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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018-02-01 to 2018-07-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
10/2008
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco
EC Number:
500-303-2
EC Name:
4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco
Cas Number:
115340-85-7
IUPAC Name:
4,4'-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco
Test material form:
liquid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:
R-127 / batch 180131
- Expiration date of the lot/batch:
2019-01-31

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:
Dry and dark at ambient temperature (10 – 30 °C)

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: InVivos Pte Ltd
9 Perahu Road,
Lim Chu Kang,
Singapore 718793
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 7 weeks
- Weight at study initiation: males 216 - 298 g, females 162 - 208 g
- Housing: Individual Ventilated Cage System
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 d

DETAILS OF FOOD AND WATER QUALITY:
Altromin Maintenance Diet #1324
Tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 26 °C
- Humidity (%): 30 - 70 %

IN-LIFE DATES: From: 2017-12-28 To:2018-01-30

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
The test substance was administered by gavage feeding needle. The test substance and control substance were administered daily, 7 days per week for continuous 4 weeks.
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 d
Frequency of treatment:
Ddaily administration
Doses / concentrationsopen allclose all
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
160 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10, of wich 5 males and 5 females
Control animals:
yes
Details on study design:
- Dose selection rationale: results from acute oral toxicity study
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once per day
- Cage side observations were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: before the first exposure and 1 week thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 7, 14, 21 and 28

OPHTHALMOSCOPIC EXAMINATION: Yes (clinical signs in the eyes)
- Time schedule for examinations: before the first exposure and once a week thereafter
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of study
- Anaesthetic used for blood collection: No (animals euthaniized before)
- Animals fasted: No
- How many animals: alll
- Parameters checked: haematocrit (HCT), haemoglobin (Hb) concentration, erythrocyte count (RBC), total (WBC) and differential leukocyte count and platelet count (PLT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of study
- Animals fasted: No
- How many animals: all
- Parameters checked: sodium, potassium, glucose, creatinine, total protein and albumin, alanine aminotransferase (ALT), alkaline phosphatase and total bilirubin

URINALYSIS: Yes
number of pools of urine
- Animals fasted:No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: 4th week of exposure
- Dose groups that were examined: all
- Battery of functions tested: Forelimb and hindlimb grip strength / response to visual stimuli / response to sudden sound / pupil response / pinna reflex / proprioception / pain perception / air righting reflex / landing foot splay measurement

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

The liver, kidneys, adrenals, testes, epididymides, prostate + seminal vesicles with coagulating glands (as a whole), thymus, spleen, brain and heart of all animals were trimmed of any adherent tissues, and their wet weight were taken and recorded.

HISTOPATHOLOGY: Yes

Full histopathology analysis were carried out on the preserved organs and tissues of all animals in the control and highest dosing group. The following tissues were preserved in 10% formalin or other suitable fixative for histology and pathology analysis:
Gross lesions (if any), brain (representative regions including cerebrum, cerebellum and pons), spinal cord, eye, stomach, small and large intestine (including Peyer’s patches), liver, kidneys, adrenals, spleen, heart, thymus, thyroid, trachea and lungs, gonads (testis and ovaries), accessory sex organs (e.g. uterus and cervix, epididymides, prostate + seminal vesicles with coagulating glands), vagina, urinary bladder, lymph nodes, peripheral nerve (sciatic or tibial), skeletal muscle and bone with bone marrow.
Statistics:
Data were summarized in tabular form. In each group, the form showed the number of animals at the start of the test, the number of animals showing lesions, the types of lesions and the percentage of animals displaying each type of lesion, if any.

Data for body weight, organ weight, quantitative functional observation, grip strength measurement, haematology and clinical biochemistry were analyzed statistically. Student T-test was used to compare differences of mean values between the control and test group (significance level: two-tailed test, p = 0.05).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No obvious body weight loss (>10%) was observed on all the test animals during test period.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The t-test indicated that there is no significant difference (p < 0.05) in all the parameters between the male T1, T2 and T3 groups and male negative control group, except that the RBC and HCT value in male T2 group are significantly decreased (p = 0.02) comparing with negative control group.
The t-test indicated that there is no significant difference (p < 0.05) in all the parameters between the female T1, T2 and T3 groups and female negative control group, except that a) the lymphocyte count in female T1 and T3 group is significantly increased (p < 0.05) comparing with negative control group; it is also notable that the p value of lymphocyte count in female T2 group is 0.05 comparing with negative control group; b) the Hb value in female T1 group is signifantly decreased (p = 0.03) comparing with negative control group.

Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
The t-test indicated that there is no significant difference (p < 0.05) in all the parameters between the male T1, T2 and T3 groups and male negative control group.
The t-test indicated that there is no significant difference (p < 0.05) in all the parameters between the female T1, T2 and T3 groups and female negative control group, except that a) Alkaline Phosphatase in female T1 group is significantly decreased (p = 0.00) comparing with negative control group; b) Sodium in female T3 group is significantly decreased (p = 0.01) comparing with negative control group.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Forelimps grip strength measurements: No effect
Hindlimps grip strength measurements: No effect
Land foot splay measurement: No effect
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
No significant difference (p < 0.05) in body weight and organ weight between test and control groups, except that significant decreased weight of adrenals in all three female test groups when comparing with female negative control group. Microscopic examination indicated that the decreased weight of adrenals is an incidental finding due to an unusually high weight in the control group.
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Macroscopic observation during necropsy

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: all results

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the study, using both male and female rats as test system, with daily oral administration of 1000 mg/kg, 400 mg/kg and 160 mg/kg body weight per day of the test item- 4, 4’-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco, for a period of 28 days, no systemic toxicity of the test system was observed.
Executive summary:

The substance 4, 4’-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco, was tested for toxic effects in a repeated-dose 28 day oral study according to OECD 407.

Based on the study, using both male and female rats as test system, with daily oral administration of 1000 mg/kg, 400 mg/kg and 160 mg/kg body weight per day of the test item- 4, 4’-Isopropylidenediphenol, ethoxylated, esters with fatty acids, coco, for a period of 28 days, no systemic toxicity of the test system was observed.