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Administrative data

Description of key information

In a subchronic toxicity study (90-day) a structurally analogous substance was administered to 10 Wistar rats/sex/dose by oral gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day. There were no compound-related mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights or gross or histopathology. The NOAEL is estimated to be 1000 mg/kg bw/day, the highest dose tested.

This data is deemed to be acceptable to address the repeated dose toxicity endpoints for Modified Small Vinyl Ester, in line with the read-across approach outlined within the REACH regulation and guidance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

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Endpoint:
sub-chronic toxicity: oral
Type of 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:
Remarks:
Read-across to a K1 study, therefore K2 is the maximum Klimisch value that can be allocated
Justification for type of information:
A full read-across justification is attached to section 13 of the dossier - please refer to this document to find the full detailed argumentation in support of the analogue approach.
Reason / purpose:
read-across source
Species:
rat
Strain:
Wistar
Remarks:
Wistar Han™:RccHan™:WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Envigo RMS (UK) Limited, Oxon, UK- Acclimation period: Nine days
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Administered daily, for ninety consecutive days.
Frequency of treatment:
Daily.
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
All animals were examined for overt signs of toxicity, ill-health or behavioral change immediately before dosing, up to thirty minutes post dosing and approximately one hour after dosing. 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 was recorded for each cage group at weekly intervals throughout the study. Water intake was observed daily, for each cage group.Detailed individual clinical observations were performed for each animal using a purpose built arena.Functional performance tests such as motor activity and forelimb/hindlimb grip strength.Sensory reactivity, opthalmoscopic examination (pre-treatment and at termination of treatment).Haematology and blood chemistry were exsmined at the end of the study.Terminal investigations included necropsy, organ weights, histopathology and pathology.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes Adrenals OvariesBrain SpleenEpididymides TestesHeart ThymusKidneys UterusLiverHISTOPATHOLOGY: Yes Adrenals OvariesAorta (thoracic) PancreasBone & bone marrow (femur including stifle joint)PituitaryBone & bone marrow (sternum) ProstateBrain (including cerebrum, cerebellum and pons) RectumCaecum Salivary glands (submaxillary)Colon Sciatic nerveDuodenum Seminal vesiclesEpididymides Skin (hind limb)Esophagus Spinal cord (cervical, mid-thoracic and lumbar)EyesGross lesions SpleenHeart StomachIleum (including Peyer’s patches) Testes Jejunum ThymusKidneys Thyroid/ParathyroidLiver TongueLungs (with bronchi) TracheaLymph nodes (mandibular and mesenteric)Urinary bladderMammary glandsUterus (with cervix)Muscle (skeletal)Vagina
Statistics:
Data were processed to give summary incidence or group mean and standard deviation values where appropriate. 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. 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 nonhomogeneity 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 w re unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric).
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Increased post-dosing salivation at 100, 300 and 1000 mg/kg bw/day. All animals were affected at top dose. Six males and eight females were affected at 300 mg/kg bw/day. At 100 mg/kg bw/day, this clinical sign was restricted to only one male and one female, on one single occasion for each animal.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Males showed statistically significant lower body weight gain intermittently throughout the study compared to controls at all dose groups. Females did not show this effect. There was no effect on food consumption at any of the dose groups that could attribute to the lower body weight gains.
Food efficiency:
no effects observed
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Ophthalmoscopic examinations of animals receiving 1000 mg/kg bw/day did not indicate any effect of treatment.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Males100 mg/kg bw/day300 mg/kg bw/day1000 mg/kg bw/dayHemoglobin ↓ ↓Hematocrit ↓ ↓ Erythrocyte count ↓Mean corpuscular volume ↓Females100 mg/kg bw/day300 mg/kg bw/day1000 mg/kg bw/dayErythrocyte count ↑ ↑Mean corpuscular volume ↓ ↓Leukocyte (lymphocyte) ↑ ↑
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Males100 mg/kg bw/day300 mg/kg bw/day1000 mg/kg bw/dayAspartate aminotransferase ↑Mean total cholesterol ↑Mean total protein ↓ ↓Mean bile acids ↑ ↑Total bilirubin ↑ ↑Females100 mg/kg bw/day300 mg/kg bw/day1000 mg/kg bw/dayAlanine aminotransferase ↑Total bilirubin ↑ ↑ ↑
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Grip strength and motor activity were unaffected by treatment at 100, 300 or 1000 mg/kg bw/day.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
In females absolute and body weight relative liver weights were higher in all dose groups. females also had statistically significant higher absolute and body weight relative thyroid weights at all dose groups, however this was not dose-dependent.In males lower mean absolute and higher mean body weight relative kidney weight attained statistical significance at 300 and 1000 mg/kg bw/day, however this was not dose-dependent.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
At 1000 mg/kg bw/day, adaptive minimal centrilobular hepatocyte hypertrophy of the liver was observed in 7/10 males and 8/10 females. Similar minimal centrilobular hepatocyte hypertrophy was also observed for one male at 300 mg/kg bw/day.At 1000 mg/kg bw/day, minimal hypertrophy of the follicular epithelium of the thyroid gland was observed in one male and female.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
ophthalmological examination
haematology
clinical biochemistry
behaviour (functional findings)
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Critical effects observed:
not specified
Conclusions:
A No Observed Adverse Effect Level (NOAEL) of 1000 mg/kg bw/day (the highest dose tested) is estimated for the test material based on the absence of any other findings considered to represent an adverse effect of treatment. Although body weight gain for males at both 300 and 100 mg/kg bw/day was lower than control, the lack of dosage dependency made any association with treatment equivocal and were not considered to be an adverse effect. The increased salivation observed in this study was not considered to be an adverse effect. The changes observed in the hematological, parameters blood chemistry parameters and organ weights were not considered to be adverse effects given that there were no accompanying adverse pathological findings. As the histopathological findings observed were considered to represent, or to be a consequence of , adaptive change for the liver, they were not considered to be represent an adverse effect.
Executive summary:

In a subchronic toxicity study the substance was administered to 10 Wistar rats/sex/dose by oral gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day). There were no compound-related mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights or gross or histopathology. The NOAEL is estimated to be 1000 mg/kg bw/day, the highest dose tested.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14th August 2015 to 12th November 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
The Study Plan target values for relative humidity (RH) was 50 ± 20%. This target range was exceeded on a number of occasions (ten days affected) with a maximum value of 78% RH being reached.
GLP compliance:
yes
Species:
rat
Strain:
Wistar
Remarks:
Wistar Han™:RccHan™:WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Envigo RMS (UK) Limited, Oxon, UK- Acclimation period: Nine days
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Administered daily, for ninety consecutive days.
Frequency of treatment:
Daily.
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
All animals were examined for overt signs of toxicity, ill-health or behavioral change immediately before dosing, up to thirty minutes post dosing and approximately one hour after dosing. 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 was recorded for each cage group at weekly intervals throughout the study. Water intake was observed daily, for each cage group.Detailed individual clinical observations were performed for each animal using a purpose built arena.Functional performance tests such as motor activity and forelimb/hindlimb grip strength.Sensory reactivity, opthalmoscopic examination (pre-treatment and at termination of treatment).Haematology and blood chemistry were exsmined at the end of the study.Terminal investigations included necropsy, organ weights, histopathology and pathology.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes Adrenals OvariesBrain SpleenEpididymides TestesHeart ThymusKidneys UterusLiverHISTOPATHOLOGY: Yes Adrenals OvariesAorta (thoracic) PancreasBone & bone marrow (femur including stifle joint)PituitaryBone & bone marrow (sternum) ProstateBrain (including cerebrum, cerebellum and pons) RectumCaecum Salivary glands (submaxillary)Colon Sciatic nerveDuodenum Seminal vesiclesEpididymides Skin (hind limb)Esophagus Spinal cord (cervical, mid-thoracic and lumbar)EyesGross lesions SpleenHeart StomachIleum (including Peyer’s patches) Testes Jejunum ThymusKidneys Thyroid/ParathyroidLiver TongueLungs (with bronchi) TracheaLymph nodes (mandibular and mesenteric)Urinary bladderMammary glandsUterus (with cervix)Muscle (skeletal)Vagina
Statistics:
Data were processed to give summary incidence or group mean and standard deviation values where appropriate. 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. 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 nonhomogeneity 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 w re unsuitable for these analyses, pair-wise tests was performed using the Student t-test (parametric) or the Mann-Whitney U test (non-parametric).
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Increased post-dosing salivation at 100, 300 and 1000 mg/kg bw/day. All animals were affected at top dose. Six males and eight females were affected at 300 mg/kg bw/day. At 100 mg/kg bw/day, this clinical sign was restricted to only one male and one female, on one single occasion for each animal.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Males showed statistically significant lower body weight gain intermittently throughout the study compared to controls at all dose groups. Females did not show this effect. There was no effect on food consumption at any of the dose groups that could attribute to the lower body weight gains.
Food efficiency:
no effects observed
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Ophthalmoscopic examinations of animals receiving 1000 mg/kg bw/day did not indicate any effect of treatment.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Males100 mg/kg bw/day300 mg/kg bw/day1000 mg/kg bw/dayHemoglobin ↓ ↓Hematocrit ↓ ↓ Erythrocyte count ↓Mean corpuscular volume ↓Females100 mg/kg bw/day300 mg/kg bw/day1000 mg/kg bw/dayErythrocyte count ↑ ↑Mean corpuscular volume ↓ ↓Leukocyte (lymphocyte) ↑ ↑
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Males100 mg/kg bw/day300 mg/kg bw/day1000 mg/kg bw/dayAspartate aminotransferase ↑Mean total cholesterol ↑Mean total protein ↓ ↓Mean bile acids ↑ ↑Total bilirubin ↑ ↑Females100 mg/kg bw/day300 mg/kg bw/day1000 mg/kg bw/dayAlanine aminotransferase ↑Total bilirubin ↑ ↑ ↑
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Grip strength and motor activity were unaffected by treatment at 100, 300 or 1000 mg/kg bw/day.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
In females absolute and body weight relative liver weights were higher in all dose groups. females also had statistically significant higher absolute and body weight relative thyroid weights at all dose groups, however this was not dose-dependent.In males lower mean absolute and higher mean body weight relative kidney weight attained statistical significance at 300 and 1000 mg/kg bw/day, however this was not dose-dependent.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
At 1000 mg/kg bw/day, adaptive minimal centrilobular hepatocyte hypertrophy of the liver was observed in 7/10 males and 8/10 females. Similar minimal centrilobular hepatocyte hypertrophy was also observed for one male at 300 mg/kg bw/day.At 1000 mg/kg bw/day, minimal hypertrophy of the follicular epithelium of the thyroid gland was observed in one male and female.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
ophthalmological examination
haematology
clinical biochemistry
behaviour (functional findings)
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Critical effects observed:
not specified
Conclusions:
A No Observed Adverse Effect Level (NOAEL) of 1000 mg/kg bw/day (the highest dose tested) is estimated for the test material based on the absence of any other findings considered to represent an adverse effect of treatment. Although body weight gain for males at both 300 and 100 mg/kg bw/day was lower than control, the lack of dosage dependency made any association with treatment equivocal and were not considered to be an adverse effect. The increased salivation observed in this study was not considered to be an adverse effect. The changes observed in the hematological, parameters blood chemistry parameters and organ weights were not considered to be adverse effects given that there were no accompanying adverse pathological findings. As the histopathological findings observed were considered to represent, or to be a consequence of , adaptive change for the liver, they were not considered to be represent an adverse effect.
Executive summary:

In a subchronic toxicity study the substance was administered to 10 Wistar rats/sex/dose by oral gavage at dose levels of 0, 100, 300 or 1000 mg/kg bw/day). There were no compound-related mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights or gross or histopathology. The NOAEL is estimated to be 1000 mg/kg bw/day, the highest dose tested.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Sufficient to address requirements

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Based on the findings of a reliable 90 day sub-chronic toxicity study conducted on a structurally analogous substance, classification of the substance is not justified.