Registration Dossier

Administrative data

Description of key information

The NOAEL of the 28-day oral repeat dose toxicity study in rats (OECD407) was 100 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with guideline OECD407 and EU B.7 and to GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Guidelines for Screening, Toxicity Testing of Chemicals: Testing Methods for New Substances 1974
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Test animal: HanBrl:WIST (SPF) rat
- Source: RCC Ltd Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland
- Age at study initiation: 6weeks
- Weight at study initiation: Males: 136.0 - 161.5 grams (mean 148.6 grams) Females: 114.8 - 129.6 grams (mean 122.4 grams)
- Housing: In groups of five in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding ('Lignocel' Schill AG).
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 (batch no. 17/03and 40/03) rat maintenance diet ab libitum
- Water (e.g. ad libitum): Community tap-water was available ad libitum in water bottles.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):20 ± 3 °C
- Humidity (%):30-70 %.
- Air changes (per hr):10-15 air changes per hour
- Photoperiod (hrs dark / hrs light):12 hours fluorescent light / 12 hours dark
Route of administration:
oral: gavage
Vehicle:
other: 2.5% ethanol in distilled water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- The test item formulations were prepared weekly. Decan-1,2-diol was weighed on a tared Mettler balance and the vehicle (2.5% ethanol in distilled water) was added w/v. The mixtures were stored at room temperature (17 - 23 °C). Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.

VEHICLE
- Justification for use and choice of vehicle (if other than water): not reported
- Concentration in vehicle: 10mg/mL to 100mg/mL
- Amount of vehicle (if gavage): 10 mL/kg body weight
- Purity: not reported
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability (alter 2 hours and 7 days) of the dose formulations were determined in samples taken after experimental start.Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment. The analyses were performed by RCC Ltd Environmental Chemistry & Pharmanalytics according to a GC method supplied by the Sponsor
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
100, 300 and 1000mg/kg
Basis:
other: gavage
No. of animals per sex per dose:
Control - 10 males + 10 females (5 males and 5 females in a 14 day recovery group)
100mg/kg - 5 males + 5 females
300mg/kg - 5 males + 5 females
1000mg/kg - 10 males + 10 females (5 males and 5 females in a 14 day recovery group)
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for animal assignment (if not random):Computer-generated random algorithm
- Rationale for selecting satellite groups: to assess reversibility of effects of treatment
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random): not reported
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed for clinical signs once before commencement of administration; twice daily on days 1-3; as well as once daily on days 4-28 and once daily during days 29-42 (recovery).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: performed in random sequence once before commencement of administration and once weekly (weeks 1-3) thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: during pre-test, treatment and recovery and before necropsy

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):recorded once during the pre-test period and weekly thereafter

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 weeks and 6 weeks (recovery group)
- Animals fasted: Yes
- How many animals: All animals
- Parameters: Erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, red cell volume distribution width, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hemoglobin concentration distribution width, platelet (thrombocyte) count, reticulocyte count, reticulocyte maturity index, methemoglobin, total leukocyte count, differential leukocyte count, coagulation, thromboplasin time and activated partial thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 weeks and 6 weeks (recovery group)
- Animals fasted: Yes
- How many animals: All animals
- Parameters: Glucose, urea, creatinine, bilirubin (total), cholesterol (total), triglycerides, phospholipids, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, glutamate dehydrogenase, creatine kinase, alkaline phosphate, Gamma-glutamyl-transferase, sodium, potassium chloride, calcium, phosphorus inorganic, protein (total), albumin, globulin and the albumin/globulin ratio.

URINALYSIS: Yes
- Time schedule for collection of urine:after 4 weeks and 6 weeks (recovery group)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters: Volume (18-hours), specific gravity (relative density), colour, appearance, pH, nitrite, protein, glucose, ketones, urobilinogen, bilirubin, erythrocytes and leukocytes.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 4 of treatment
- Dose groups that were examined: all
- Battery of functions tested: grip strength and locomotor activity

OTHER: FUNCTIONAL OBSERVATIONAL BATTERY
- During week 4, relevant parameters from a modified Irwin screen test were evaluated in all animals.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals

after 4 weeks 04 August 2003 (Allocation A)
after 6 weeks 18 August 2003 (Allocation B)

All animals were weighed and necropsied. Descriptions of all macroscopic abnormalities were recorded. All animals were anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination. Samples of the following tissues and organs were collected from all animals at necropsy and fixed in neutral phosphate buffered 4 % formaldehyde solution (unless otherwise indicated):
Adrenal glands
Aorta
Bone (sternum, femur including Joint)
Bone marrow (femur)
Brain (3 levels)
Cecum
Colon
Duodenum
Epididymides (fixed in Bouin's solution)
Esophagus
Eyes with optic nerve (fixed in Davidson's
solution)
Harderian gland (fixed in Davidson's solution)
Heart
Ileum, with Peyer's patches
Jejunum with Peyer's patches
Kidneys
Larynx
Lacrimal gland (exorbital)
Liver
Lungs (infused with formalin at necropsy)
Lymph nodes (mesenteric, mandibular)
Memmen,/ gland area
Nasal cavity
Ovaries
Pancreas
Pituitary gland
Prostate gland
Rectum
Salivary glands (mandibular, sublingual)
Sciatic nerve
Seminal vesicies
Skeletal muscle
Skin
Spinal cord (cervical, midthoracic, lumbar)
Spleen
Stomach
Testes (fixed in Bouin's solution)
Thymus
Thyroid (incl. parathyroid gland)
Tongue
Trachea
Urinary bladder (infused with formalin at
necropsy)
Uterus
Vagina
Gross lesions

HISTOPATHOLOGY: Yes

Slides of all organs and tissues listed below which were collected at scheduled sacrifice from the animals of control and high-dose groups were examined by a pathologist. All organ and tissue samples, were processed, embedded and cut at an approximate thickness of 2 to 4 micrometers, and stained with hematoxylin and eosin. As test item-related morphologic changes were detected in the organs of high-dose animals, the stomachs from animals of the mid- and low-dose groups were examined:
Bone marrow (femur)
Brain (3 levels)
Cecum
Colon
Duodenum
Epididymides (fixed in Bouin's solution)
Heart
Ileum, with Peyer's patches
Jejunum with Peyer's patches
Kidneys
Liver
Lungs (infused with formalin at necropsy)
Lymph nodes (mesenteric, mandibular)
Ovaries
Prostate gland
Rectum
Sciatic nerve
Seminal vesicies
Spinal cord (cervical, midthoracic, lumbar)
Spleen
Stomach
Testes (fixed in Bouin's solution)
Thymus
Thyroid (incl. parathyroid gland)
Trachea
Urinary bladder (infused with formalin at
necropsy)
Uterus
Vagina
Gross lesions
Other examinations:
The following organ weights were recorded an the scheduled dates of necropsy: Brain, Thymus, Spleen, Ovaries, Heart, Kidneys, Testes, Liver, Adrenals and the Epididymides. The organ to terminal body weight ratlos as well as organ to brain weight ratios were determined. The determination of the terminal body weight was performed immediately prior to necropsy.
Statistics:
The following statistical methods were used to analyse the grip strength, locomotor activity, body weight, organ weights and ratios, as well as:

- The Dunnett-test (many to one t-test) based on a pooled variance estimate were applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
- Fisher's exact-test were applied to the macroscopic findings. The following statistical methods were used for statistical analysis of clinical laboratory data:
- Quantitative data were analyzed by a one-way analysis of variance (ANOVA) when the variances are considered homogeneous according to Bartlett. - Alternatively, if the variances are considered to be heterogenous (p = 0.05), a non-parametric Kruskal-Wallis test was used. Treated groups were compared to the control groups using Dunnett's test if the ANOVA was significant at the 5% level and by Dunn's test in the case of a significant Kruskal-Wallis test (p = 0.05)
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Scattered external findings (such as diverse hair loss and scabbing) were noted in control males as well as rats treated with 100 or 1000 mg/kg/day. Rales were observed in one female treated with 300 mg/kg/day (week 3), and one or two females treated with 1000 mg/kg/day (weeks 2 and 3), and one male treated with 1000 mg/kg/day (week 3). These findings were considered to be incidental changes of no toxicological significance.
Mortality:
mortality observed, treatment-related
Description (incidence):
Scattered external findings (such as diverse hair loss and scabbing) were noted in control males as well as rats treated with 100 or 1000 mg/kg/day. Rales were observed in one female treated with 300 mg/kg/day (week 3), and one or two females treated with 1000 mg/kg/day (weeks 2 and 3), and one male treated with 1000 mg/kg/day (week 3). These findings were considered to be incidental changes of no toxicological significance.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weights of the test item-treated males and females were generally similar to those of their respective controls during the treatment and recovery periods.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean daily food consumption of the test item-related males compared favourably with those of the control males.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
The females treated with 1000 mg/kg/day, however, consumed less feed during study (10% less during days 1-8, 13% less during days 8-15, 15% . Males unaffected
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Some effects -elevation of reticulocytes in females at 300mg/kg only ; recovery group females had significantly lowered hematocrit - not considered to be treatment related.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
The absolute and relative organ weights of the test item-treated rats compared favorably with those of the control rats after the treatment and recovery periods
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
High dose males and females presented elevated ketone levels, but not evident after recovery period
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
The mean locomotor activity of the males and females treated with 1000 mg/kg/day were significantly reduced during several measurement intervals.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The absolute and relative organ weights of the test item-treated rats compared favorably with those of the control rats after the treatment and recovery periods
Gross pathological findings:
no effects observed
Description (incidence and severity):
No macroscopical findings of toxicological relevance were noted after 4 weeks of treatment or 2 weeks of recovery.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment for 28 days resulted in squamous epithelial hyperplasia, ulceration and inflammation of the forestomach in the 1000 mg/kg/day dose group -largerly reversible,
Details on results:
CLINICAL SIGNS AND MORTALITY
Diverse hair loss was noted in single control males, and in males treated with 100 mg/kg/day and 1000 mg/kg/day. Transient incidents of rales were seen in one male and one female treated with 1000 mg/kg/day. These changes were considered to be incidental. Pale faeces were noted in males and females treated with 1000 mg/kg/day from treatment day 4-28 and from recovery day 1-2, and this was considered to be a passive test item-related finding of no toxicological relevance. This finding is often seen in oral gavage studies in which high doses of light-coloured test items are administered. Scattered external findings (such as diverse hair loss and scabbing) were noted in control males as well as rats treated with 100 or 1000 mg/kg/day. Rales were observed in one female treated with 300 mg/kg/day (week 3), and one or two females treated with 1000 mg/kg/day (weeks 2 and 3), and one male treated with 1000 mg/kg/day (week 3). These findings were considered to be incidental changes of na toxicological significance.

BODY WEIGHT AND WEIGHT GAIN
The mean body weights of the test item-treated males and females were generally similar to those of their respective controls during the treatment and recovery periods. In males treated with 1000 mg/kg/day, the mean body weight gain were slightly lower than those of the control males during the recovery period. The difference attained statistical significance (p<0.05) an day 1 of recovery when compared with the control males. This difference was not considered to be test item related. The mean body weight gain values of the females were unaffected during treatment and recovery

FOOD CONSUMPTION AND COMPOUND INTAKE
The mean daily food consumption of the test item-related males compared favourably with those of the control males. The females treated with 1000 mg/kg/day, however, consumed less feed during study (10% less during days 1-8, 13% less during days 8-15, 15% less during days 15-22 and 11% less during days 22-28) when compared with the control females. A relationship with the test item administration could not be eliminated. The mean daily food consumption during the recovery period was similar in all females

HAEMATOLOGY
No statistically significant or toxicologically relevant differences were noted after 4 weeks treatment in the hematology parameters of the test item-treated males_ After 2 weeks' recovery, significant reductions were noted in red blood cell count (p<0.05), hemoglobin (p<0.01), hematocrit (p<0.01) and mean cell volume (p<0.01) of males previously treated with 1000 mg/kg/day when compared with the control males, but all remained within the
range of variation for the historical control data and were considered to be incidental. In females treated with 300 mg/kg/day, the number of high flurorescence reticulocytes was significantly elevated (p<0.05) when compared with the control females. In the absence of a dose response relationship, this finding was considered to be incidental. The recovery females treated previously with 1000 mg/kg/day had significantly lower mean cell volume
(p<0.05) and red cell distribution width (p<0.05), as well as a reduction in the number of "large unstained cells" but these differences were well within the ranges of the historical control data and considered to be fortuitous.

CLINICAL CHEMISTRY
No test item-related differences of toxicological relevance were noted in the clinical biochemistry parameters alter 4 weeks of treatment or 2 weeks of recovery. After 4 weeks of treatment, significantly elevated sodium levels were seen in males treated with 100 mg/kg/day (p<0.05) and 1000 mg/kg/day (p<0.05), whereas significantly lower chloride levels (p<0.05) were seen in the latter males when compared with the controls. The sodium levels exceeded the range of the historical control data, but was considered unlikely to be test item-related. The observed difference in the chloride levels remained within the range of the historical control data and therefore considered to be incidental.

Creatinine was significantly lower in females treated with 1000 mg/kg/day (p<0.05), in the absence of a dose-response relationship, this finding was considered to be incidental. Females treated with 1000 mg/kg/day had significantly elevated lactate dehydrogenase (p<0.05) and significantly elevated creatine kinase (p<0.01) when compared with the control females. These parameters are subject to wide variation and were generally due to a small number of variant animals. These differences were not considered to be of toxicological relevance. Cholesterol levels were significantly lower (p<0.05) alter the recovery period in females treated previously with 1000 mg/kg/day, but as no differences were seen after the treatment period (although females treated with 100 mg/kg/day had a fortuitous dose-unrelated reduction (p<0.05) in cholesterol after the end of the treatment period), this finding was considered to be incidental.

Phospholipids were significantly reduced after 4 weeks' treatment in females treated with 100 mg/kg/day and after two weeks' recovery in the females treated previously with 1000 mg/kg/day (both p<0.05). These changes were not dose related or not seen after the end of the treatment period, respectively, and therefore considered to be inconsequential.

URINALYSIS
A significant amount of ketone were evident after the end of the treatment period in the urine of males (p<0.01) and females (p<0.01) treated with 1000 mg/kg/day. This finding was considered likely to represent metabolic adaptation to the test item, as it was no longer evident after the recovery period. The urinary pH was significantly reduced (p<0.01) after the treatment period in males treated with 1000 mg/kg/day and significantly increased (p<0.05) after the recovery period when compared with the controls, but all differences were within the range of normal variation seen in the historical control data.

NEUROBEHAVIOUR
The mean locomotor activity of the males treated with 1000 mg/kg/day were significantly reduced during the measurement intervals of 0-15 minutes (p<0.01), 15-30 minutes (p<0.01) and 30-45 minutes (p<0.05) and during the overall measurement interval of 0-60 minutes (p<0.01) when compared with the control males. In females treated with 1000 mg/kg/day, significantly reduced mean locomotor activity was noted during 0-15 minutes (p<0.05) and 15-30 minutes (p<0.05). These differences were considered to be test item-related-scattered significant differences in locomotor activity (from 30-45 minutes in males treated with 100 mg/kg/day, from 15-30 minutes in females treated with 100 mg/kg/day and from 30-45 minutes in females treated with 300 mg/kg/day) were considered to be unrelated to the test item treatment and incidental. The mean fore- and hindlimb grip strength values of the test item-treated rats were unaffected.

The mean forelimb grip strength was significantly lower in females treated with 100 mg/kg/day (p<0.01), when compared with the control females. This difference, in the absence of a dose-response relationship, was considered to be an incidental change and unrelated to the treatment with the test item.

ORGAN WEIGHTS
After 4 Weeks the absolute and relative organ weights of the test item-treated rats compared favorably with those of the control rats.
After 6 Weeks the absolute testes weight and the testes-to-brain weight ratio of the males previously treated with 1000 mg/kg/day were significantly higher (p<0.05) than those of the control males.

Similarly, the epididymide-to-body weight ratio was significantly elevated (p<0.05) in these males when compared with the controls. In the absence of microscopical changes, these differences were considered to be incidental. Uni- or bilateral renal pelvis dilation was noted alter 4 weeks' treatment in one control male and one male treated with 100 mg/kg/day. All other animals were without macroscopic findings. No macroscopical findings were noted after 2 weeks of recovery

GROSS PATHOLOGY
Uni- or bilateral renal pelvis dilation was noted alter 4 weeks' treatment in one control male and one male treated with 100 mg/kg/day. All other animals were without macroscopic findings. No macroscopical findings were noted after 2 weeks of recovery

HISTOPATHOLOGY: NON-NEOPLASTIC

HISTOPATHOLOGY: NEOPLASTIC
Test item-related changes in rats treated with 1000 mg/kg/day were noted in the forestomach after 4 weeks of treatment. These findings included:
- squamous epithelial hyperplasia of moderate to marked severity in all males and all females;
- increased severity of squamous epithelial hyperplasia at the limiting ridge in all males and all females;
- slight ulceration in one of five males;
- increased severity of inflammatory infiltrates.

Similar, if less severe findings were noted after 4 weeks in the forestomachs of rats treated with 300 mg/kg/day. These findings amounted to:
- slight squamous epithelial hyperplasia in one of five males and one of five females;
- squamous epithelial hyperplasia at the limiting ridge of moderate severity in one of five males and one of five females. The severity of this finding noted in the No test item-related changes were seen after 4 weeks in rats treated with 100 mg/kg/day.

After the recovery period, partial reversabiltiy of the test item-related changes were seen in the affected tissue of rats previously treated with 1000 mg/kg/day. The following forestomach findings remained:
- squamous epithelial hyperplasia of slight to moderate to severity in four of five males and minimal to slight severity in three of five females.remaining animals was comparable to the control rats.
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Conclusions:
Oral administration ofdecan-1,2-diol to Wistar rats at doses of 100, 300 and 1000 mg/kg/day, for 28 days resulted in no deaths, no clinical signs of toxicological relevance during daily or weekly observations, as well as functional observational battery (including no changes in grip strength), no differences in body weight development, no toxicologically relevant differences in hematology, clinical biochemistry or urinalysis parameters, no differences in absolute or relative organ weights and no test item-related macroscopical changes.

Test item-related findings were generally restricted to reduced mean locomotor activity at 1000 mg/kg/day, reduced food consumption in females at 1000 mg/kg/day, and a dose related severity and incidence of squamous epithelial hyperplasia of the forestomach in rats treated with 300 mg/kg/day or 1000 mg/kg/day dose group, whereas ulceration and inflammation was restricted to rats treated with 1000 mg/kg/day only. Although the squamous epithelial hyperplasia was still present after the recovery period in the animals previously treated with 1000 mg/kg/day, the severity and incidence seen in after the treatment period was largely reversible.

Based on the results of this study, the no-observed-effect-level (NOEL) and the no-observed adverse-effect-level (NOAEL) of decan-1,2 -diol was established as 100 mg/kg body weight/day.
Executive summary:

In this subacute toxicity study, decan-1,2 -diol was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 100, 300 and 1000 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, 2.5% ethanol in distilled water, only. The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 14-day treatment-free recovery period after which they were sacrificed.

All animals survived until scheduled necropsy.

No clinical signs of toxicological relevance were noted during daily observations or during weekly behavioural observations (weeks 1-3). No clinical signs of toxicological relevance were noted during the functional observational battery (week 4). Grip Strength The fore- and hind limb grip strength values of the test item-treated rats compared favourably with those of the controls. Locomotor Activity The mean locomotor activity of the males and females treated with 1000 mg/kg/day were significantly reduced during several measurement intervals. These differences were considered to be test item-related.

Reduced food consumption was noted during the treatment period in females at 1000 mg/kg/day. During the recovery period, the mean daily food consumption was similar in all females. The mean daily food consumption of the test item-related males compared favourably with those of the control males during treatment and recovery.

The mean body weights of the test item-treated males and females were generally similar to those of their respective controls during the treatment and recovery periods. No test item-related differences of toxicological relevance were noted in the hematology or clinical biochemistry parameters after 4 weeks of treatment or 2 weeks of recovery. After the treatment period, ketone were evident in the urine of males and females treated with 1000 mg/kg/day. This finding was considered likely to represent metabolic adaptation to the test item, as it was no longer evident after the recovery period.

Treatment for 28 days resulted in squamous epithelial hyperplasia, ulceration and inflammation of the forestomach in the 1000 mg/kg/day dose group, whereas treatment with 300 mg/kg/day resulted in squamous epithelial hyperplasia of the forestomach at a reduced severity and incidence. Following a 14-day recovery period, squamous epithelial hyperplasia was still present in the animals previously treated with 1000 mg/kg/day, but the severity and incidence seen in after the treatment period was largely reversible.

Based on the results of this study, the no-observed-effect-level (NOEL) and the no-observed adverse- effect-level (NOAEL) of decan-1,2 -diol was established as 100 mg/kg body weight/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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

Oral administration of decan-1,2 -diol to Wistar rats at doses of 100, 300 and 1000 mg/kg/day, for 28 days resulted in no deaths, no clinical signs of toxicological relevance during daily or weekly observations, as well as functional observational battery (including no changes in grip strength), no differences in body weight development, no toxicologically relevant differences in hematology, clinical biochemistry or urinalysis parameters, no differences in absolute or relative organ weights and no test item-related macroscopical changes. Test item-related findings were generally restricted to reduced mean locomotor activity at 1000 mg/kg/day, reduced food consumption in females at 1000 mg/kg/day, and a dose related severity and incidence of squamous epithelial hyperplasia of the forestomach in rats treated with 300 mg/kg/day or 1000 mg/kg/day dose group, whereas ulceration and inflammation was restricted to rats treated with 1000 mg/kg/day only. Although the squamous epithelial hyperplasia was still present after the recovery period in the animals previously treated with 1000 mg/kg/day, the severity and incidence seen in after the treatment period was largely reversible.

Based on the results of this study, the no-observed-effect-level (NOEL) and the no-observed adverse- effect-level (NOAEL) of decan-1,2 -diol was established as 100 mg/kg body weight/day.

Repeat dose studies by the dermal and inhalation routes have not been conducted.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study conducted in accordance with guideline OECD407 and EU B.7 and to GLP

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach; neurologic: central nervous system

Justification for classification or non-classification

With a NOAEL of 100 mg/kg/day from a 28-day oral exposure, and with only moderate pathological changes in the forestomach of rats dosed orally at 300 mg/kg/day, decan-1,2 -diol was considered to be on the limits of the classification criteria for Specific Target Organ Toxicity -Repeat Exposure (STOT-RE) Category 2 which is generally considered to be within 30 to 300 mg/kg/day for oral administration to rats (ECHA CLP Guidance V4.1 June 2015). However, the pathology in the forestomach was considered not to be of systemic exposure origin and classification for this endpoint was not achieved.