancy and 3-4 during lactation

FOOD EFFICIENCY:
- Body weight gain in g: Yes

WATER CONSUMPTION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: male: one day after the end of dosing period, males and females in satellite groups: 15 day after the end of treatment, females: day 4 during lactation
- Animals fasted: 18 - 24 hours before anatomy
- How many animals: 5 per group
- Parameters checked: red blood cell count, white blood cell count, leukocyte classification, amount of hemoglobin, mean corpuscular volume, platelet count, hematocrit, mean corpuscular hemoglobin content, mean corpuscular hemoglobin concentration, prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: male: one day after the end of dosing period, males and females in satellite groups: 15 day after the end of treatment, females: day 4 during lactation
- Animals fasted: 18 - 24 hours before anatomy
- How many animals: 5 per group
- Parameters checked: total protein concentration, total cholesterol concentration, urea nitrogen level, AST (GOT), ALT (GPT), γ-GTP, inorganic phosphorus concentration, sodium ion concentration, potassium ion concentration, chloride ion concentration

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: males: at the end of dosing period, males and females in satellite groups: at the end of recovery period, females: day 4 during lactation
- Dose groups that were examined: 0, 40, 200, 1000 mg/kg
- Battery of functions tested: reaction function testing, pupillary reflex, visual orientation, surprised reaction, hind limb retraction reflex, experimental eye (blink) reflex, observed the presence or absence of righting reflex
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
brain, heart, thymus, liver, kidney, spleen tiles, adrenal gland, testis and epididymis were weighed (actual weight). Pituitary, spinal cord, heart, trachea, lung (including bronchus), liver, kidney, thymus, spleen tiles, adrenals, thyroid, stomach, duodenum, jejunum, cecum, colon, rectum, testis, epididymis, ventral prostate, seminal vesicles including coagulation glands, ovary, uterus,mandibular lymph node, mesenteric lymph nodes, sciatic nerve, and femoral bone marrow were preserved.

HISTOPATHOLOGY: Yes
brain, heart, thymus, liver, kidney, spleen tiles, adrenal gland, testis, epididymis, pituitary, spinal cord, heart, trachea, lung (including bronchus), liver, kidney, thymus, spleen tiles, adrenals, thyroid, stomach, duodenum, jejunum, cecum, colon, rectum, testis, epididymis, ventral prostate, seminal vesicles including coagulation glands, ovary, uterus,mandibular lymph node, mesenteric lymph nodes, sciatic nerve, and femoral bone marrow
Other examinations:
sexual cycle, mating, pup delivery, external malformations offspring
Statistics:
Fisher´s exact test, Mann-Whitney U-grade test, Student´s t-test, Aspin-Welch test, Bartlett test, Dunnett multiple comparison method, Kruskal-Wallis 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 specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
non-adverse effects
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
non-adverse effects
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
non-adverse effects
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
non-adverse effects
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
non-adverse effects, as also observed in control group.
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality was observed.
200 mg/kg bw/d: loss of fur with ulcer (between day 14 and day 41 during treatment) in one male animal
control group: loss of fur with ulcer (between day 14 and day 42) in one female animal

HAEMATOLOGY
200 mg/kg bw/d: increased mean corpuscular haemoglobin in females

CLINICAL CHEMISTRY
1000 mg/kg bw/d: reduced total protein and albumin in males
200 mg/kg bw/d: reduced albumin in males
40 mg/kg bw/d: increased triglycerides in females
1000 mg/kg bw/d (satellite group): increased ALP in females

NEUROBEHAVIOUR
No abnormal behaviour in all groups.

ORGAN WEIGHTS
1000 mg/kg bw/d: decreased relative weights of epididymis in males
200 mg/kg bw/d: decreased relative weight of brain in males
1000 mg/kg bw/d (satellite group): increased absolute epididymis weight in males and increased absolute brain weight in females
GROSS PATHOLOGY
200 mg/kg bw/d: spots in glandular stomach in females

HISTOPATHOLOGY: NON-NEOPLASTIC
In the control group and in the 40, 200, 1000 mg/kg bw/d dose groups, tubular atrophy and cell debris in the testes was observed.
- 1000 mg/kg bw/d: heart muscle degeneration, metaplasia in lungs, fat in the periportal hepatocytes, infiltration of lymphocytes in stomach, extramedullary hematopoiesis and brown pigment in spleen, basophilic tubules and mineral deposition in localized renal cortical and circumscribed cyst in kidney in male and female animals; neutrophil and lymphocyte infiltration in prostatic stroma and epithelium additionally in male animals
- Control group: heart muscle degeneration, neutrophil infiltration in lugs, fat in the periportal hepatocytes, subcapsule necrotic spot in liver, extramedullary hematopoiesis and brown pigment in spleen, basophilic tubules and mineral deposition in localized renal cortical and circumscribed lymphocytic infiltration in kidney, neutrophil and lymphocyte infiltration in prostatic stroma and epithelium in male animals and myocardial degeneration, periportal hepatocytes, extramedullary hematopoiesis and brown pigment in spleen, tubular basophilia in kidney in female animals Testes and epididymes and ovaries showed no abnormal findings at the end of the study period.

REPRODUCTIVE TOXICITY
No significant or dose-related effects on reproduction.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion