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REACH

2,3-epoxypropyl neodecanoate

EC number: 247-979-2 | CAS number: 26761-45-5

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:: sub-chronic toxicity: oral
Type of information:: experimental study
Adequacy of study:: key study
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Qualifier:: according to guideline
Guideline:: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:: not applicable
GLP compliance:: yes
Limit test:: no
Specific details on test material used for the study:: See Section 1.2 and 1.4.
Species:: rat
Strain:: Wistar
Details on species / strain selection:: Species: Rat
Strain: Wistar HanTM
Sub-strain: RccHanTMzWIST
Source of supply: Envigo RMS (UK) Ltd., Oxon, UK
Number: 80
Sex: Males and females
Age: Approximately 7 weeks on arrival
Weight Range: Males 188 — 235 g and Females 143 — 186 g
Sex:: male/female
Details on test animals or test system and environmental conditions:: Environmental conditions will be maintained within the following target parameters:
Target temperature: 22 +/- 3 °C
Target humidity: 30 to 70%
Lighting: Twelve hours of continuous artiﬁcial light in each twenty-four hour
period
Ventilation: At least ﬁfteen air changes per hour
Animals will be housed in accordance with the ‘Code of Practice for the Housing and Care of
Animals Used in Scientiﬁc Procedures’ and in alignment with the United Kingdom Home
Ofﬁce recommendations and requirements.

Animals were gang-housed in groups of up to four by sex in polypropylene cages with stainless steel mesh lids and furnished with softwood ﬂake bedding (Datesand Ltd., Cheshire, UK).

Certiﬁcates of analysis for the bedding will be provided by the supplier.

The bedding is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity ofthe study.

Diet and Water
The animals were provided with Rodent 2014C Teklad Global Certiﬁed Pelleted Diet (Envigo RMS (UK) Ltd., Oxon, UK) and tap water ad libitum.

Drinking water is routinely analyzed (at least annually) and certiﬁcates of analysis for diet will be provided by the supplier.

The diet and drinking water are considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity ofthe study.

Environmental Enrichment
The animals were provided with environmental enrichment items: wooden chew blocks and cardboard fun tunnels (Datesand Ltd., Cheshire, UK) or suitable alternatives. Any alternatives used will be documented in the raw data for the study.

Certiﬁcates of analysis for the environmental enrichment items will be provided by the supplier.

These enrichment items are considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity ofthe study.

Pre—Test Procedures
Acclimatization Period
From arrival to the start of treatment was nine days A proportion ofthe animals will be weighed to conﬁrm arrival body weights are ofthe correct speciﬁcation.

Allocation
Animals were allocated to dose groups using a randomization procedure based on body weight at least ﬁve days prior to the start oftreatment. Animals were weighed on Day — 2 to ensure group mean are within an acceptable range.

Identification
Each animal was uniquely identiﬁed within the study by ear-punch. A color-coded cage card will be prepared with details of test item, study number, dose level, sex, numbers of animals, route of administration and Study Director responsible for the study.
Route of administration:: oral: gavage
Details on route of administration:: Once daily, by gavage, using a stainless steel dosing cannula attached to a graduated syringe for ninety consecutive days.
Vehicle:: arachis oil
Details on oral exposure:: Animals will be allocated to test groups as follows:

Dose groups Group Size Animal Numbers Treatment Necropsy
& Sex Males Females period Day
1. Control 10 male & 10 female 1-10 11-20 90 days 91
2. 100 mg/kg bw/d 10 male & 10 female 21-30 31-40 90 days 91
3. 300 mg/kg bw/d 10 male & 10 female 41-50 51-60 90 days 91
4. 1000 mg/kg bw/d 10 male & 10 female 61-70 71-80 90 days 91
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: For the purpose of this study the test item was prepared at the appropriate concentrations as a solution in Arachis oil BP. The stability and homogeneity of the test item formulations were determined by Envigo Research Limited, Shardlow, UK, Analytical Services as part of this study. Results from the previous study show the formulations to be stable for at least 23 days when stored at approximately 4 °C in the dark. Formulations were therefore prepared fortnightly and stored at approximately 4 °C in the dark.

Samples of each test item formulation were taken on two occasions during the study and analyzed for concentration of 2,3-epoxypropyl neodecanoate at Envigo Research Limited, Shardlow, UK, Analytical Services. The method used for analysis of formulations and the results obtained are given in Annex 2. The results indicate that the prepared formulations were within 95-100% of the nominal concentration.
Duration of treatment / exposure:: 90 days
Frequency of treatment:: Once per day
Dose / conc.:: 0 mg/kg bw/day (actual dose received)
Dose / conc.:: 100 mg/kg bw/day (actual dose received)
Dose / conc.:: 300 mg/kg bw/day (actual dose received)
Dose / conc.:: 1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:: 10
Control animals:: yes, concurrent vehicle
Observations and examinations performed and frequency:: Morbidity/Mortality Inspection
Twice daily, early and late during the working period.

Clinical Observations
All animals were examined for overt signs of toxicity, ill-health or behavioral change immediately before dosing, up to thirty minutes post dosing and one hour after dosing. All observations were recorded.

Body Weights
Individual body weights were recorded on Day 1 (prior to dosing) and at weekly intervals thereafter. Body weights were also recorded at terminal kill.

Food Consumption
Food consumption was recorded for each cage group at weekly intervals throughout the study. Food conversion efficiency was calculated retrospectively.

Water Consumption
Water intake was measured and recorded daily for each cage group during the first two weeks of the study and during Weeks 10 to 11.

Specialist Evaluations
Functional Observations
Prior to the start of treatment and at weekly intervals thereafter, all animals were observed for signs of functional/behavioral toxicity. During Week 12 functional performance tests were also performed on all animals together with an assessment of sensory reactivity to different stimuli.

Behavioral Assessment
Detailed individual clinical observations were performed for each animal using a purpose built arena. The following parameters were observed:
Gait Hyper/Hypothermia
Tremors Skin color
Twitches Respiration
Convulsions Palpebral closure
Bizarre/Abnormal/Stereotypic behavior Urination
Salivation Defecation
Pilo-erection Transfer arousal
Exophthalmia Tail elevation
Lachrymation

This test was developed from the methods used by Irwin (1968) and Moser et al (1988). The scoring system used is outlined in The Key to Scoring System and Explanation for Behavioral Assessments and Sensory Reactivity Tests.

Ophthalmoscopy
The eyes of all animals were examined pre-treatment and before termination of treatment (during Week 12). The eyes of all surviving control and high dose animals were examined before termination of treatment (during Week 12). Examinations included observation of the anterior structures of the eye, pupillary and corneal blink reflex. Following pupil dilation with 0.5% Tropicamide solution (Mydriacyl® 0.5%, Alcon Laboratories (UK) Ltd., Pentagon Park, Boundary Way, Hemel Hampstead, Hertfordshire), detailed examination of the internal structure of the eye using a direct ophthalmoscope was performed.

In-life Sampling and Analysis
Hematological and blood chemical investigations were performed on all surviving animals from each test and control group at the end of the study (Day 90). Blood samples were obtained from the lateral tail vein. Where necessary repeat samples were obtained by cardiac puncture prior to necropsy on Day 91. Animals were not fasted prior to sampling.

Hematology
Hemoglobin (Hb)
Erythrocyte count (RBC)
Hematocrit (Hot)
Erythrocyte indices
- mean corpuscular hemoglobin (MCH)
- mean corpuscular volume (MCV)
- mean corpuscular hemoglobin concentration (MCHC)
Total leucocyte count (WBC)
Differential leucocyte count
- neutrophils (Neut)
- lymphocytes (Lymph)
- monocytes (Mono)
- eosinophils (Eos)
- basophils (Bas)
Prothrombin time (CT)
Platelet count (PLT)
Activated partial thromboplastin time (APTT)
Reticulocyte count* (Retic)

*Blood ﬁlm will be prepared but only examined at Study Director’s discretion

Blood Chemistry
Urea Inorganic phosphorus (P)
Glucose Aspartate aminotransferase (ASAT)
Total protein (Tot.Prot.) Alanine aminotransferase (ALAT)
Albumin Alkaline phosphatase (AP)
Albumin/Globulin (A/G) ratio (by calculation) Creatinine (Creat)
Sodium (Na+) Total cholesterol (Chol)
Potassium (K+) Total bilirubin (Bili)
Chloride (Cl-) Bile acids
Calcium (CaH)
Sacrifice and pathology:: On completion of the dosing period all surviving animals were killed by intravenous overdose of a suitable barbiturate agent followed by exsanguination.
All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.

Gross Examination
Full external and internal macroscopic examination of all animals.

Organ Weights
The following organs, removed from animals that were killed at the end of the study, were dissected free from fat and weighed before fixation:
Adrenals Ovaries
Brain Spleen
Epididymides Testes
Heart Thymus
Kidneys Uterus
Liver

Histopathology
Samples of the following tissues were removed from all animals and preserved in buffered 10% formalin, except where stated:
Adrenals Ovaries
Aorta (thoracic) Pancreas
Bone & bone marrow (femur including stifle joint)• Pituitary
Bone & bone marrow (sternum) Prostate
Brain (including cerebrum, cerebellum and pons) Rectum
Caecum Salivary glands (submaxillary)
Colon Sciatic nerve
Duodenum Seminal vesicles
Epididymides ♦ Skin
Esophagus Spinal cord (cervical, mid-thoracic
Eyes* and lumbar)
Gross lesions Spleen
Heart Stomach
Ileum (including Peyer’s patches) Testes ♦
Jejunum Thymus
Kidneys Thyroid/Parathyroid
Liver Tongue•
Lungs (with bronchi) # Trachea
Lymph nodes (mandibular and mesenteric) Urinary bladder
Mammary glands Uterus (with cervix)
Muscle (skeletal)• Vagina
• Retained only and not processed
* Eyes fixed in Davidson’s fluid
♦ Preserved in Modified Davidson’s fluid
# Lungs were inflated to approximately normal inspiratory volume with buffered 10% formalin before immersion in fixative
• Retained only and not processed

All tissues were dispatched to the Test Site (Propath UK Ltd, Willow Court, Netherwood Road, Rotherwas, Hereford, HR2 6JU) for processing (Principal Investigator: N Fower). All tissues from control and 1000 mg/kg bw/day dose group animals were prepared as paraffin blocks, sectioned at a nominal thickness of 5 µm and stained with Hematoxylin and Eosin for subsequent microscopic examination. Any macroscopically observed lesions were also processed.
Since there were indications of treatment-related changes, examination was subsequently extended to include similarly prepared sections of liver and thyroid gland (both sexes), kidney (males only) from animals in the low and intermediate groups.

Pathology
Microscopic examination was conducted by the Study Pathologist (W Henderson). A peer review of the findings observed was conducted by V Mowat at Envigo CRS Limited, Woolley Road, Alconbury, Huntingdon, Cambridgeshire, PE28 4HS. A complete histopathology phase report is presented in Annex 1 and represents the consensus view of both pathologists.
Statistics:: Data Evaluation
Data were processed to give summary incidence or group mean and standard deviation values where appropriate. All data were summarized in tabular form.

Statistical Analysis
Where considered appropriate, quantitative data was subjected to statistical analysis to detect the significance of intergroup differences from control; statistical significance was achieved at a level of p<0.05. Statistical analysis was performed on the following parameters:
Grip Strength, Motor Activity, Body Weight Change, Hematology, Blood Chemistry, Absolute Organ Weights, Body Weight-Relative Organ Weights.

Data were analyzed using the decision tree from the ProvantisTM Tables and Statistics Module as detailed as follows:
Where appropriate, data transformations were performed using the most suitable method. The homogeneity of variance from mean values was analyzed using Bartlett’s test. Intergroup variances were assessed using suitable ANOVA, or if required, ANCOVA with appropriate covariates. Any transformed data were analyzed to find the lowest treatment level that showed a significant effect using the Williams Test for parametric data or the Shirley Test for non-parametric data. If no dose response was found but the data shows non-homogeneity of means, the data were analyzed by a stepwise Dunnett’s (parametric) or Steel (non-parametric) test to determine significant difference from the control group. Where the data were unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric).

Probability values (p) are presented as follows:
p<0.01 **
p<0.05 *
p>0.05 (not significant)
Description (incidence and severity):: Incidences of increased salivation were evident in animals of either sex treated with 300 or 1000 mg/kg bw/day throughout the treatment period and, to a lesser extent, in males treated with 100 mg/kg bw/day. Observation of this nature are commonly observed following the oral administration of an unpalatable or slightly irritant test item and, in isolation, are considered not to be associated with systemic toxicity.

Incidental findings included two males and one female treated with 1000 mg/kg bw/day, and two males treated with 300 mg/kg bw/day showed sporadic instances of noisy respiration during the treatment period. Isolated instances of hunched posture, staining around the mouth and scab formations followed by fur loss were also evident at 1000 mg/kg bw/day.
Mortality:: mortality observed, non-treatment-related
Description (incidence):: There were two unscheduled deaths on the study; two control females.

On Day 38 of treatment, one control female (No. 14) was killed in extremis due to a physical injury to the tail (55mm of skin was missing). There were no clinical signs or body weight issues prior to death. There were no further macroscopic findings at necropsy.

A further control female (No. 16) died during the blood sampling procedure on Day 90 of treatment. There were no clinical signs or macroscopic necropsy findings.
Description (incidence and severity):: There were no adverse effects to body weight development at 100, 300 or 1000 mg/kg bw/day.

Males at 1000 mg/kg bw/day showed comparable body weight gains to controls during the first three weeks of treatment. For the majority of the remaining treatment period these males showed statistically significantly lower (p<0.05 - p<0.01) group mean body weight gains compared to controls, as a number of animals showed low body weight gains during this time. This resulted in overall body weight gains to be 16% lower than controls, as all the animals showed body weight gains this reduction was considered to be associated with biological variation.

At 300 mg/kg bw/day, males also showed some fluctuation in body weight gains during the treatment period. These fluctuations resulted in overall body weight gains to be slightly lower (5%) than controls.

Females treated with 300 or 1000 mg/kg bw/day generally showed similar body weight gains to controls, however, the overall body weight gain for these animals was 7% and 3% lower than controls.

Animals of either sex treated with 100 mg/kg bw/day generally showed no effects to treatment in relation to controls. On some occasions these animals exceeded the weights gains of the controls. Therefore the overall body weight gains were 15% and 7% higher than controls (males and females respectively).
Description (incidence and severity):: There were no adverse effects detected for food consumption or food conversion efficiency at 100, 300 or 1000 mg/kg bw/day.
Description (incidence and severity):: Gravimetric measuring of water intake was performed during weeks 1, 2, 10 and 11 of treatment. An increase in water intake was apparent in animals of either sex treated with 1000 mg/kg bw/day of approximately 25%. This would correlate with the frequency and severity of the increased salivation in these animals.
Description (incidence and severity):: Ophthalmoscopic examination of surviving animals of both sexes from the control and animals from the 1000 mg/kg bw/day dose group during Week 12 of the treatment period did not indicate any treatment-related differences.
Description (incidence and severity):: At 1000 mg/kg bw/day, males showed a statistically significant reduction in hemaglobin (Hb) (p<0.01), erythrocyte count (RBC) (p<0.05) and hematocrit (Hct) (p<0.05) compared to controls. The majority of the individual values for each parameter were below the background control ranges which may indicate hemolytic anemia influenced by the histopathological changes to the liver.

There was considered to be no toxicological significant differences in hematology parameters for both sexes at 100 or 300 mg/kg bw/day or for females at 1000 mg/kg bw/day. Females treated with 100 mg/kg bw/day showed a statistically significant increase (p<0.05) in mean corpuscular hemaglobin concentration (MCHC) compared to controls. All individual values were within the background control ranges; albeit at the upper end of the range which could have influenced the statistical significance and as there were no histopathological correlates, it is considered that this finding is of no toxicological significance.
Description (incidence and severity):: All treatment dose groups for males and females showed an increase in bilirubin (p<0.05 – p<0.01) with the exception of 100 mg/kg bw/day females. Animals of either sex did not show a dose related response and the majority of individual values were within the background control ranges. Two male and three female control values were actually below historical control values. However, increased bilirubin can be associated with the reductions in Hb, Hct and RBC in the 1000 mg/kg bw/day males.

At 1000 mg/kg bw/day males displayed an increase in alkaline phosphatase (AP) and bile acid (p<0.01 and p<0.05, respectively) when compared to controls. The majority of individual values were within the background control ranges, however, these elevations may be associated to the histopathological changes of the liver.

Males treated with 100 or 300 mg/kg bw/day showed a statistically significant reduction in albumin/globulin ratio (p<0.05) without a dose related response. The majority of the individual values were below the background control ranges and without a similar response at the higher dose level, this finding is considered to be of no toxicological significance.

Females treated with 300 or 1000 mg/kg bw/day showed a reduction in urea (p<0.05) in a dose related manner. The majority of individual values were within the background control range and with no histopathological correlates this finding was considered to be of no toxicological importance. The 1000 mg/kg bw/day females also had a reduction in phosphorus (p<0.05) in a dose related response, the majority of individual values were within the background control ranges; however, four control values were above these ranges and may influenced the statistical significance attained due to the higher group mean of the controls. Therefore the significance of this finding is considered to be of no toxicological importance.
Description (incidence and severity):: A number of animals treated at 1000 mg/kgbw/day showed sporadic instances of increased salivation during behavioral assessments in the treatment period with a range of severity from slight to extreme. These observations correlate with the daily clinical observations evident at this dosage. In isolation one female treated at 1000 mg/kg bw/day showed hunched posture during these assessments on Weeks 3 to 6 and exhibited decreased respiratory rate during Week 3.

No observations were detected for animals treated with 100 or 300 mg/kg bw/day.

There were no toxicological changes in the functional parameters measured at 100, 300 or 1000 mg/kg bw/day.

Females treated with 100 mg/kg bw/day showed a statistically significant increase (p<0.05) in overall motor activity. Without similar effects at the higher dose levels and in the absence of any clinical signs of neurotoxicity, the intergroup difference was considered not to be of toxicological importance.

Intergroup differences observed in the scores for sensory reactivity did not indicate any effect of treatment for either sex at 100, 300 or 1000 mg/kg bw/day.
Description (incidence and severity):: Kidney: Males treated with 300 or 1000 mg/kg bw/day showed an increase (p<0.05 and p<0.01, respectively) in both absolute and relative kidney weights compared to controls. The individual values for one and eight males (300 or 1000 mg/kg bw/day, respectively) showed absolute kidneys weights were above the background control ranges. The values for relative kidney weights showed that two and all ten males treated with 300 and 1000 mg/kg bw/day, respectively were above the background control ranges.
An increase was also evident in the corresponding female kidney weights at 300 and 1000 mg/kg bw/day (p<0.01) compared to controls. The individual absolute values showed that 2/10 kidneys weights from each dose group were above the background control ranges, showing a dose related response. Relative values also showed a dose related increase with four and eight females exceeding the background control ranges. The increase may be related to the increase of water intake but with no histopathological correlates this finding is considered to be of no toxicological significance.

Liver: All male treated dose groups showed an increase (p<0.05 - p<0.01) in absolute liver weight compared to controls, without a dose relationship present. The individual values of five, four and seven males (100, 300 and 1000 mg/kg bw/day, respectively) showed their liver weights were above the background control ranges. A further review of these liver weights relative to terminal body weight indicated six, eight and all ten males exceeded the background control ranges (100, 300 and 1000 mg/kg bw/day, respectively) although one control male value was also above historical control values. The corresponding females treated with 100, 300 or 1000 mg/kg bw/day also showed an increase (p<0.05 - p<0.01) in liver weights both absolute and relative to terminal body weight in a dose related response. Absolute individual values for females treated with 100 or 300 mg/kg bw/day were all within the background control ranges and all 1000 mg/kg bw/day values were above this range. The relative individual values showed that two, five and all ten females (100, 300 and 1000 mg/kg bw/day, respectively). The increase in liver weight for both males and females at 1000 mg/kg bw/day is considered to be associated with the histopathological changes.

Testes: At 1000 mg/kg bw/day males showed a statistically significant increase (p<0.05) in testis weights compared to controls for both absolute and relative organ weights. The individual values indicated that 3/10 and 6/10 values were above the normal background ranges for absolute and relative weights, respectively and with no histopathological correlates this finding was considered to be of no toxicological significance. It is also noted that 3/10 control absolute testis weights were above historical control values.
Description (incidence and severity):: Kidney
Increased hyaline droplets, granular casts and multifocal basophilic tubules or nephropathy were present in all males treated with 1000 mg/kg bw/day. The hyaline droplet formation extended to all males at 300 mg/kg bw/day with 5/10 males also showing granular casts and tubular basophilia. Hyaline droplet formation was seen in 4/10 males at 100 mg/kg bw/day. Hyaline droplet accumulation is specific to the male rat and is not generally considered to be significant in man. However, multifocal basophilic tubules/nephropathy and granular casts, generally considered to be associated with the hyaline droplet accumulation, are considered to be adverse.

Liver
Hepatocellular hypertrophy, mainly in the centrilobular area was present in 4/10 males and 5/10 females treated with 1000 mg/kg bw/day. One male at 100 mg/kg bw/day was also found to have this condition. These changes are suggestive of an adaptive response to mixed function oxidase induction in the liver and correlates with the increase in organ weights

Thyroid Glands
Hypertrophy of the follicular epithelium was present in 6/10 males and 5/10 females treated with 1000 mg/kg bw/day. It was also observed amongst 6/10 males and 1/10 females at 300 mg/kg bw/day and 3/10 males and 1/10 females at 100 mg/kg bw/day. The hypertrophy was considered likely to be linked to the histopathological change in the liver where the underlying mechanism is considered to be increased hepatic clearance of thyroid hormones, causing compensatory hypertrophy of follicular cells.
: Key result
Dose descriptor:: NOAEL
Effect level:: 100 mg/kg bw/day (actual dose received)
Based on:: test mat.
Sex:: male
Basis for effect level:: histopathology: non-neoplastic
: Key result
Dose descriptor:: NOAEL
Effect level:: 1 000 mg/kg bw/day (actual dose received)
Based on:: test mat.
Sex:: female
Basis for effect level:: other: No adverse effect
Critical effects observed:: not specified