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Administrative data

Description of key information

2 oral subacute toxicity studies were performed (OECD 407 and OECD 421) with the test substance and no significant adverse effect was observed.

A NOAEL of 1000 mg/kg was determined for subchronic toxicity based on a weight of evidence strategy using the read-across; indeed 2 subchronic toxicity studies (OECD 408) are available on supporting "source substances", "xylitol" and " D-Glucose, ether with glycerol optonal (CAS 100402-60-6 / EC 309-496-6)" and showed no significant adverse effect (NOAEL for systemic toxicity = 1000 mg/kg).

Based on robust 90d studies available on the source substances and taking into consideration that the 28d study failed to demonstrate any significant adverse effect related to the target substance (NOAEL = 1000 mg/kg) , the NOAEL value of the target substance for the systemic sub-chronic toxicity (OECD 408, oral, rat) can be determined at 1000 mg/kg bw by read-across.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline, GLP study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
2003-02-13
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
A sufficient number of male and female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats were obtained from Charles River (UK) Limited, Margate, Kent. On receipt the animals were examined for signs of ill-health or injury. The animals were acclimatised for 7 days during which time their health status was assessed. A total of forty animals (twenty males and twenty females) were accepted into the study. At the start of treatment the males weighed 147 to 182g, the females weighed 129 to 159g, and were approximately five to eight weeks old.

The animals were housed in groups of five by sex in polypropylene grid-floor cages suspended over trays lined with absorbent paper. The animals were allowed free access to food and water.
A pelleted diet (Rodent 5LF2 (Certified), BCM IPS Limited, London, UK) was used.
Mains drinking water was supplied from polycarbonate bottles attached to the cage. The diet and drinking water were considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study. Environmental enrichment was provided in the form of wooden chew blocks (B & K Universal Ltd., Hull, UK) and cardboard fun tunnels (Datesand Ltd., Cheshire, UK).
The animals were housed in a single air-conditioned room within the Safepharm Barrier Maintained Rodent Facility. The rate of air exchange was at least fifteen air changes per hour and the low intensity fluorescent lighting was controlled to give twelve hours continuous light and
twelve hours darkness. Environmental conditions were continuously monitored by a computerised system, and print-outs of hourly mean temperatures and humidities were included in the study records. The temperature and relative humidity controls were set to achieve target
values of 21 ± 2ºC and 55 ± 15% respectively. Deviations from these targets were considered not to have affected the purpose or integrity of the study.

The animals were randomly allocated to treatment groups using a total randomisation procedure and the group mean bodyweights were determined to ensure similarity between the treatment groups. The cage distribution within the holding rack was also randomised. The animals were
uniquely identified within the study by an ear punching system routinely used in these laboratories.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distilled
Details on oral exposure:
Method of administration:
gavage
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of water were accurately fortified with known amounts of test material, and analysed.
The analytical method has been considered to be sufficiently accurate for the purpose of this study. The test sample results have not been corrected for recovery.
The analytical method has been satisfactorily validated in terms of linearity, specificity and accuracy for the purposes of the study.
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
Remarks:
Doses / Concentrations:
0 mg/L
Basis:
actual ingested
Remarks:
Doses / Concentrations:
15 mg/L
Basis:
actual ingested
Remarks:
Doses / Concentrations:
150 mg/L
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/L
Basis:

No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Details on study design:
The animals were randomly allocated to treatment groups using a total randomisation procedure and the group mean bodyweights were determined to ensure similarity between the treatment groups. The cage distribution within the holding rack was also randomised. The animals were uniquely identified within the study by an ear punching system routinely used in these laboratories.

The dose levels were chosen based on the results of the range-finder presented in the second part of the report. The oral gavage route was selected as the most appropriate route of exposure, based on the physical properties of the test material, and the results of the study are believed to be of value in predicting the likely toxicity of the test material to man.
Observations and examinations performed and frequency:
Clinical Observations
All animals were examined for overt signs of toxicity, ill-health or behavioural change immediately before dosing, immediately post dosing and one and five hours after dosing during the working week. Animals were observed immediately before dosing, immediately post dosing and one hour after dosing at weekends. All observations were recorded.

Functional Observations
Prior to the start of treatment and on Days 6, 13, 20 and 24, all animals were observed for signs of functional/behavioural toxicity. Functional performance tests were also performed on all animals during Week 4, together with an assessment of sensory reactivity to different stimuli.
Observations were carried out from approximately two hours after dosing on each occasion.

Behavioural Assessments
Detailed individual clinical observations were performed for each animal using a purpose built arena. The following parameters were observed:
Gait Hyper/Hypothermia
Tremors Skin colour
Twitches Respiration
Convulsions Palpebral closure
Bizarre/Abnormal/Stereotypic behaviour Urination
Salivation Defecation
Pilo-erection Transfer arousal
Exophthalmia Tail elevation
Lachrymation
The scoring system used is outlined in the Key to Scoring System and Explanation for
Behavioural Assessments and Sensory Reactivity Tests.

Functional Performance Tests
Motor Activity. Twenty purpose built 44 infra-red beam automated activity monitors were used to assess motor activity. Animals of one sex were tested on each occasion and were randomly allocated to the activity monitors. The tests were performed at approximately the same time, under similar laboratory conditions. The evaluation period was one hour for each animal. The percentage of time each animal was active and mobile was recorded for the overall one hour period and also during the final 20% of the period (considered to be the asymptotic period).
Forelimb/Hindlimb Grip Strength. An automated grip strength meter was used. Each animal was allowed to grip the proximal metal bar of the meter with its forepaws. The animal was pulled by the base of the tail until its grip was broken. The animal was drawn along the trough of the
meter by the tail until its hind paws gripped the distal metal bar. The animal was pulled by the base of the tail until its grip was broken. A record of the force required to break the grip for each animal was made. Three consecutive trials were performed for each animal.

Sensory Reactivity
Each animal was individually assessed for sensory reactivity to auditory, visual and proprioceptive stimuli. The scoring system used is outlined in the key to scoring system and explanation for behavioural assessments and sensory reactivity tests. The following parameters
were observed:
Grasp response Touch escape
Vocalisation Pupil reflex
Toe pinch Blink reflex
Tail pinch Startle reflex
Finger approach

Bodyweight
Individual bodyweights were recorded on Day 1 and at weekly intervals thereafter. Bodyweights were also performed prior to terminal kill.

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

Water Consumption
Water intake was observed daily, for each cage group, by visual inspection of the water bottles for any overt changes.

Laboratory Investigations
Haematological and blood chemical investigations were performed on all animals from each test and control group at the end of the study (Day 28). Blood samples were obtained from the lateral tail vein. Where necessary repeat samples were obtained by cardiac puncture prior to necropsy on Day 29. Animals were not fasted prior to sampling.

Haematology
The following parameters were measured on blood collected into tubes containing potassium EDTA anti-coagulant:
Haemoglobin (Hb)
Erythrocyte count (RBC)
Haematocrit (Hct)
Erythrocyte indices - mean corpuscular haemoglobin (MCH)
- mean corpuscular volume (MCV)
- mean corpuscular haemoglobin concentration (MCHC)
Total leucocyte count (WBC)
Differential leucocyte count - neutrophils (Neut)
- lymphocytes (Lymph)
- monocytes (Mono)
- eosinophils (Eos)
- basophils (Bas)
Platelet count (PLT)
Reticulocyte count (Retic) - Cresyl blue stained slides were prepared but reticulocytes were not assessed
Prothrombin time (CT) was assessed by ‘Thrombomax HS with calcium’ and Activated partial thromboplastin time (APTT) was assessed by ‘CK Prest’ using samples collected into sodium citrate solution (0.11 mol/l)

Blood Chemistry
The following parameters were measured on plasma from blood collected into tubes containing lithium heparin anti-coagulant:
Urea Calcium (Ca++)
Glucose Inorganic phosphorus (P)
Total protein (Tot.Prot.) Aspartate aminotransferase (ASAT)
Albumin Alanine aminotransferase (ALAT)
Albumin/Globulin (A/G) ratio (by calculation) Alkaline phosphatase (AP)
Sodium (Na+) Creatinine (Creat)
Potassium (K+) Total cholesterol (Chol)
Chloride (Cl-) Total bilirubin (Bili)
Sacrifice and pathology:
Pathology
On completion of the dosing period all animals were killed by intravenous overdose of sodium pentobarbitone followed by exsanguination.
All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
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
Brain (including cerebrum, cerebellum and pons)
Epididymides
Heart
Kidneys
Liver
Ovaries
Spleen
Testes
Thymus

Histopathology
Samples of the following tissues were removed from all animals, plus any gross lesions, and preserved in buffered 10% formalin:
Adrenals
Aorta (thoracic)
Bone and bone marrow (femur including stifle joint)
Bone and bone marrow (sternum)
Brain (including cerebrum, cerebellum and pons)
Caecum
Colon
Duodenum
Epididymides
Eyes
Heart
Ileum
Jejunum
Kidneys
Liver
Lungs (with bronchi)
Lymph nodes (cervical)
Lymph nodes (mesenteric)
Muscle (skeletal)
Oesophagus
Ovaries
Parathyroid
Pancreas
Pituitary
Prostate
Rectum
Salivary glands (submaxillary)
Sciatic nerve
Seminal vesicles
Skin (hind limb)
Spinal cord (cervical)
Spleen
Stomach
Testes
Thymus
Thyroid
Trachea
Urinary bladder
Uterus

All tissues were despatched to the Test Site (histology processing) for processing (Principal Investigator: M Carpenter). The tissues shown below, plus any gross lesions, from all control and 1000 mg/kg/day dose group animals were prepared as paraffin blocks, sectioned at nominal thickness of 5 μm and stained with haematoxylin and eosin for subsequent microscopic examination.
Adrenals
Bone and bone marrow (sternum)
Brain (including cerebrum, cerebellum and pons)
Caecum
Colon
Duodenum
Epididymides
Heart
Ileum
Jejunum
Kidneys
Liver
Lungs (with bronchi)
Lymph nodes (cervical)
Lymph nodes (mesenteric)
Ovaries
Parathyroid
Prostate
Rectum
Sciatic nerve
Seminal vesicles
Spinal cord (cervical)
Spleen
Stomach
Testes
Thymus
Thyroid
Trachea
Urinary bladder
Uterus
Any macroscopically observed lesions were also processed together with the liver and spleen from all 15 and 150 mg/kg/day dose group animals.
Since there were no indications of treatment-related changes, examination was not subsequently extended to the remaining groups.
Microscopic examination was conducted by the Study Pathologist. All findings were entered into the ROELEE Pathology computerisation system for tabulation and report production.
Clinical signs:
no effects observed
Description (incidence and severity):
There were no unscheduled deaths during the study.
Mortality:
no mortality observed
Description (incidence):
There were no unscheduled deaths during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No adverse effect on bodyweight development was detected for test or control animals throughout the treatment period.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There was no adverse effect on food consumption during the study.
Food efficiency:
no effects observed
Description (incidence and severity):
Food efficiency (the percentage ratio of bodyweight gain to dietary intake) in test animals was similar to that of controls. Statistical analysis of the data revealed no significant intergroup differences.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Daily visual inspection of water bottles revealed no intergroup differences.
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related changes detected in the haematological parameters measured.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no treatment-related changes detected in the blood chemical parameters measured.
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no treatment-related organ weight changes detected.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no treatment-related histological changes in the tissues examined.
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
<= 1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Critical effects observed:
not specified
Conclusions:
Oral administration of test item to rats for a period of twenty-eight consecutive days, at dose levels of up to 1000 mg/kg/day, produced no toxicologically significant effects in the parameters investigated.
The ‘No Observed Effect Level’ (NOEL) was therefore considered to be 1000 mg/kg/day.
Executive summary:

Introduction.

The study was designed to investigate the systemic toxicity of the test material. It complies with the requirements for notification of a new chemical substance in the EC and follows the testing method described in Commission Directive 96/54/EC (Method B7) and OECD Guidelines for Testing of Chemicals No. 407 "Repeated Dose 28 Day Oral Toxicity Study in Rodents" (Adopted 27 July 1995). This study complies with the GLP.

Methods.

The test material was administered by oral gavage to three groups, each of five male and five female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for twenty-eight consecutive days, at dose levels of 15, 150 and 1000 mg/kg/day. A control group of five males and five females was dosed with vehicle alone (Distilled water).

Clinical signs, functional observations, bodyweight development and food and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for all animals at the end of the study. All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues from high dose and control animals was performed.

Results.

Mortality. There were no unscheduled deaths during the study. Clinical Observations. No clinically observable signs of toxicity were detected in test or control animals throughout the treatment period. Behavioural Assessment. There were no treatment-related changes detected. Functional Performance Tests. There were no treatment-related changes detected. Sensory Reactivity

Assessments.

There were no treatment-related changes detected. Bodyweight. No adverse effect on bodyweight development was detected.

Food Consumption. No adverse effect on dietary intake or food efficiency was detected.

Water Consumption. No overt intergroup differences were detected.

Haematology. No treatment-related haematological effects were detected.

Blood Chemistry. No treatment-related blood chemical effects were detected.

Organ Weights. No treatment-related organ weight changes were detected.

Necropsy. No treatment-related macroscopic abnormalities effects were detected.

Histopathology. No treatment-related microscopic abnormalities effects were detected.

Conclusion.

Oral administration of test item to rats for a period of twenty-eight consecutive

days, at dose levels of up to 1000 mg/kg/day, produced no toxicologically significant effects in

the parameters investigated.

The ‘No Observed Effect Level’ (NOEL) was therefore considered to be 1000 mg/kg/day.

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
See the document in section 13 of IUCLID entitled "Rationale & justification for the read-across for “D-glucopyranose, oligomers, xylityl glycosides and 1,4 anhydro D-xylitol and D-xylitol” (Human health endpoints)"
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
not specified
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: no siginificant adverse effect noted
Critical effects observed:
not specified
Conclusions:
Based on robust 90d studies available on the source substances and taking into consideration that the 28d study failed to demonstrate any significant adverse effect related to the target substance (NOAEL = 1000 mg/kg) , the NOAEL of the target substance for the systemic sub-chronic toxicity (OECD 408, oral, rat) can be determined at 1000 mg/kg bw by read-across.
See the document in section 13 of IUCLID entitled "Rationale & justification for the read-across for “D-glucopyranose, oligomers, xylityl glycosides and 1,4 anhydro D-xylitol and D-xylitol” (Human health endpoints)"
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
Critical effects observed:
not specified
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

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a short-term toxicity study does not need to be conducted because a reliable sub-chronic (90 days) or chronic toxicity study is available, conducted with an appropriate species, dosage, solvent and route of administration
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Reliable subacute toxicity studies are available with the registered substance (NOAEL for systemic toxicity = 1000 mg/kg) as well as subchronic toxicity studies from source substances (xylitol and D-Glucose, ether with glycerol) with no significant adverse effect observed

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Based on exposure considerations, this endpoint is not relevant for the test item.
This substance is not volatile (vapor pressure of 3.6 10-4 Pa at 25°C).
No exposition is expected via this route.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Based on exposure considerations, this endpoint is not relevant for the test item.
This substance is not volatile (vapor pressure of 3.6 10-4 Pa at 25°C).
No exposition is expected via this route.
Furtermore, the substance is not irritating to eyes and skin.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
No mortality was observed when the substance was administered one time by dermal route.
According to ECHA guidance - Chapter R7C, if water solubility is above 10000 mg/l and the log Kow value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low.
So it is more relevant to take into considerations the oral repeated toxicity study.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
According to ECHA guidance - Chapter R7C, if water solubility is above 10000 mg/l and the log Kow value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances will be low.
Furthermore, the substance is not irritating to the skin.

Justification for classification or non-classification

Based on data available on the registered substance and source substances, no target organ was identified as no significant adverse effect was observed. The test substance is not classified according to the tests performed, based on the criteria of the CLP regulation n°1272/2008/EC.