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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26 Mar - 27 Jul 2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: Guidelines for the testing of chemicals section 4: Health effects (ministry of environmental protection of people's republic of china)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
adopted in 2018
Deviations:
yes
Remarks:
There are major deviations from the current OECD guideline. For details, please refer to "Princip les of method if other than guideline".
Principles of method if other than guideline:
Deviations from the current OECD 408 guideline included the following:
stability of test substance in vehicle not shown, justification for choice of vehicle not given, achieved concentration, stability and homogeneity of the test substance formulation not analysed, no detailed clinical observation, no ophthalmological changes and sensory reactivity examined, no individual animal data provided, haematocrit, HDL, LDL and thyroid parameters in the blood not measured, epididymides, prostate, uterus, pituitary gland and thyroid not weighed, histopathology not performed on pituitary gland, eye, salivary glands, oesophagus, parathyroid, aorta, trachea, cervix, mammary gland, vagina, skeletal muscle, bone and skin, no historical control data provided and not GLP.
GLP compliance:
no
Remarks:
The study was performed to meet the requirements of a non-EU Regulatory Authority. A quality assurance statement was included.
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
482-140-6
EC Name:
-
Cas Number:
13641-96-8
Molecular formula:
Hill formula: C6 H7 N O3 CAS formula: C6 H7 N O3
IUPAC Name:
2-isocyanatoethyl prop-2-enoate
Test material form:
liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Shanghai SLAC Laboratory Animal Co., Ltd., China
- Females (if applicable) nulliparous and non-pregnant: not specified
- Weight at study initiation: 110 - 140 g (males and females)
- Housing: Two animals were housed in one polycarbonate cage.
- Diet: fed with powdered animal diet (Suzhou Shuangshi Laboratory Animal Feed Co., Ltd.), ad libitum
- Water: sterilized water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 25
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 09 May 2010 To: 28 Jun 2010

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
The test substance was administered orally to animals once daily by a metallic stomach catheter for 90 days. The administered dose volume, 5 mL/kg bw, was calculated on the basis of individual body weight at the beginning of each week.
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Prescribed amount of test substance was weighed and diluted with corn oil to the correct concentrations.

VEHICLE
- Justification for use and choice of vehicle: not provided
- Amount of vehicle: 5 mL/kg bw
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
not applicable
Duration of treatment / exposure:
90 days
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
2 mg/kg bw/day (actual dose received)
Dose / conc.:
8 mg/kg bw/day (actual dose received)
Dose / conc.:
32 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
10 animals per sex were administered 0, 2, 8 and 32 mg/kg bw/day for 90 consecutive days. A satellite high dose group (32 mg/kg bw/day) and a satellite control group were also included and observed for 14 days after treatment.

- Dose selection rationale: Doses were selected according to the results of acute oral toxicity and repeated dose 28-day oral toxicity study.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: not specified
- Cage side observations checked: mortality, moribund condition and clinical signs of toxicity

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: No

WATER CONSUMPTION AND COMPOUND INTAKE: No

FOOD EFFICIENCY: Yes
- The method of calculation was not specified.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of treatment
- Anaesthetic used for blood collection: not specified
- Animals fasted: not specified
- How many animals: in all the treatment and control groups
- Parameters checked: haemoglobin (Hb), red blood cell count (RBC), differential white blood cell count (WBC), platelate count (PLT), plasma prothrombin time (PT) and activated partial thromboplatin (APTT).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of treatment period
- Animals fasted: not specified
- How many animals: in all the treatment and control groups
- Parameters checked: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total cholesterol (CHOL), total bilirubin (TBIL), glucose (GLU), blood urea nitrogen (BUN), creatinine (CREA), cholesterase (CHE), total protein (TP), albumin (ALB), sodium, potassium, chloride, calcium and phosphorous.

PLASMA/SERUM HORMONES/LIPIDS: No

URINALYSIS: Yes
- Time schedule for collection of urine: at the end of the treatment period
- Metabolism cages used for collection of urine: not specified
- Animals fasted: not specified
- Parameters checked: specific gravity, color, pH, protein contents, blood/blood cells and glucose concentration.

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All rats were subjected to gross necropsy and macroscopic examination at the end of the study period.

The following organs and tissues were weighed: brain, heart, lung, liver, spleen, kidney, adrenal gland, testis or ovary and thymus.

HISTOPATHOLOGY: Yes
The following tissues were fixed with 10% formaldehyde and sampled for histopathology: brain, heart, lung, liver, thymus, spleen, kidney, adrenal gland, testis or ovary, nervus ischiadicus, cervical, spinal cord, thyroid, pancreas, stomach, duodenum, jejunum, ileum, colon, rectum, mesenteric lymph node, prostate, epididymides, urinary bladder and uterus.
Statistics:
Data was analyzed by ANOVA, and the additional high and control dose group were analyzed by t-test.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Main groups:
Control: No clinical signs were observed.
2 mg/kg bw/day: No clinical signs were observed.
8 mg/kg bw/day: No clinical signs were observed.
32 mg/kg bw/day: fluffy hair (10/10 females and 10/10 males), slow breathing (5/10 females and 5/10 males), arched back (5/10 females and 5/10 males), lethargic (10/10 females and 10/10 males), delayed reaction (5/10 females and 5/10 males) and salivation (10/10 females and 10/10 males).

Satellite groups:
Control: No clinical signs were observed.
32 mg/kg bw/day: fluffy hair (10/10 females and 10/10 males), slow breathing (1/10 females and 3/10 males), arched back (1/10 females and 3/10 males), lethargic (10/10 females and 10/10 males), retard reaction (1/10 females and 3/10 males) and salivation (10/10 females and 10/10 males)

For details, please refer to the attached background material 1.
Mortality:
no mortality observed
Description (incidence):
No deaths were observed during the treatment.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Main groups:
The body weight of the females given 32 mg/kg bw/day was statistically significantly reduced during Weeks 5 to 10 and during Week 12 compared to the control animals (maximum of -12%) whereas the body weight of the male animals treated with 32 mg/kg bw/day was statistically significantly reduced from Week 1 to 13 compared to the control group (maximum -25%). This reduction in body weight at 32 mg/kg bw/day is considered toxicollogically relevant. A statistically significant reduction of body weight was also observed in males treated with 8 mg/kg bw/day during Weeks 1 and 2 (approximately -7%) when compared to the control animal. This effect is not considered toxicologically relevant as the reduction in body weight was less than 10%. No statistically significant changes in body weight were observed for males given 2 mg/kg bw/day of the test substance and for females treated with 2 or 8 mg/kg bw/day compared to the controls. For all animals body weight gain was observed throughout the study period.

Satellite groups:
Similar to the above-mentioned observation, the body weight of the satellite animals treated with the high dose of the test substance (32 mg/kg bw/day) was statistically significantly reduced for both sexes. In male rats, the reduction in body weights was statistically significant during the whole study duration (Weeks 1 - 15, maximum of -20%) compared to the control group. In females, statistically significantly reduced body weights were observed during Week 1 to 11 and during Week 13 (maximum of -11%) when compared to the control animals. For all animals in the satellite groups, body weight gain was observed throughout the study period.

For details, please refer to the attached background material 2.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
no effects observed
Description (incidence and severity):
There were no changes regarding the food efficiency in male and female rats during the study.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were observed in any treatment group (main and satellite groups). In males of the satellite group treated with 32 mg/kg bw/day, there was a statistically significant increase in basophiles compared to the control. As the increase of basophils was minor and showed no dose-dependency, the effect was not considered treatment-related.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Main groups:
Biochemical detection of blood exhibited that TP was significantly decreased in the high and middle dose groups of male rats, and calcium ions was significantly increased in the middle dose groups of male rats compared to the control animals.

Satellite groups:
TBIL and calcium ions of female rats in the satellite high dose group were increased, while in male rats AST and ALP were increased compared to the additional control group.

All changes were not considered treatment-related, as the effects were only transient or where only observed in the satellite group and in one sex.
Endocrine findings:
not examined
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
Main groups:
No treatment-related urinary findings were observed in female rats. The urine of male rats (1/10) treated with 2, 8 and 32 mg/kg bw/day was protein positive. Since only one male animal was affected in each dose group, this effect was considered incidental and not related to the treatment with the test substance.

Satellite groups:
No treatment-related findings were observed in the animals during the study.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Main groups:
The absolute organ weights of brain, lung and kidney of the high dose group of female rats were statistically significantly decreased, whereas the relative heart weight was statistically significantly increased in the middle dose group of female rats compared to the control group.
For male rats, the absolute weights of heart, kidney and thymus were statistically significantly reduced in the high dose group, whereas the absolute lung weight was statistically significantly increased in the middle dose group. The relative weights of the brain, heart, lung, adrenal gland, and testis in the high dose group and the relative lung weight of the middle dose group were statistically significantly increased compared to the control.

Satellite groups:
The absolute and relative weight of the lung of female rats in the satellite group were statistically significantly increased. The relative brain and testis weight of male rats in the satellite group were significantly increased, but the absolute heart, liver, lung and kidney weights as well as the relative liver weight were statistically significantly decreased compared to the satellite control group.

All effects were considered not treatment-related, because the observed changes were opposite for absolute and relative organ weights, or occurred only in absolute weight, or were small (<20%), or were opposite for the main and satellite groups, or occurred only in one sex, or occurred differently in each sex, or were not accompanied by histopathological effects.

For details, please refer to the attached background material 1.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross abnormalities were observed.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Main groups:
Control: No histopathological findings were observed in female rats. In male rats incidental findings were observed including light-grade necrosis of myocardial cells (1/10), light-graded fatty degeneration of liver cells accompanied with light-grade infiltration of inflammatory cells (1/10), light-grade fatty degeneration of liver cells (1/10), light-grade of infiltration of inflammatory cells of prostate (2/10).
2 mg/kg bw/day: No treatment-related abnormalities were observed in males and females.
8 mg/kg bw/day: In females light-grade of proliferation of squamous epithelium of forestomach (3/10) was observed. In males light-grade lymphocyte necrosis of thymus (2/10) was observed.
32 mg/kg bw/day: In female rats isolated cases of light-grade consolidation of pulmonary aveoli (1/10), light-grade infiltration of inflammatory cells of gastric mucosa (1/10), light-grade infiltration of inflammatory cells of gastric mucosa of the forestomach (1/10), light-grade proliferation of squamous epithelium accompanied with light-grade infiltration of inflammatory cells of the forestomach (1/10), middle-grade proliferation of squamous epithelium of the forestomach (1/10), light-grade proliferation of squamous epithelium of the forestomach (1/10) and middle-grade proliferation of squamous epithelium accompanied with light-grade filtration of inflammatory cells of forestomach (1/10)
In male rats light-grade fatty degeneration of the liver cells (1/10), middle-grade lymphocyte necrosis of thymus (3/10), middle-grade proliferation of squamous epithelium of the forestomach (2/10), light-grade proliferation of squamous epithelium of the forestomach (1/10) and light-grade of infiltration of inflammatory cells of prostate (2/10) were observed.

Satellite groups:
Control: In females, no treatment-related abnormalities were observed. In males, observed histopathological findings included middle-grade fatty degeneration of liver cells (1/10), light-grade fatty degeneration of liver cells (1/10), middle-grade of infiltration of inflammatory cells of prostate (2/10), light-grade of infiltration of inflammatory cells of prostate (1/10) and light-grade of prostate epithelium (1/10).
32 mg/kg bw/day: In females, no treatment-related abnormalities were observed. In males, observed histopathological findings included light-grade fatty degeneration of the liver cells (1/10) and light-grade of infiltration of inflammatory cells of prostate (2/10).

Only the effects observed on the forestomach in the main groups are considered to be treatment-related, but reversibile as they were not observed in the satellite animals.
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
Neoplastic changes were not examined.
Other effects:
not examined
Description (incidence and severity):
not applicable.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
2 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed at this dose level.
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
8 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed at this dose level.
Key result
Dose descriptor:
LOAEL
Remarks:
local
Effect level:
8 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
LOAEL
Remarks:
systemic
Effect level:
32 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical signs

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
The present study was conducted to assess the effects of the test substance on rats when given for 90 days. The study was performed according to the guidelines for the testing of chemicals section 4: Health effects (Ministry of Environmental Protection of People's Republic of China) and similar to OECD TG 408 under non-GLP conditions. Rats received the test substance via gavage at doses of 2, 8 and 32 mg/kg bw/day. Under the conditions of the test, the test substance caused a reduction in body weight and clinical signs including fluffy fur, slow breathing, ached back, delayed reaction and salivation were observed in rats treated with 32 mg/kg bw/day. Local effects were observed in the forestomach (histopathology) in animals treated with 8 mg/kg bw/day. Therefore, the systemic NOAEL was set to 8 mg/kg bw/day, while the local NOAEL was set to 2 mg/kg bw/day.