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Description of key information

Repeated dose toxicity: via oral route

The test chemical was administered daily to groups of rats at levels up to 1000 mg/kg for 26 weeks. Body weight and food consumption was not affected by treatment. Haematology, clinical chemistry and gross necropsy investigations showed no evidence of toxicity. There were no treatment related microscopic changes.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the test chemical, which is reported as 0.0099 kPa at temperature 101 Deg C & 101.324 kPa at temperature 280.45 Deg C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron to 53micron which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study:

The acute toxicity value for the given test chemical (as provided in section 7.2.3) is >2600 mg/kg body weight. The OECD study result for acute toxicity by the dermal indicates the LD50 value to be greater than 2000 mg/kg body weight. In addition, the skin sensitization also indicates negative skin sensitization potential by the chemical. Also considering the use of the chemical as a fragrance chemical and considering the volatility absorption by the dermal route is not considered to be significant. Thus, given the above considerations, it is assumed that Tridecanol shall not exhibit repeated dose toxicity by the dermal route.. Therefore this study is considered for waiver.

 

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
Data is from publication
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
Well-conducted study according to a protocol very similar to OECD guideline 408, but with a treatment duration of 26 weeks
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: CD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: ~21-28 days at purchase
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5/cage in stainless steel cages, containing absorbent paper
- Diet (e.g. ad libitum): expanded rodent diet (Special Diets Services, UK), ad libitum
- Water (e.g. ad libitum): public supply (Suffolk Water Company, UK), ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 55
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data
Route of administration:
oral: gavage
Vehicle:
other: 1% aqueous Tween 80
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- test material heated to approx. 80 deg C
- vehicle heated to approx. 75 deg C
- vehicle added to test material while being magnetically stirred at high speed
- resulting 20% (w/w) suspension homogenized and slowly cooled to below 60 deg C
- when cooled to 30 deg C, suspension slowly homogenized again for >=2 min
- cooled to room temp.
- stored at 13 deg C
- prepared once weekly
- 20% suspension used for top dose; for low and mid doses, suspension magnetically stirred and aliquots taken for dilution on day of use; constant dose volume of 5 ml/kg bw per dose
- dilutions mixed by hand swirling followed by magnetic stirring

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 1%
- Amount of vehicle (if gavage): 5 ml/kg bw per dose
- Lot/batch no. (if required): no data
- Purity: no data
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
26 weeks
Frequency of treatment:
daily, 7 days/week
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: additional 10/sex per treatment group for toxicokinetic study, 6/sex controls
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): random
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS (including mortality): Yes
- Time schedule: >=twice daily
- Cage side observations included: evidence of reaction to treatment or moribund condition, evidence of ill health such as blood or loose faeces

DETAILED CLINICAL OBSERVATIONS: Yes, individual observations
- Time schedule: once daily during week 1, twice weekly during weeks 2 to 4, once weekly during weeks 5 to 13, once every 2 weeks from week 14 onwards

BODY WEIGHT: Yes
- Time schedule for examinations: pre-study, weekly during the study or more frequently if appropriate (for animals in moribund condition), at necropsy

FOOD CONSUMPTION:
- Food consumption for each cage determined: Yes

FOOD EFFICIENCY:
- Weekly group mean food conversion efficiencies calculated from the consumption and body weight gain data: Yes, for the first 14 weeks of treatment

WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes, prestudy and at weeks 12 and 25

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 14 and 26
- Anaesthetic used for blood collection: Yes - halothane/nitrous oxide
- Animals fasted: Yes
- How many animals: 10/sex per dose level
- Parameters examined: packed cell volume, haemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, mean cell haemoglobin concentration, mean cell haemoglobin, mean cell volume; blood film samples examined for abnormal morphologhy and unusual cell types including normoblasts; prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 14 and 26
- Animals fasted: Yes
- How many animals: 10/sex per dose level
- Parameters examined: alkaline phosphatase activity, alanine amino transferase, aspartate amino transferase, gamma-glutamyl transpeptidase, glucose, total bilirubin, total cholesterol, urea, total triglyceride, total protein, electrolyte levels (Na, Cl, Ca), inorganic phosphorus, electrophorectic protein, creatine concentration

URINALYSIS: Yes
- Time schedule for collection of urine: weeks 12 and 25
- Metabolism cages used for collection of urine: No data
- Animals fasted: No, but water deprived
- Parameters examined: pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, specific gravity, appearance, volume

NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
- Bone marrow samples from femur: myeloid:erythroid ratio, cellularity and composition of marrow
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: adrenals, brain, kidneys, liver, lungs (with main stem bronchi), ovaries, pituitary, prostate, spleen, testes, thymus, thyroid (with parathyroids), uterus (with cervix)

HISTOPATHOLOGY: Yes - adrenals, brain, eyes, optic nerve, femur, heart, kidneys, liver, lungs, seminal vesicles, spinal cord, stomach, thyroid, uterus
Other examinations:

Satellite group for toxicokinetic study:
- Blood taken from satellite groups (3M+3F) non-fasted on days 1, during weeks 13 and 26 at 0.5, 1, 2, 4, 8 and 24 hours after dosing.
Statistics:
Bartlett's test for homogeneity of variance (organ weights, body weight changes); if significant, Behrens-Fisher test, otherwise Dunnett's test.
Two-tailed Fisher's exact test (macroscopic/microscopic pathological findings).
Student's t-test (haematology, clinical chemistry, urinalysis).
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:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
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
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- one male in the mid-dose group died at week 25 (examination suggested aspiration of test material through mis-dosing; not considered to be treatment-related)
- no other clinical signs of systemic toxicity or mortality

BODY WEIGHT AND WEIGHT GAIN
- no effects

FOOD CONSUMPTION
- presumably no effects

FOOD EFFICIENCY
- no effects

WATER CONSUMPTION
- not examined

OPHTHALMOSCOPIC EXAMINATION
- no effects

HAEMATOLOGY
- no effects
- no effects seen in bone marrow smears

CLINICAL CHEMISTRY
- no effects

URINALYSIS
- no effects

NEUROBEHAVIOUR
- not examined

ORGAN WEIGHTS
- no effects

GROSS PATHOLOGY
- no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
- no effects

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
- no effects

HISTORICAL CONTROL DATA (if applicable)
- no data

OTHER FINDINGS
- toxicokinetic study: concentrations of behenyl alcohol in the blood were measured on day 1 and in weeks 13 and 26; maximum mean plasma concentration (Cmax) of behenyl alcohol occurred 1 hour after dosing in all males and most females; 24 hours after dosing plasma concentrations were below the limit of quantification (<10ng/ml) at the 10 and 100 mg/kg dose levels while levels following administration of 1000 mg/kg/day remained quantifiable on each sampling day; Cmax in the top dose group ranged from 203.68 to 528.82 ng/ml throughout the duration of the study; statistically significant differences in area under the curve (AUC24) were observed between males and females treated with 10 and 1000 mg/kg/day on day 1 and during week 13; the rate and extent of systemic exposure to rats as shown by AUC24 and Cmax on day 1 and in weeks 13 and 26 increased with increasing dose level; increases were less than the proportionate dose increment and there was statistically significant evidence of non-proportionality on each sampling day.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Conclusions:
In a reliable study conducted according to a protocol very similar to OECD guideline 408, a repeated oral dose (26-week) NOAEL of 1000 mg/kg bw/day was determined in the rat. The study was performed in compliance with GLP. The result is a read across from 1-docosanol (CAS 661-19-8).
Executive summary:

Docosan-1-ol (CAS 661-19-8) was administered daily to groups of rats at levels up to 1000 mg/kg for 26 weeks. Body weight and food consumption was not affected by treatment. Haematology, clinical chemistry and gross necropsy investigations showed no evidence of toxicity. There were no treatment related microscopic changes.

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:
K2 reliability experimental data

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation, other
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Quality of whole database:
waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal, other
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
Endpoint conclusion
Quality of whole database:
waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity: via oral route

Experimental study on test chemical and structurally and functionally similar RA's was reviewed to determine the toxic nature of the test chemical upon repeated exposure by oral route. The study is as mentioned below:

1) The test chemical was administered daily to groups of rats at levels up to 1000 mg/kg for 26 weeks. Body weight and food consumption was not affected by treatment. Haematology, clinical chemistry and gross necropsy investigations showed no evidence of toxicity. There were no treatment related microscopic changes.

2) In a reliable study conducted to the draft OECD guideline 422 Twenty-four rats (12 male and 12 female) were used in each dose group, which received 1-Dodecanol in the diet in concentrations of 0, 1500, 7500, and 30000 ppm (ca. 0, 100, 500 and 2000 mg/kg/bw/day) for a period of 37 days. The test chemical had no influence on body weight, weight gain, food consumption and food efficiency in either sex at the doses employed. All pathological and histopathological findings were considered incidental, and not related to the dosing. With the exception of the small effect on white blood cells and biological parameters mentioned above, no toxic effects were observed.

3) The study was conducted to evaluate the toxic nature of the given test chemical. Repeated dose oral study for test chemical was assessed for its possible toxic potential. For this purpose Sub acute study for 14 days was conducted on Wistar (Alderley Park derived)) male rats. The test material was exposed at the concentration of 0, and 184 mg/kg bw by oralgavage . Animals received the test substance by oral gavage every morning for 14 days. The animal’s body weight, were recorded. days. Animals were killed by halothane overdose and blood was withdrawn by cardiac puncture, and assayed for plasma cholesterol and plasma triglyceride. The liver was removed, weighed and samples taken for light and electron microscopy using standard histopathological procedures. Morphometric analysis of electron micrographs was made by the method of Weibel et al. No effect on bodyweight gain and clinical chemistry were observed in treated male rats compared to control. In addition, No effect on liver and Testis weight and histopathology were also observed in treated male rats as compared to control. Therefore, NOAEL was considered to be 184 mg/kg bw /day for(Wistar Alderley Park derived)male rats when they were treated with test chemical orally by gavage for14 days. 

 

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the test chemical, which is reported as 0.0099 kPa at temperature 101 Deg C & 101.324 kPa at temperature 280.45 Deg C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron to 53micron which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver.

Repeated dermal study:

The acute toxicity value for the given test chemical (as provided in section 7.2.3) is >2600 mg/kg body weight. The OECD study result for acute toxicity by the dermal indicates the LD50 value to be greater than 2000 mg/kg body weight. In addition, the skin sensitization also indicates negative skin sensitization potential by the chemical. Also considering the use of the chemical as a fragrance chemical and considering the volatility absorption by the dermal route is not considered to be significant. Thus, given the above considerations, it is assumed that Tridecanol shall not exhibit repeated dose toxicity by the dermal route.. Therefore this study is considered for waiver.

 

 

Thus based on the above annotation for the test chemical and CLP criteria, the given test chemical does not exhibit toxic nature upon repeated exposure by oral route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation. For repeated inhalation and repeated dermal toxicity wavier was added so, not possible to classify.

Justification for classification or non-classification

Thus based on the above annotation for the test chemical and CLP criteria, the given test chemical does not exhibit toxic nature upon repeated exposure by oral route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation. For repeated inhalation and repeated dermal toxicity wavier was added so, not possible to classify.

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