Registration Dossier

Administrative data

Description of key information

NOAEL = 1000  mg kg bw/day, read-across substance (OECD 408, GLP, K, rel. 2) 

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From 1997-02-05 to 1997-09-03
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study performed according to OECD test guideline No. 408 and in compliance with GLP. The read-across is considered appropriate and scientifically justified based on the structural and physico-chemical similarity and the common toxicological profiles of the two substances.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Program (inspection date: 1996-01-22)
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS: Sprague-Dawley Crl:CD®BR strain
- Source: Charles River (UK) Limited, Manston, Kent- U.K.
- Age at study initiation: six to seven weeks old
- Weight at study initiation: males: 158 to 206 g, females: 142 to 185 g
- Housing: animals were housed in groups of up to four by sex in polypropylene grid-floor cages suspended over trays lined with absorbent paper
- Diet (e.g. ad libitum): ad libitum (pelleted diet (Rat and Mouse SQC Expanded Diet No.1, Special Diets Services Limited, Witham, Essex, UK) Analysis certified
- Water (e.g. ad libitum): ad libitum (Analysis certified)
- Acclimation period: at least 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 05 February 1997 To: 03 September 1997
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: the test material was prepared at the appropriate concentrations as a suspension/emulsion in 0.5% carboxymethyl cellulose. Formulations were prepared weekly and stored at approximately +4 °C in the dark. The stability and homogeneity of the test material formulations were determined by Safepharm Analytical Laboratory. Samples were taken of each test material formulation and were analysed for concentration of ST 11 C 91 at Safepharm Analytical Laboratory.


VEHICLE
- Justification for use and choice of vehicle (if other than water): test substance not soluble in water
- Amount of vehicle (if gavage): 5 mL/kg bw/day.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The ST 11 C 91 concentration in the test material formulations was determined by gas chromatography (GC) using an external standard technique. Analytical data indicated that actual dosages were close to nominal concentrations and acceptable.
HOMOGENEITY of test material formulation (nominal concentrations: 10, 50 and 200 mg/mL) were in the range of 92.1-106%, 96.4-103.6 % and 95.5 to 104.5% of the nominal concentrations with mean values of 100.1 %, 98.2 % and 100.5% of nominal concentrations respectively.
STABILITY ANALYSIS: the concentrations found after 11 days of storage were 97%, 97% and 99 % of the nominal concentration for the following nominal concentrations: 10, 50 & 200 mg/mL
CONCENTRATION ANALYSIS: Daily measured concentrations for 10, 50 & 200 mg/mL nominal concentrations were in the range of 91-113%, 90-126% & 93-107 % of nominal concentrations respectively.
Duration of treatment / exposure:
90 days
Frequency of treatment:
once daily, 7 days a week
Remarks:
Doses / Concentrations:
0, 50, 250 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
15 animals/sex/dose+ 10 recovery animals/sex/control and high dose groups
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on previous studies. In the 7-day oral gavage dose range finding study in the rat, twenty-four rats of the Crl:CD(SD)BR strain were divided into 4 groups consisting of 3 males and 3 females. Three groups received the test compound, orally by gavage once daily, for 7 days at dose levels of 500, 750 and 1000 mg/kg bw/day. The fourth group received the vehicle 0.5% (w/v) aqueous carboxymethylcellulose and acted as a control. No adverse significant effects (mortality, clinical signs, bodyweight change, food consumption, organ weight, necropsy & histopathology) were measured for any of the concentrations tested. In the 28-day oral gavage toxicity study in the rat, the NOEL was determined to be 1000 mg/kg bw/d.
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: control and high dose groups
- Post-exposure recovery period in satellite groups: 28 days
Positive control:
Not applicable
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily (immediately after dosing and 1 and 5 hours after dosing)


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily (immediately after dosing and 1 and 5 hours after dosing)


BODY WEIGHT: Yes
- Time schedule for examinations: on day 0 (the day before the start of treatment) and at weekly intervals thereafter. Bodyweights were also recorded at necropsy


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): NOT A FEEDING STUDY, food consumption was recorded wherever possible for each cage group at weekly intervals throughout the study.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): NOT A DRINKING WATER STUDY, water intake was observed daily, for each cage group, by visual inspection of the water bottles for any overt changes.


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-treatment and before termination (during week 12)
- Dose groups that were examined: all non-recovery control and 1000 mg/kg bw/day dose animals
- Examinations included observation of the anterior structures of the eye, pupillary and corneal blink reflex and, following pupil dilation with 0.5% Tropicamide solution ("Mydriacyl") detailed examination of the internal structure of each eye using a direct ophthalmoscope.


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment and treatment-free period (Day 90 and on Day 118 for recovery group). Blood samples were obtained from the lateral tail vein. Where necessary repeat samples were obtained by cardiac puncture prior to necropsy on Days 91 and 119.
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: all surviving animals, and all recovery groups animals
- Parameters checked in table 7.5.1/1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment (Day 90 and on Day 118 for recovery group). Blood samples were obtained from the lateral tail vein. Where necessary repeat samples were obtained by cardiac puncture prior to necropsy on Days 91 and 119.
- Animals fasted: No
- How many animals: all surviving animals and all recovery group animals
- Parameters checked in table 7.5.1/1 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: performed on all surviving non-recovery animals during Week 13 wherever possible and on all recovery group animals during Week 17. Urine samples were collected overnight by housing the rats in metabolism cages. Animals were maintained under conditions of normal hydration during collection but without access to food.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes, overnight
- Parameters checked in table 7.5.1/1 were examined.


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
PATHOLOGY
On completion of the dosing period all surviving animals were killed by intravenous overdose of sodium pentobarbitone (Sagatal, 60 mg/ml; May
and Baker Limited, Dagenham, Essex, UK) followed by exsanguination. Animal number 76 was killed in extremis by intravenous overdose of
sodium pentobarbitone followed by exsanguination. All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
ORGAN WEIGHTS: The following organs were removed from animals killed either at the end of the dosing period or at the end of the treatment-free period, dissected free from fat and weighed before fixation: Adrenals, Brain, Heart, Kidneys, Liver, Lungs (with bronchi), Ovaries/testes, Pituitary, Spleen, Thymus, Thyroid).
HISTOPATHOLOGY: Samples of the main tissues (40) were removed from all animals and preserved in buffered 10% formalin.
GROSS PATHOLOGY: Yes (See table 7.5.1/2)
HISTOPATHOLOGY: Yes (See table 7.5.1/2)
All tissues were despatched to Propath UK Ltd, Willow Court, Netherwood Road, Rotherwas, Hereford, UK for processing. All preserved tissues from control and 1000 mg/kg/day animals and the 250 mg/kg/day female killed in extremis were prepared as paraffin blocks, sectioned at nominal thickness of 5 micrometer and stained with haematoxylin and eosin for subsequent microscopic examination. The kidneys, liver and lungs from all surviving animals in the remaining non-recovery and recovery dose groups were also processed, and examined microscopically.
Microscopic examination was conducted by the Study Pathologist. All findings were entered into the ROELEE 84 pathology computerisation system for tabulation and report production.


Other examinations:
None.
Statistics:
Haematological, blood chemical, organ weight (absolute and relative to terminal bodyweight), quantitative urinalytical and weekly bodyweight gain data, were assessed for dose response relationships using linear regression analysis followed by one way analysis of variance (ANOVA) incorporating Levene's test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparisons were conducted using Dunnett's test.
Data showing heterogeneous variances were re-analysed using nonparametric methods: Kruskal-Wallis ANOVA and Mann-Whitney "U"-test.
The haematology variable basophils was not analysed since consistently greater than 30% of the data were recorded as the same value.
Histopathology data were analysed using the following methods to determine significant differences between control and treatment groups for the individual sexes:
1. Chi squared analysis for differences in the incidence of lesions occurring with an overall frequency of 1 or greater.
2. Kruskal-Wallis one way non-parametric analysis of variance for the comparison of severity grades for the more frequently observed graded conditions.
Analyses were undertaken using the non-recovery control groups for intergroup comparison with non-recovery treatment groups. In the absence of any treatment-related findings, an intergroup comparison was not conducted between the recovery control and treatment groups.
Animal that died during the course of the study were excluded from statistical analysis.
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):
no effects observed
Ophthalmological findings:
no effects observed
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:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no treatment-related deaths and signs of toxicity during the study.
Two males treated with 1000 mg/kg bw/day were found dead during the treatment period one each on Days 34 and 85, almost certainly following a mal-dose.

Males and females treated with 1000 mg/kg bw/day showed increased salivation either before or approximately two minutes after dosing from Days 6 and 5 onwards respectively. Associated signs detected sporadically throughout the treatment period included increased salivation approximately one hour after dosing, red/brown staining of the mouth and fur wetting. Increased salivation and its associated findings are commonly reported following the oral administration of a test material formulation and are considered to be attributable to an unpleasant tasting or locally irritant formulation rather than an indication of systemic toxicity.
One 250 mg/kg bw/day female briefly developed clinical signs on Days 9 and 10 of the study including pallor of the extremities, hunched posture, lethargy, decreased respiratory rate and gasping, laboured and noisy respiration. The lack of dose relationship exhibited by these observations coupled with their transiency suggests that they were most probably a consequence of a slight mal-dose and, accordingly, were considered to be of no toxicological importance.
One female treated with 250 mg/kg bw/day developed a large swelling around the lower left abdominal region on Day 43 of the study. By Day 49 this swelling had darkened and the animal was consequently killed in extremis.
The remaining incidental signs detected during the study, including generalised fur loss, an open wound, a scab and a swollen ear were minor physical injuries and were of no toxicological importance.


BODY WEIGHT AND WEIGHT GAIN
There was no adverse effect detected on bodyweight development during the study. Treated animals showed a bodyweight gain similar to or greater than controls during the study.
Recovery 1000 mg/kg bw/day females showed a slight but statistically significant reduction in bodyweight gain during the first week of the recovery period compared with controls. No such reductions were detected during the treatment period for non-recovery individuals and such a minimal change (p < 0.05) was considered to be of no toxicological significance. These females also showed a slight statistically significant increase in bodyweight gain during the final week of the recovery period but this is unlikely to represent an adverse effect on health.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
This was NOT a feeding study, however there was no adverse effect detected on dietary intake during the study.
Treated animals showed a dietary intake and food efficiency (the ratio of bodyweight gain to food consumption) similar to or greater than controls during the study.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
This was NOT a feeding study, however there were no overt intergroup differences detected during the study.


OPHTHALMOSCOPIC EXAMINATION
There were no treatment-related ocular effects. The incidental findings recorded were those normally encountered in laboratory maintained rats of the strain and age employed and were confined to pre-test observations, having completely resolved by the end of the study.


HAEMATOLOGY
There were no treatment-related changes detected in the haematological parameters measured.
Recovery 1000 mg/kg bw/day animals of either sex showed a statistically significant reduction in monocyte count with males also showing a reduction in neutrophil count in comparison with controls. Similar reductions were not apparent among non-recovery animals following ninety days of treatment and accordingly these intergroup differences were considered to be of no toxicological significance.


CLINICAL CHEMISTRY
There were no treatment-related changes detected in the blood chemical parameters measured.
Females treated with 1000 mg/kg bw/day showed a statistically significant reduction in plasma triglyceride concentration compared with controls. All of the individual values were within the normally expected range for rats of the strain and age used and in the absence of any changes in the plasma protein profile or any other evidence of hepatic dysfunction which might otherwise account for hypotriglyceridaemia in these individuals, the reduction was considered to have arisen fortuitously.
Males treated with 250 mg/kg bw/day showed a statistically significant reduction in plasma alkaline phosphatase compared with controls. In the absence of a similar change in this parameter at the highest dose level a dose-relationship could not be established and in any case a reduction in the activity of this enzyme is unlikely to be of toxicological importance.
The remaining statistically significant intergroup differences were confined to increases in plasma alanine amino transferase and creatinine concentration among recovery 1000 mg/kg bw/day females when compared with controls. No such increases were evident among non-recovery animals following ninety days of treatment and as such these differences were considered to be of no toxicological importance.


URINALYSIS
There were no treatment-related changes detected in the urinalytical parameters measured. All inter and intra group differences were considered to be a result of normal variation for rats of the species and strain used and, therefore, of no toxicological significance.


ORGAN WEIGHTS
There were no treatment-related changes detected in the organ weights measured.
Females treated with 250 mg/kg bw/day showed a statistically significant increase (p< 0.01) in thymus weight, both absolute and relative to terminal bodyweight, compared with controls. A slight but statistically significant increase (p < 0.05) in relative thymus weight was also evident among 1000 mg/kg bw/day females. The severity of the differences was, however, not dose-related and in the absence of any histopathological evidence of thymus changes these intergroup differences were considered to be of no toxicological significance.


GROSS PATHOLOGY
There were no treatment-related macroscopic lesions which could convincingly be attributed to test material toxicity.
Five males treated with 1000 mg/kg bw/day and one 250 mg/kg bw/day male were reported to have speckled kidneys at terminal kill, however, in the absence of any toxicological correlates, such as an altered relative kidney weight, microscopically observed lesions or blood chemical changes indicative of renal dysfunction, these findings were, in isolation, considered to be of no toxicological importance.
The two male decedents from the 1000 mg/kg bw/day treatment group showed pulmonary lesions suggestive of a mal-dose together with normally expected post mortem changes.
The remaining macroscopic abnormalities, including a small or large abdominal mass, hydronephrosis of one or both kidneys, pallor of and multiple dark foci on the left and caudal lobes of the lung, a malformed or misshapen spleen and small testes represent congenital or low incidence findings of the type normally encountered among rats of the strain and age used. In particular there was no difference in the incidence or severity of findings between treated animals and controls.


HISTOPATHOLOGY:
No treatment-related changes were observed.
There were three unscheduled deaths during the study. Rat number 95 male and 97 male (1000 mg/kg bw/day) died as a probable result of maldosing, although there was no histopathological evidence in support of this or any other cause of death, and rat number 76 female (250 mg/kg bw/day) was killed as a result of a malignant mammary tumour. Mammary adenocarcinomas are relatively common in aged Sprague Dawley CD female rats, and it is not unusual for mammary neoplasia to develop amongst female rats at an earlier age.
Although there were indications of an increased incidence of eosinophilic globular accumulations in the proximal renal tubular epithelium of high dose male rats, the difference, which attained statistical significance (p < 0.05), was not sufficiently great, to indicate a relationship to treatment. The between group variation in incidence and severity of the condition was pronounced (p< 0.001) and further precluded an association with treatment.
All remaining morphological changes were those commonly observed in laboratory maintained rats of the age and strain employed. Although group differences in the incidence or severity of lesions occasionally attained statistical significance, none were considered to be related to treatment.
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified

no other information

Conclusions:
Under the test conditions, the "No Observed Effect level" (NOEL) was considered to be 1000 mg/kg bw/day.ST 11 C 91 is not classified for damage to organs through prolonged oral dose repeated exposure according to the criteria of the Annex VI of the Regulation (EC) No 1272/2008 (CLP) and of the Directive 67/548/EEC.
Executive summary:

In a sub-chronic toxicity study performed according to the OECD test guideline No. 408 and in compliance with GLP, ST 11 C 91 diluted in carboxymethylcellulose was administered by gavage to Sprague-Dawley Crl:CD®BR rats (15/sex/group) at 50, 250 or 1000 mg/kg bw/day for 90 days A control group received vehicle alone at the same volume-dosage (5 mL/kg bw/day). Control and high dose group contained an additional 10 rats/sex/group for evaluation of recovery from any test substance-related effects, following a 28-day recovery period.

 

There were no treatment-related deaths during the study. Two males treated with 1000 mg/kg bw/day were found dead during the treatment period one each on Days 34 and 85 almost certainly following a mal-dose. A 250 mg/kg bw/day female was killed in extremis on Day 49 after a large mass developed around its abdominal region.

No clinically observable signs of toxicity were detected during the study. No adverse effect on bodyweight development, on dietary intake, on water consumption was detected during the study. No treatment-related effects were observed during ophthalmoscopic examination. Haematology, clinical chemistry and urinalysis were normal. At necropsy, no treatment-related macroscopic or microscopic lesions were noticed, organ weight were within normal ranges.

Based on these observations, the "No Observed Effect level" (NOEL) was considered to be 1000 mg/kg bw/day. St 11 C 91 is not classified for damage to organs through prolonged oral dose repeated exposure according to the criteria of the Annex VI of the Regulation (EC) No 1272/2008 (CLP) and of the Directive 67/548/EEC.

This study is considered as acceptable and satisfies the requirement for repeated dose toxicity endpoint.

The read-across is considered appropriate and scientifically justified based on the structural and physico-chemical similarity and the common toxicological profiles of the two substances (see §Toxicokinetics for read-across justification).

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:
The key study is GLP-compliant and of high quality (Klimisch score = 2)

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

A key study was identified on a read-across substance, Globalide/Habanolide (Thomas, 1998, rel. 2) (see §Toxicokinetics for read-across justification). In this sub-chronic toxicity study performed according to the OECD test guideline No. 408 and in compliance with GLP, ELINCS 422 -320 -3, diluted in carboxymethylcellulose, was administered by gavage to rats (15/sex/group) at 50, 250 or 1000 mg/kg bw/day for 90 days A control group received vehicle alone at the same volume-dosage (5 mL/kg bw/day). Control and high dose group contained an additional 10 rats/sex/group, which were retained following dosing for a recovery period of 28 days to assess whether any test substance-related effects were reversible. 

There were no treatment-related deaths during the study. Two males treated with 1000 mg/kg bw/day were found dead during the treatment period one each on Days 34 and 85 almost certainly following a mal-dose. A 250 mg/kg bw/day female was killed in extremis on Day 49 after a large mass developed around its abdominal region.

No clinically observable signs of toxicity were detected during the study. No adverse effect on bodyweight development, on dietary intake, or on water consumption was detected during the study. No treatment-related effects were observed during ophtalmoscopic examination. Haematology, clinical chemistry and urinalysis were normal. At necropsy, no treatment-related macroscopic or microscopic lesions were noticed, organ weights were within normal ranges.

Based on these observations, the NOAE) was considered to be 1000 mg/kg bw/day.

This conclusion is confirmed by the sub-acute study conducted on the analogue substance, 1,4-dioxacyclohexadecane-5,16-dione (Paffett, 2000, rel.2). In this sub-acute toxicity study performed according to the OECD test guideline No. 407 and in compliance with GLP, Zenolide diluted in corn oil was administered by gavage to Sprague-Dawley rats (5/sex/group) at 15, 150 and 400 or 1000 mg/kg bw/day for 28 days A control group received vehicle alone at the same volume-dosage (5 mL/kg bw/day). Control and high dose group contained an additional 5 rats/sex/group for evaluation of recovery from any test substance-related effects, following a two-week recovery period.

There were neither treatment-related deaths nor any clinical signs which were considered to be toxicologically important. There were no effects on bodyweight gain, food consumption and efficiency to be associated with treatment. Haematology and urinalysis were normal.

On Day 30, group mean GOT levels were lower than concurrent controls for males and females receiving 1000 mg/kg/day and females only receiving 400 mg/kg/day. On Recovery Day 16, there was no similar finding apparent. These lower GOT levels are not considered to be of toxicological importance. Slight increases in sodium and chloride were noted among females receiving 1000 or 400 mg/kg/day. A similar finding was not apparent in males. These slight increases in sodium and chloride are not considered to be related to treatment.

Group mean bodyweight-adjusted kidney weights were higher for females receiving 1000 or 400 mg/kg/day in comparison with controls, the differences attaining statistical significance. A similar finding was apparent for males at these dosages but to a lesser (not statistically significant) degree. These increases were not apparent following the recovery period. No macroscopic or histopathologic changes were observed in the kidneys of females receiving 1000 or 400 mg/kg/day which were associated with treatment. These increases were not considered to be of toxicological importance.

Macroscopic examination performed at both the terminal and recovery post mortems revealed no changes associated with treatment.

No treatment-related changes were detected during histopathology.

Based on these observations, the NOAEL was considered to be 1000 mg/kg bw/day.

The read-across is considered appropriate and scientifically justified based on the structural and physico-chemical similarity and the common toxicological profiles of the three substances (see §Toxicokinetics for read-across justification).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No study was located on Ethylene Brassylate. Therefore a read-across approach using two supporting substances, Globalide/Habanolide and 1,4-dioxacyclohexadecane-5,16-dione, was used to fulfil this endpoint. The study with the longest duration (90-days) was selected as the key study.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
A 20-day study is available, however it does not meet important criteria of today's standard methods as the test site was abraded and an occluded dressing was not used to prevent ingestion.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008 including ATP3.

Self-classification:

Based on the available information, no additional classification is proposed.