Pentaerythritol

Endpoint summary

Description of key information

The repeated dose oral toxicity of pentaerythritol has been investigated in the rat; the findings of these studies indicate low toxicity.  A 28-day limit dose study reports a NOAEL of 1000 mg/kg bw/d; there was some indication of an effect on haematological and clinical chemistry parameters in this study, however the report author concluded that the findings were without toxicological significance.  In a combined reproductive and developmental toxicity screening study, the effects of treatment in this study were limited to soft stool and/or diarrhoea at dose levels of 300 mg/kg bw/d and above.   A 90-day study on pentaerythritol has been conducted in the rat where the NOAEL was considered to be 1000 mg/kg bw/day; the findings were limited to increased ploughing and salivation, attributed to be a palatability effect of the test item and vehicle and of no toxicological significance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study not performed to GLP, but is broadly comparable to current OECD guidelines.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

The study is broadly comparable to the 28 day repeated dose toxicity test in rats; the authors state that the study was compliant with regulatory guidelines, but no further information is given.

GLP compliance:

no

Limit test:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): Mitsubishi Pentaerythritol (PE)
- Molecular formula (if other than submission substance): C5H12O4
- Molecular weight (if other than submission substance): 136.15


- Substance type: fine white powder, resin based, surface activating agent
- Physical state: solid
- Analytical purity: 96.4%

- Stability under test conditions: maintains stability in air
- Storage condition of test material:
- Other:

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Corporation, Japan
- Age at study initiation: 5 weeks
- Weight at study initiation: females: 100-125g; males: 125-150g
- Fasting period before study:
- Housing: plastic cage with soft-chip (by courtesy of Sankyo laboratory services)
- Diet: solid food (CRF-1, oriental yeast) ad libitum
- Water: tap water ad libitum
- Acclimation period: one week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 1°C
- Humidity (%): 55+/- 5%
- Air changes (per hr): 18 per hour
- Photoperiod (hrs dark / hrs light): 12 (from 7am to 7pm)


IN-LIFE DATES: From: To:

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

Pentaerythritol was melted in distilled water to make a 10% solvent. 10 ml/kg was administered orally by gavage using 'metallic rat-probes'. The control group was similarly treated with distilled water only.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once daily

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

7 rats/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Toxicity was found to be low at a preliminary examination, and the dose corresponded to the terms of the toxicity test limit regulatory guideline, therefore 1000 mg/kg was selected for this study.

Positive control:

Not examined; not required for this study type.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table were included.

BODY WEIGHT: Yes
- Time schedule for examinations: every three days


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, but only once per week.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data



OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: morning following last day of administration
- Anaesthetic used for blood collection: Yes : ether-deep -anesthesia
- Animals fasted: Yes, for 1 night
- How many animals:
- Parameters:erythrocyte count, leukocyte count, platelet count, hemoglobin count, hematocrit value, MCV, MCH, and MCHC


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood
- Animals fasted: Yes, for 1 night
- How many animals:
- Parameters examined: Serological examination was performed, by courtesy of SRL Corporation (Inc.), on GOT, GPT, alkaline phosphatase (AIP), γ-GPT, total bilirubin, choline sterase, total cholesterol, total protein, albumin, A/G ratio, urea nitrogen (BUN), creatinine, calcium (Ca), inorganic phosphorus (P), sodium (Na), potassium (K), and esteraseinhibitor (C1) after freezing the isolated serum.


URINALYSIS: Yes
- Time schedule for collection of urine: evening of the final administration day
- Metabolism cages used for collection of urine: No data
- Animals fasted: No
- Parameters examined: pH, protein, glucose, ketone, bilirubin, occult blood and urobilinogen


NEUROBEHAVIOURAL EXAMINATION: No data



OTHER:

Sacrifice and pathology:

Autopsies were performed on all animals. Gross observation of the body was made, and close examination was made on the extracted organs and tuissues. 10% neutral-buffered-formalin fixation was carried out on the brain, pituitary gland, salivary gland, thymus gland, heart, lung, kidney, adrenal gland, spleen, liver, testes, Harderan gland, spinal cord, breast bone, femur, stomach, small intestine, large intestine, pancreas, bladder, skin, mammary gland, lymph node, paranasal sinus, trachea, esophagus, thyroid gland, tongue, femur muscle, epidermis, vesicular gland, prostate gland, uterus, and vagina.

Other examinations:

None reported.

Statistics:

Analysis of variance was performed on the body weight, food-intake amount, hematological examination, serological exanimation, and organ weight by employing a t-test for significant difference assessment.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY

No death cases were reported during the entire assessment period. Abnormality of the general condition of the animals in both groups was not
observed.

BODY WEIGHT AND WEIGHT GAIN
No significant difference in body weight and food intake amount within the male and female group was observed during the experiment.
HAEMATOLOGY
The statistics of the hematological examination shows that there was a slight increase in MCV and decrease in MCHC (P<0.01) for female animals, however findings are not considered to be of toxicological significance. No changes were observed for male animals. There was no significant difference in leukocyte percentage for both male and female animals.

CLINICAL CHEMISTRY
No significant changes were observed for each of the examined content. However a slight degree of statistical fluctuation was observed for male animals in which decrease in alkaline phosphatase value (P <0.01) was evidenced, and female animals showed an elevation (P<0.05 or P<0.01) of GOT, urea nitrogen, sodium, and esterase-inhibitor.

URINALYSIS
No significant change in each of the contents was observed in both male and female animal groups.

ORGAN WEIGHTS: No significant change for each internal organ weight was observed for both male and female animal groups. Organs assessed: Brain, Pituitary, salivary glands, thymus, lung, heart, spleen liver, adrenal, kidney, testis, ovary.

GROSS PATHOLOGY
There was no findings of any changes to the internal organs and tissues in both male and female animal groups evident to the naked eye.

HISTOPATHOLOGY: NON-NEOPLASTIC
Heart: Findings of cell infiltration with main constituent of a small necrosis area and macrophages were evidenced throughout the neighboring muscular coat of the right ventricle endocardium in one case of the male animal in the comparison group and in one case of the male animal in the PE administration group. Bone marrow: A slight degree of decrease was found in the hematopoietic region in one case of the male animal in the PE administration group. There were no special findings on other internal organs other than what is mentioned above.

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:

other: No treatment-related effects were apparent in this study.

Critical effects observed:

not specified

Summary of haematology and clinical chemistry

Parameter	Dose level (mg/kg bw/d)
	M		F
	0	1000	0	10000
Clinical chemistry
GOT (IU/L)	103	110	60.5	73.9**
GPT (IU/L)	39.8	40.9	33.7	34.3
AP (IU/L)	539	505**	368	360
GGT (IU/L)	-	0.14	0.33	0.29
Bilirubin (mg/dL)	0.07	0.03	-	-
Cholesterol (mg/dL)	56.8	54.9	85.5	80.6
Total protein (g/dL)	6.45	6.40	5.97	6.11
Albumin (g/dL)	4.65	4.70	4.47	4.50
A/G ratio	5.62	2.80	3.00	2.79
BUN (mg/dL)	20.7	2.01	16.5	19.7**
Creatinine (mg/dL)	0.43	0.47	0.37	0.44
Ca (mg/dL)	10.2	10.1	10.4	10.2
P (mg/dL)	7.70	7.77	6.92	7.09
Na (meq/L)	145	145	144	147**
K (meq/L)	4.82	4.64	3.82	4.17
Cl (meq/L)	104	104	107	109*
Haematology
RBC (10^4/µl)	991	1036	948	974
Hb (g/dL)	16.5	17.1	16.1	16.4
Hct (%)	54.3	56.6	51.0	52.9
MCV (fL)	54.8	54.6	53.7	54.3**
MCH (pg)	16.7	16.6	17.0	16.8
WBC (10^2/µl)	42.0	48.3	41.8	42.3
Platelets (10^4/µl)	105	110	102	98

The results show statistically significant changes in hematological and clinical chemistry parameters, seen as a decrease in alkaline phosphatase value in male rats; increase in GOT, urea nitrogen, sodium, esterase-inhibitor along with MCV elevation and MCHC decrease in female rats. GOT is used as a prominent indicator of hepatopathy and in the event that it increases along with elevation of alkaline phosphatase, liver damage is strongly suspected. In this case there was no fluctuation in these values and no pathological change was observed in the liver. Urea nitrogen elevation mainly is caused by nephropathy, hyper-metabolism of tissue protein, increase in protein intake, gastrointestinal bleeding, and dehydration, however there was no difference in the weight level and food-intake amount between the treated and control groups and there was no pathological finding to support any changes. As for elevation in the sodium and esterase-inhibitor value, the Cl/Na ratio was almost identical to controls and no health condition due to acid/base equilibrium imbalance were noted. Histological results revealed no changes to the kidney.

For the MCV elevation, it is concluded that this change is within normal limits as the erythrocyte and hematocrit value was basically the same value as the control group. As for the decrease in MCHC, it is concluded that this change is within normal limits as the haemoglobin and hematocrit values are almost identical to the controls.

Conclusions:

There were no significant changes resulting from the administration of pentaerythritol to male and female rats at a limit dose of 1000 mg/kg bw/d . The NOAEL for the study is therefore 1000 mg/kg bw/d.

Executive summary:

A twenty-eight-day repeated dose toxicity test of pentaerythritol at a limit dose level of 1000 mg/kg bw/d was carried out in male and female F344 rats.

Thirteen animals of each sex were divided into 2 groups with 7 rats receiving pentaerythritol treatment and 6 rats receiving distilled water only (vehicle control). All groups received a gavage administration daily for 28 days. No deaths occurred during the study, no clinical signs of toxicity were reported and there were no effects on body weight and food intake. There were no significant effects on haematology parameters or serum chemistry between treated and control rats. No specific changes were observed at histopathological examination in the pentaerythritol- treated rats. Based on these results, the no-observed-effect level of pentaerythritol can be concluded to be 1000 mg/kg bw/d.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

November 2016 to October 2017

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)

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Species:

rat

Strain:

Wistar

Details on species / strain selection:

The Han Wistar rat was chosen as the animal model for this study as it is a rodent species and strain accepted by regulatory agencies for toxicity testing.

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source: Charles River UK Limited
Age of animals at initiation of dosing: 7-8 weeks
Weight of animals at initiation of dosing: 202 to 277 g (males) and 139 to 199g (females)
Housing: Prior to stratification, animals were housed up to 5 per cage per sex. Following stratification, animals were housed 2 per cage by sex.
Caging: polycarbonate cages with stainless steel grip tops and and solid bottoms
Bedding: sterilised wood shavings with no known contaminants
Temperature: 20-21°C
Relative humidity: 40-70%
Photoperiod: 12 hour light/dark cycle
Air changes: At least 10 changes/hour
Diet: SDS Rat and Mouse (modified) No. 1 Diet SQC Expanded; ad libitum
Water: Public supply; ad libitum
Enrichment: Chew devices and devices for hiding in provided

Route of administration:

oral: gavage

Details on route of administration:

The dose volume was 10 mL/kg. The dose volume was based on the most recent body weight measurement. Doses were given using a syringe with attached gavage cannula.

Vehicle:

corn oil

Details on oral exposure:

The oral route of administration was selected for this study as this was the preferred route of exposure specified by the regulatory requirements.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dose formulation samples were collected for analysis on Day 1, during Week 3, 6 and 12 of dosing. The dosing solutions for all groups (including the vehicle contol) were analysed for acheived concentration and the test item formulations were analysed for homogeneity.

Duplicate top, middle and bottom (duplicate middle only for control) sets of samples (0.1 mL) for each sampling time point were sent to the analytical laboratory for analysis. Triplicate top, middle and bottom (duplicate middle only for control) samples (0.1mL) were maintained at the Test Facility as backup samples.

Concentration results were considered acceptable if mean sample concentration results were within or equal to ± 10% of theoretical concentration. Each individual sample concentration result was considered acceptable if it was within or equal to ± 15%. Homogeneity results were considered acceptable if the relative standard deviation (RSD) of the mean value at each sampling location was ≤10%. After acceptance of the analytical results, backup samples were discarded.

Stability analyses performed previously demonstrated that the test item was stable in the vehicle when prepared and stored under the same conditions at concentrations bracketing those used in this study.

Duration of treatment / exposure:

91 days

Frequency of treatment:

Daily

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Remarks:

Vehicle control

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/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

The dose levels were justified based on previous repeated dose studies. A 14-day range-finding study reported effects limited to soft faeces/diarrhoea in females at 1000 mg/kg bw/d. An OECD 422 screening study reported intermittent soft faeces /diarrhoea at 300 and 1000 mg/kg bw/d and a tendency to increased water consumption in males at 1000 mg/kg bw/d. A 28-day study reported no effects at 1000 mg/kg bw/d.

Positive control:

Not required for this study type

Observations and examinations performed and frequency:

Animals were observed, twice daily (once at the start and once towards the end of the working day throughout the study), for general health/mortality and moribundity. Animals were not removed from the cage during observation, unless necessary for identification or confirmation of possible findings.

All animals were removed from the cage for detailed clinical observations and examined weekly commencing in Week -1.

All the animals were examined for reaction to treatment regularly throughout the day. The onset, intensity and duration of these signs were recorded (if appropriate), particular attention being paid to the animals during and for the first hour after dosing.

All animals were individually weighed twice during pretreatment then daily from Day 1 to completion of the study. A weight was recorded on the days of scheduled necropsy.

Food consumption was quantitatively measured twice during pretreatment then weekly from Day 1 to completion of the study.

The eyes were examined once during pretreatment for all animals, and control and high dose animals in Week 13, using an indirect ophthalmoscope after the application of a mydriatic agent (1% Tropicamide, Mydriacyl®).

Detailed functional observations were performed once during pretreatment and once during Week 12. These examinations were conducted by a technician not involved in the dosing procedures or in the collection of body weight and food consumption data, and were performed at an approximately standardised time of day. Before the independent technician entered the animal room to perform the examinations, the cage card showing treatment group was removed from each cage, leaving the second pre-prepared card as the functional observation animal identifier. In each cage all animals had their tail marked with their functional observation battery number to allow the independent technician to identify each animal.

Homecage observations:
Posture/condition on first approach (animal undisturbed), checking for: Prostration, Stereotypy / bizarre behaviour, Tremors (head, limbs, whole body), Convulsions, Ease of removal from the cage.

Body temperature:
The rectal temperature was recorded in degrees Celsius (ºC), using a probe inserted approximately 2cm past the anal sphincter.

Handling observations:
Condition of the eyes, checking for:Pupillary function, Miosis / Mydriasis, Enophthalmos/ Exophthalmos, Lacrimation and Evaluation of diameter of the pupil.
Condition of the coat
Body tone
Pinna response
Presence of salivation
Overall ease of handling
Respiration rate and pattern

Air righting:
Holding the animal in a supine position, it was dropped from approximately 30 cm and the air righting response was rated.

Extensor thrust
The animal was grasped at the thorax gently from behind and raised off the surface in a vertical position. With their free hand the observer gently but briskly pressed the tips of two fingers (or one finger and thumb) into the middle of the plantar surface (i.e. footpads) of each hind limb (one digit into each footpad). As the rodent extended the hind limbs, the presence/strength of the extensor thrust reflex was evaluated via digital palpation. Several presses were sometimes required to elicit the extensor response.

Observations in a standardised arena (2 minute observation period):
Rearing
Grooming
Urination and defecation
Arousal (level of alertness)
Posture
Tremor (head, limbs, whole body)
Convulsions
Vocalisation
Piloerection
Palpebral closure
Gait abnormalities.
Stereotypy (excessive repetition of behaviours) and/or unusual behaviours.

Functional tests:
Detailed functional observations were performed once during pretreatment and once during Week 12.
The following additional functional tests were performed. Again, these assessments were performed at an approximately standardised time of day: Reaction to sudden sound (click above the head) and reaction to touch on the rump with a blunt probe.
Grip strength:
This was measured using a Dual/Single Channel Grip Strength Meter (Linton Instruments) to which was attached a wire screen assembly. Once the animal had gripped the screen, the body was pulled until its grasp was broken; the strain gauge recorded the force required. The procedure was repeated 3 times for the forelimbs and 3 times for the hindlimbs, and the mean fore and hind grip strengths calculated.
Pain perception:
This was assessed by measurement of the tail flick response, using a technique based on the method devised by D`Amour and Smith (1941)(ii). The apparatus used shone a calibrated infra-red heat source onto the tail and automatically measured the reaction time of the animal (accurate to 0.1 s). It was ensured that no visible injury to the tail was caused in this test.
Landing Foot Splay:
Tempera paint was applied to the hind feet of each animal. The animal was then held in a horizontal, prone position with the nose ca 30 cm above a bench surface covered with absorbent paper. When the animal was calm, it was dropped. The distance between the prints of the central footpads was measured and the average measurement recorded. The procedure was repeated twice. If the rat did not land
properly on its feet, this was recorded.
Motor activity:
Each animal was placed in an individual cage held within a SmartFrame utilising infra-red pyroelectric detectors. Movement was detected in 2 dimensions anywhere in the cage, and was differentiated into basic and fine movements, and X and Y ambulation. Each animal was monitored for one session of 1 h, activity counts being recorded over successive period of 5 minutes each.
Other physical/functional abnormalities:
Any other abnormality not already recorded in the above screening battery.

Clinical pathology:
Blood was collected from the orbital sinus under isoflurane anaesthesia using a capillary tube. Urine was collected over 6 hours with absence of food but presence of water. After collection, samples were transferred to the appropriate laboratory for processing. Prior to blood sampling, animals were not deprived of food. Samples were collected from all animals during week 13 for urinalysis and from all animals prior to necropsy for haematology, coagulation and clinical chemistry.

For haematology, blood samples (0.5 mL) were collected, transferred into tubes containing K2EDTA and analysed for the following parameters:
Red blood cell count
Haemoglobin concentration
Haematocrit
Mean corpuscular volume
Red Blood Cell Distribution Width
Mean corpuscular haemoglobin
concentration
Mean corpuscular haemoglobin
Reticulocyte count (absolute)
Platelet count
White blood cell count
Neutrophil count (absolute)
Lymphocyte count (absolute)
Monocyte count (absolute)
Eosinophil count (absolute)
Basophil count (absolute)
Large unstained cells (absolute)
A blood smear was prepared from each haematology sample. Blood smears were labelled, stained, and stored. Blood smears were evaluated as required to confirm analyser results as per Test Facility SOPs.

For coagulation: Blood samples (0.9 mL) were collected, transferred into tubes containing 3.8% (w/v) trisodium citrate and processed for plasma, which was analysed for the parameters as follows:
Activated partial thromboplastin time
Fibrinogen
Prothrombin time
Sample Quality

For clinical biochemistry: Blood samples (1.0 mL) were collected, transferred into tubes containing lithium heparin and processed for plasma, which was analysed for the parameters as follows:
Alanine aminotransferase
Aspartate aminotransferase
Alkaline phosphatase
Gamma-glutamyltransferase
Creatine Kinase
Total bilirubina
Urea
Creatinine
Calcium
Phosphate
Total protein
Albumin
Globulin
Albumin/globulin ratio
Glucose
Cholesterol
Triglycerides
Sodium
Potassium
Chloride
Sample Quality

Urine samples were analysed for the following parameters:
Colour
Appearance/Clarity
Specific gravity
Volume
pH
Protein
Glucose
Bilirubin
Ketones
Blood

Sacrifice and pathology:

All animals were euthanised by exposure to carbon dioxide, weighed and exsanguinated. When possible, the animals were euthanised in a rotating order across dose groups such that similar numbers of animals from each group, including controls were necropsied at similar times throughout the day. Animals were not fasted before their scheduled necropsy. All animals were subjected to a complete necropsy examination, which included evaluation of the carcass and musculoskeletal system; all external surfaces and orifices; cranial cavity and external surfaces of the brain; and thoracic, abdominal, and pelvic cavities with their associated organs and tissues.
Necropsy procedures were performed by qualified personnel with appropriate training and experience in animal anatomy and gross pathology. A veterinary pathologist, or other suitably qualified person, was available.

The brain, epididymis (paired organ), adrenal gland (paired organ), pituitary gland, prostate gland, thyroid gland (paired organ weighed after fixation), heart, kidney (paired organ), liver, lung, ovary (paired organ), spleen, testis (paired organ), thymus and uterus were weighed at necropsy for all scheduled euthanasia animals. Paired organs were weighed together. Organs were weighed before fixation unless stated. Organ to body weight percentage (using the terminal body weight) were calculated.

Representative samples of the tissueslisted below were collected from all animals and preserved in 10% neutral buffered formalin, unless otherwise indicated:
Artery, aorta
Bone marrow smear (air dried and fixed in methanol)
Bone marrow, femur
Bone marrow, sternum
Bone, femur
Bone, sternum
Brain
Cervix
Epididymis
Eye (preserved in Davidson's fixative)
Gland, adrenal
Gland, harderian
Gland, lacrimal
Gland, mammary
Gland, parathyroid
Gland, pituitary
Gland, prostate
Gland, salivary (mandibular)
Gland, seminal vesicle
Gland, thyroid
Gut-associated lymphoid tissue (Peyer’s patches)
Heart
Kidney
Large intestine, caecum
Large intestine, colon
Large intestine, rectum
Lesions/masses
Liver
Lung
Lymph node, mandibular
Lymph node, mesenteric
Muscle, skeletal
Nerve, optic (preserved in Davidson's fixative)
Nerve, sciatic
Oesophagus
Ovary
Oviduct
Pancreas
Skin
Small intestine, duodenum
Small intestine, ileum
Small intestine, jejunum
Spinal cord
Spleen
Stomach
Testis (preserved in Modified Davidson's fixative)
Thymus
Tongue
Trachea
Ureter
Urinary bladder
Uterus
Vagina
The tissue samples, with the exception of bone marrow smears) were embedded in paraffin, sectioned, mounted on glass slides, and stained with haematoxylin and eosin.Histopathological evaluation was performed by a veterinary pathologist with training and experience in laboratory animal pathology.
Two bone marrow smears were taken from the femur. Both bone marrow smears were air dried, fixed in methanol, stained with May-Grunwald-Giemsa stain and coverslipped. Bone marrow smears were not evaluated.

Other examinations:

None

Statistics:

All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 0.1%, 1%, and 5% levels. Numerical data collected on scheduled occasions for the listed variables were analysed as indicated according to sex and occasion. Descriptive statistics number, mean and standard deviation (or %CV or SE when deemed appropriate) were reported whenever possible.
Values were also expressed as a percentage of predose or control values when deemed appropriate. Inferential statistics were performed when possible,
(but excluded semi-quantitative data, and any group with less than 3 observations) for the following variables:
Body Weight
Food Consumption
Haematology Variables
Coagulation Variables
Clinical Chemistry Variables
Urinalysis Variables
Organ Weights
FOB Quantitative Variables
Body Weight Change
Organ Weight relative to Body Weight

Pairwise comprisons were made for each test article treated group versus the control group.

Levene’s test was used to assess the homogeneity of group variances. Datasets with at least 3 groups were compared using an overall one-way ANOVA F-test if Levene’s test was not significant or the Kruskal-Wallis test if it was. If the overall F-test or Kruskal-Wallis test was found to be significant, then the above pairwise comparisons were conducted using Dunnett’s or Dunn’s test, respectively. Datasets with 2 groups (the designated control group and 1 other group) were compared using a t-test if Levene’s test was not significant or Wilcoxon Rank-Sum test if it was.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Ploughing behaviour (pushing nose into shavings) and salivation were observed at all dose levels throughout the study, including the control group. Although also observed in the control group, the number of occasions of ploughing and salivation were observed was generally higher in the groups receiving Pentaerythritol. Ploughing was seen on 7/18, 119/52, 86/58 or 126/109 occasions in males/females, respectively and salivation was seen on 4/29, 73/36, 38/31, or 55/57 occasions in males/females, respectively at 0, 100, 300 or 1000 mg/kg/day. These observations were considered to be a palatability effect of the test item and vehicle and of no toxicological significance. Isolated instances of decreased activity, erect fur and pedalling behaviours were observed, however, there were no patterns, trends or dose response relationships and therefore these were considered of no toxicological significance.

Mortality:

no mortality observed

Description (incidence):

There were no unscheduled deaths throughout the course of this study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Bodyweights and body weight gain in treated groups were generally comparable to controls throughout the study.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption was unaffected by treatment throughout the course of this study.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

There were no ophthalmoscopy findings considered to be related to Pentaerythritol.

Haematological findings:

no effects observed

Description (incidence and severity):

There were no changes in any haematology or coagulation parameters that were considered to be related to Pentaerythritol.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

There were no changes in any clinical chemistry parameters that were considered to be related to Pentaerythritol. Any observed changes were within normal background ranges and therefore considered unrelated to administration of Pentaerythritol.

Urinalysis findings:

no effects observed

Description (incidence and severity):

There were no changes in any urinalysis parameters that were considered to be related to Pentaerythritol.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

There were no changes in any function observation parameter that were considered to be related to Pentaerythritol.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No treatment-related organ and body weight changes were noted. Minor, organ and body weight differences observed were considered incidental and unrelated to administration of Pentaerythritol.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment-related gross findings were noted. The gross findings observed were considered incidental, of nature commonly observed in this strain and age of rats, and/or were of similar incidence in control and treated animals and, therefore, were considered unrelated to administration of Pentaerythritol.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No treatment-related microscopic findings were noted. The microscopic findings observed were considered incidental, of the nature commonly observed in this strain and age of rats, and/or were of similar incidence and severity in control and treated animals and, therefore, were considered unrelated to administration of Pentaerythritol.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No neoplastic findings were observed in any group

Other effects:

not examined

Details on results:

There were no effects of treatment in this study with the exception of post-dose salivation and ploughing

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

Remarks on result:

other: There were no toxicologically relevant effects of treatment at the highest dose level

Key result

Critical effects observed:

no

All study samples analysed had mean concentrations within or equal to the acceptance criteria of ±10% (individual values within or equal to ±15%) of their theoretical concentrations, except for Day 1, Groups 2-4 (16.0%, 12.7% and 13.0% respectively), and Week 3, Group 3 (-10.7%). Day 1, Group 4 was rerun and found to confirm these results (13.6%). Day 1, Groups 2-3 analytical samples were also reran for confirmation but these results cannot be reported due to there being no proven stability in solution at these concentrations. The backup samples for Day 1 were not successfully analysed due to a sample preparation error. No residues from Day 1 dose aliquots were available to be analysed as they had been discarded. For these reasons it cannot therefore be confirmed whether the Day 1 samples are actually out of specification or whether the initial results are due to an analytical issue so an extra analytical timepoint at Week 3 was added by the Study Director. As part of the investigation for Week 3, Group 3, the backup samples were analysed in triplicate, and the results (2.0%) were within the acceptance criteria. The investigation demonstrated that Week 3, Group 3 was likely within specification and that all formulations were prepared correctly, therefore this was considered to have had no impact on the outcome or integrity of the study.

For homogeneity, the RSD of concentrations for all samples in each group was within the acceptance criteria of <10%.

Clinical signs

Dose level (mg/kg bw/day)	Male				Female
	0	100	300	1000	0	100	300	1000
Decreased activity	0/10	1/10 (1)	2/10 (2)	0/10	0/10	0/10	0/10	0/10
Erect fur	0/10	4/10 (4)	5/10 (5)	10/10 (12)	0/10	0/10	0/10	0/10
Scab	0/10	0/10	0/10	0/10	0/10	0/10	0/10	1/10 (7)
Thin fur	1/10 (2)	0/10	0/10	0/10	1/10 (9)	0/10	0/10	0/10
Pedaling	0/10	1/10 (1)	0/10	0/10	1/10 (1)	0/10	0/10	1/10 (1)
Salivation	3/10 (4)	10/10 (73)	5/10 (38)	10/10 (55)	6/10 (29)	6/10 (36)	3/10 (31)	10/10 (57)
Ploughing	5/10 (7)	10/10 (119)	10/10 (86)	10/10 (126)	9/10 (18)	10/10 (52)	10/10 (58)	10/10 (109)

Numbers of observations are shown in parentheses.

Conclusions:

Administration of Pentaerythritol by once daily oral gavage was well tolerated in rats at dose levels of up to 1000 mg/kg bw/d, with only instances of ploughing and salivation noted. No target organ effects were observed at any dose level. Based on these results, the NOAEL was considered to be 1000 mg/kg bw/d.

Executive summary:

A 90-day study was conducted in groups of Han Wistar rats (10/sex) according to OECD guideline 408. The animals were dosed orally by gavage with pentaerythritol at dose levels of 0, 100, 300 and 1000 mg/kg bw/d. Ten rats of each sex were tested in each each group. The animals were examined for clinical signs, body weight, body weight gain, food consumption, ophthalmology, functional observations, clinical pathology parameters which comprised haematology, coagulation, clinical chemistry and urinalysis, gross necropsy, organ weights and histopathological analysis. No mortality was observed. Ploughing and salivation were observed at all dose levels with a generally dose related incidence. There were no treatment-related changes in food consumption, ophthalmology, functional observations, clinical pathology parameters, body weights and organ weights. No gross necropsy or histopathological findings were related to treatment. Pentaerythritol was therefore well tolerated in the rat at levels up to 1000 mg/kg bw/d when administered for 90 days. A NOAEL of 1000 mg/kg bw/d can be determined for this study in the absence of any toxicologically significant effects at any dose level. The increased incidences of post-dose salivation and ploughing seen in this study are considered to be a reaction to an unpalatable test materisl and are not considered to be an adverse effect of treatment.

Reference 3

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20 October to 20 December 1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

entaerythritol; 2,2-bis(hydroxymethyl)-1-3-propanediol, abbreviated to BHP in study report. The test sample was provided by the Ministry of Health and Welfare Environmental Health Bureau, lot no. 50825, purity 92.7%, described as a water-soluble white granule, stored at room temperature avoiding direct sunlight. The test sample was confirmed for stability (until March 1994 for this lot) for a 7 month period.

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

The animals were 8 week old Crj: CD(SD) SPF rats, received from Charles River Laboratories Japan. Males weighed 259-298 g, and females weighed 161-193 g. The rats were acclimatised for 15 days, during which time the general appearance and body weights of the rats were monitored; animals showing satisafactory growth and development were selected for the experiment.
The animals were housed in a barrier-room, maintained at a temperature of 23±3°C, humidity of 55±10%, 10-15 air changes per hour and artificial light was provided on a 12 hour light/12 hour dark cycle. During breeding the rats were housed in wire-mesh floor cages, and from gestational day (GD) 17, females were housed in cages containing a stainless-steel inner tray and bedding (White Flake, Charles River). During acclimatisation, rats were housed in groups of up to 3, then single after assignment to treatment groups. During mating they were housed in pairs (1 male:1 female), and during gestation and laction females were housed singly. Individuals were identified by felt-tip pen marks on the tail, and tattoos behind each ear.
Pelleted diet (CRF-1, Oriental Yeast Co. Ltd.) and tap water (Sapporo) were provided ad libitum. Analysis and inspection of forage was performed by Japan Food Analysis Center Juridical Foundation and it was confirmed that the contained substance impurity was respectively within the permissible range of the company’s SOP. Water quality inspection of drinking water was performed by Kan-ei Industry Corporation and by Fukuda Hydrologic Center and it was confirmed that the water quality was within the permissible range of the company’s SOP.

Route of administration:

oral: gavage

Vehicle:

other: 0.5% CMC-Na solution

Details on oral exposure:

Doses were prepared every five days. The test substance was weighed and suspended with 0.5% CMC-Na solution (Japanese Pharmacopoeia CMC-Na : Lot No. 1X04, Maruishi Pharmaceutical Co., Ltd., Japanese Pharmacopoeia Purified Water: Lot No. 38A and Lot No. 39G, Yakuhan Pharmaceutical Co., Ltd.) to create 1, 3 , and 10w/v% solution.
Doses were adminstered by gavage, at a set volume of 10 ml/kg bw, based on body weight measurements obtained on the closest day to the adminstration date. Doses were administered between 10:00h and 13:00h. Average body weight at the start of administration was 398.6g (369 – 432g) for males, and 232.1g (207 – 254g) for females.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The Mitsubishi Gas Chemical Company carried out the sample analysus using liquid chromatography: Shimadzu LC-GA; column Asahipak OPD-50 150 x 6.0 mmID; eluent water; flow rate 1.0 ml/min; detector RI. The anaylsis confirmed that the preparation solution of each concentration level of pentaerythritol matched the nominal concentration level (the analytical report states that the 10 and 20% solutions did not fully dissolve), and that 1 - 10% of the preparation solution had stability for 5 days.

Duration of treatment / exposure:

Males: 46 days starting 14 days prior to mating.
Females: 14 days prior mating, throughout mating and gestation until lactation day (LD) 3.

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:

12 rats/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

A 14 day range-finding study was conducted employing doses of 100, 300 and 1000 mg/kg/day. Soft faeces and diarrhoea were seen in males and females in the 1000 mg/kg/day group, but no other effects of toxicity were seen so doses for the main experiment were 100, 300 and 1000 mg/kg/day.
Animals were assigned to treatment groups on the last day of acclimatisation, according to the body-weight stratified random sampling method.

Positive control:

A positive control was not included.

Observations and examinations performed and frequency:

All animals were examined visually and handled daily during the test period to observe their behaviour and appearance. Male body weights were recorded on Day 1 of administration, Day 2, Day 5, Day 7, Day 10, Day 14 and every 7 days thereafter including on the day of sacrifice. Female bodyw eights were recorded on Day 1 of administration, Day 2, Day 5, Day 7, Day 10, Day 14, GD 0, GD 1, GD 3, GD 5, GD 7, GD 10, GD 14, GD 17, GD 20, LD 0, LD 1 and LD 4. Female body weights during the mating period were recorded on the same day as the male body weights. Females that failed to mate were also weighed immediately prior to sacrifice.
Food and water intake were measured on the same days as body weights were measured, excluding the mating period.

6 males from each group were housed in metabolic cages for 24 hours during the final week of administration (Day 43-44) for collected of non-fasted urine. The following parameters were determined for 3 hour pooled samples: pH, protein, glucose, ketone, occult blood and sediment; the following parameters were determined for the 21 hour pooled samples: specific gravity, volume, sodium, potassium and chloride.
Blood from male rats was collected from the femoral vein and abdominal aorta under ether anaesthesia on the day of sacrifice (the day after the last administration - Day 46) for determination of the following parameters: red blood cell count, haematocrit, haemoglobin, mean cell volume, mean cell haemoglobin volume, mean cell haemoglobin concentration, reticulocyte count, platelet count, white blood cell count, coagulation time, prothrombin time, activated partial thromboplastin time, separate leukocyte group percentage. Blood chemistry parameters determined were: GOT, GPT, gamma-GTP, cholinesterase, glucose, total cholesterol, triglyceride, phospholipid, total bilirubin, urea nitrogen, creatinine, sodium, potassium, chloride, calcium, inorganic phosphorous, total protein, albumin, A/G ratio, protein fraction.

Sacrifice and pathology:

Males were sacrificed the day after the last dose was administered for necropsy. The organs and tissues were examined grossly for abnormalities, then the following organs were weighed: liver, kidneys, thymus, adrenal glands, testicle, and epididymis. The following organs were fixed in 10% neutral buffred formalin for histopathological examination: liver, kidney, spleen, heart, lung, brain (cerebrum and cerebellulm), pituitary gland, adrenal gland, thyroid gland, parathyroid gland, thymus, messenteric lymph node, pancreas, tongue, lower jaw lymph node, submaxillary gland, sublingual gland, parotid gland, mammary gland, skin, eyeball, Harderian gland, breastbone and femur (including the bone marrow), spinal cord (neck region), skeletal muscle (lateral great muscle), thoracic aorta, larynx, trachea, bronchial tube, esophagus, stomach (anterior stomach, glandular stomach), duodenum, jejunum, ileum, appendix, colon, rectum, bladder, testicle, epididymis, seminal vesicle (including the coagulating gland), and prostate gland, and the organs were stored. Additionally, the eyeball and Harderian gland were fixed in Davidson's solution and the testicle and epididymis in Bouin's solution. The liver, kidney, spleen, heart, lung, brain, pituitary gland, thymus, adrenal gland, thyroid gland, stomach (anterior stomach, glandular stomach), duodenum, jejunum, ileum, appendix, colon, rectum, testicle, epididymis, and prostate gland were embedded in paraffin and stained with Haematoxycillin and Eosin.

Females that became pregnant and successfully littered were sacrificed on LD 4. Females that became pregnant but had not given birth by GD 25 were sacrificed on GD 26. If a female delivered an entirely still-born litter, she was sacrificed immediately after discovery of the dead pups. Females that did not become pregnant were sacrificed the day after the mating period ended.
At autopsy the organs and tissues were examined grossly. The number of uterine implantation sites and the number of corpora lutea in the ovaries were counted. Organ weights were recorded for the liver, kidneys, thymus, adrenal glands and ovaries. The following organs were fixed in 10% neutral buffered formalin: the liver, kidney, spleen, heart, lung, brain (cerebrum and cerebellulm), pituitary gland, adrenal gland, thyroid gland, parathyroid gland, thymus, messenteric lymph node, pancreas, tongue, lower jaw lymph node, submaxillary gland, sublingual gland, parotid gland, mammary gland, skin, eyeball, Harderian gland, breastbone and femur (including the bone marrow), spinal cord (neck region), skeletal muscle (lateral great muscle), thoracic aorta, larynx, trachea, bronchial tube, esophagus, stomach (anterior stomach, glandular stomach), duodenum, jejunum, ileum, appendix, colon, rectum, bladder, ovary, uterus, and vagina. Additionaly, the eye and Hrderian gland were fixed in Davidson's solution.
The following organs were embedded in paraffin and stained with Haematoxycillin and Eosin, or using the silver impregnation method: liver, kidney, spleen, heart, lung, brain, pituitary gland, thymus, adrenal gland, thyroid gland, stomach (anterior stomach, glandular stomach), duodenum, jejunum, ileum, appendix, colon, rectum, and ovary. The following organs were also stained from dams whose whole litter died: mammary gland and uterus.

Other examinations:

No other examinations were reported.

Statistics:

Homogeneity of variance was determined using Bartlett's test, followed by ANOVA and Dunnett's test, or Kruskal-Wallis and Mann-Whitney U test as appropriate. Indices were analysed using Multi-Sample analsysis and the Two-Sample analysis, or Fisher's Exact Probability Test. Significance (between treated and control rats) was accepted at or below the 5% level.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

: intermittent soft stool and diarrhoea

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

MORTALITY

There was no mortality during the study.

CLINICAL SIGNS

Four males exhibited soft faeces in the 300 mg/kg bw/d group, and 1 male in this group had diarrhoea intermittently until administration Day 9. All males in the 1000 mg/kg bw/d group had soft faeces and diarrhoea intermittently from administration Day 2 until terminal sacrifice. In the 300 mg/kg bw/d group 2 females exhibited soft faeces, and 1 female had diarrhoea on Day 5, and 1 on Day 9 of administration. All females in the 1000 mg/kg bw/d exhibited soft faeces and diarrhoea intermittently from administration Day 2 until the end of the mating period, and for 11 females the intermittent symptoms continued until the end of gestation. During lactation all females in the 1000 mg/kg bw/d group exhibited soft faeces intermittently, and 9 females had intermittent diarrhoea.

BODYWEIGHT, FOOD AND WATER CONSUMPTION

There were no effects of treatment on body weight gain in either males or females. There were no effects on food intake in males. In 300 mg/kg bw/d females, food intake was lower than the control from the day prior to the start of dosing; this difference was significant on administration Day 1, and gestational day 14. This finding was considered incidental and unrelated to treatment, as the differences in food intake were seen from the start of the study. Water consumption was increased in the 1000 mg/kg bw/d males compared to controls from Day 10 of administration, but the finding was not statistically significant. The increase in water consumption was thought to be a secondary effect of the intermittent diarrhoea observed in this group.

CLINICAL INVESTIGATIONS

There were no effects of treatment on urinalysis parameters (only determined in males).

Haematology (only determined in males) revealed a significant decrease in mean cell haemoglobin volume and mean cell haemoglobin concentration in the 300 and 1000 mg/kg bw/d males compared with controls. Findings of the clinical chemistry analysis (only determined in males) were a decrease in phospholipid and calcium in the 100 mg/kg bw/d males, and a decreaee in total cholesterol, phospholipid and calcium in the 300 mg/kg bw/d males. There was no dose-response and changes were reportedly within the normal range.

ORGAN WEIGHTS

There were no effects of treatment on organ weights in males or females.

PATHOLOGY

There were no abnormal findings at autopsy in male rats. In females, the reported findings were yellowish-white marks on the liver, fatty tissue adhesion on the spleen, liver and within the abdominal cavity, ileum diverticulum and ovarian cysts. These findings were seen in both treated and control rats, and were therefore considered unrelated to treatment. In one 1000 mg/kg bw/d female, there was placental separation on the left side of the uterus.
Histopathology revealed the following changes in both treated and control males: perilobular fatty change of the liver and hyaline droplet deposition and eosinophilic body deposition in tubular epithelium in mainly the proximal tubules of the kidney, urinary cast, ciliated epithelial cyst, cardiac focal infiltration of cells mainly composed of histiocytes , calcium deposition in lung blood vessel wall, ciliated epithelial cyst of the pituitary body, retention of homogeneous plasma-like substances in Rathke’s pouch, interstitial infiltration of cells mainly composed of lymphocytes in the prostate gland.
The following observations were noted in both treated and control females: focal necrosis of hepatocytes in the liver (included are the animal cases which showed abnormal findings during the autopsy), regeneration of tubular epithelium of the kidney (right), dilation of renal pelvis (right kidney), dilation of tubules (right kidney), urinary cast(right kidney), fibrous adhesion to liver and intra-abdominal adipose tissue and granuloma of the spleen (included are the abnormal body parts found during the autopsy), calcium deposition in lung blood vessel wall, ciliated epithelial cyst of the pituitary body, retention of homogeneous plasma-like substances in Rathke’s pouch, atrophy of the thymus, increase in RES cells in medulla, diverticulum of the ileum, and lutein cyst of the ovary (abnormal body parts found during the autopsy were included in the histopathological examination). As histopathological findings occurred in both control and treated groups, and in the absence of a dose-relationship, they were therefore not considered to be treatment related.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Critical effects observed:

not specified

Treatment-related effects in this study were limited to clinical signs (diarrhoea, soft stool) in both sexes at 300 and 1000 mg/kg bw/d and increased water consumption in males at 1000 mg/kg bw/d.

Conclusions:

The NOAEL for this study is 100 mg/kg bw/d, based on clinical signs at higher dose levels.

Executive summary:

A combined repeat dose oral toxicity and reproductive/developmental toxicity study was conducted with pentaerythritol in male and female Crj: CD(SD) rats. Pentaerythritol was adminsitered orally by gavage at doses of 0 (vehicle control), 100, 300 and 1000 mg/kg bw/d. Males were exposed for 46 days (starting 14 days prior to mating), and females were exposed for 14 days prior to mating, during mating and gestation until lactation day 3. There were no mortalities during the study. The only treatment related effects were seen in the 300 mg/kg bw/d and 1000 mg/kg bw/d groups and consisted of intermittent soft faeces and diarrhoea. There was also a tendency towards increased water consumption in 1000 mg/kg bw/d males (only determined in males), the difference was not significant and could be attributed to the occurrence of intermittent diarrhoea in this group. The NOAEL for repeated dose toxicity was therefore 100 mg/kg bw/d.

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:

A 90-day study performed with pentaerythritol is available. Based on these results, the no-observed-effect level of pentaerythritol can be concluded to be 1000 mg/kg bw/d.

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

Repeated dose oral toxicity

In a 28 -day rat study (Hayashi et al, 1992), a group of male and female F344 rats was gavaged with pentaerythritol at the limit dose of 1000 mg/kg bw/d. No deaths occurred and there were no signs of toxicity. No effects of clear toxicological significance were seen;

minimal statistically significant effects on isolated clinical chemistry and haematology parameters are not considered to be of toxicological significance in the absence of consistency and pathological correlate. The NOAEL for this study is therefore considered to be 1000 mg/kg bw/d.

In a 90 -day rat study (Coleman, 2017), a group of male and female Han Wistar rats was gavaged with pentaerythritol at the limit dose of 1000 mg/kg bw/d. Ploughing and salivation were observed at all dose levels with a generally dose related incidence. No mortality was observed. There were no test article related changes to food consumption, ophthalmology, functional observations, clinical pathology parameters, body weights and organ weights. No gross necropsy or histopathological findings were related to test article administration. Pentaerythritol was well tolerated in the rat at levels up to 1000 mg/kg bw/day when administered for 90- days. The NOAEL was considered to be 1000 mg/kg bw/day.

A combined reproductive and developmental toxicity screening study (Yahata, 1996) was performed at gavage dose levels of 0, 100, 300 and 1000 mg/kg bw/d. This study identified intermittent soft stools and diarrhoea as the only effects of treatment; the NOAEL was defined as 100 mg/kg bw/d.

Repeated dose dermal toxicity

The repeated dose toxicity of the substance has been adequately characterised by available and proposed studies using oral exposure.

Repeated exposure inhalation toxicity

The repeated dose toxicity of the substance has been adequately characterised by available and proposed studies using oral exposure.

Keplinger & Kay (1954) performed a 12 -week repeated exposure inhalation toxicity study in rats using an exposure concentration of 8 mg/L. Although the value of this study is limited by the relatively large particle size of the substance to which animals were exposed (10 -15% respirable size), the absence of any treatment-related effects demonstrates the low toxicity of the substance by this route of exposure.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study of longest duration and providing the lowest endpoint

Justification for classification or non-classification

Pentaerythritol was shown to be of relatively low toxicity; the results of the studies available do not indicate any severe toxicity and do not show any effects at dose levels of 1000 mg/kg bw/day or lower. Pentaerythritol is therefore not classified for repeated dose toxicity according to EC Regulation 1272/2008.