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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Orientating repeated dose toxicity study, conducted prior to the implementation of currently acknowledged testing guidelines such as the OECD TG 408, and according to an in-house protocol. Even if the study conduct does not fulfill current requirements, suitable basic data were given.

Data source

Reference Type:
study report

Materials and methods

Principles of method if other than guideline:
The study was an orientating repeated dose toxicity study conducted according to an in house protocol, prior to the implementation of currently acknowledged testing guidelines such as the OECD TG 408. A group of 20 male and 20 female Wistar rats received a single daily dose of 250 mg/kg bw/day of the test material by gavage (vehicle: 1% CMC), five days a week, for 84 days. A group of 20 male and 20 female rats were kept as controls and treated with the vehicle only. Additionally, satellite groups consisting of 10 males and 10 females per group were added. The animals were observed/examined for mortality, clinical symptoms, changes in body weight and body weight gain, changes in haematology, clinical chemistry and urine, changes in organ weights, gross pathology and histopathology.
GLP compliance:
Limit test:

Test material

Constituent 1
Reference substance name:
Alcohols, C6-24 and C6-24-unsatd., distn. residues
EC Number:
EC Name:
Alcohols, C6-24 and C6-24-unsatd., distn. residues
Cas Number:
Molecular formula:
Not available due to the complexity of the substance
Alcohols, C6-24 and C6-24-unsatd. even numbered, distn. residues
Details on test material:
- Name of test material (as cited in study report): Pernil RU
- Chemical designation: 18:1 fatty alkohol, unsaturated, distillation residue
- Physical state: brown liquid
- No more details provided

Test animals

Details on test animals or test system and environmental conditions:
- Source: Mus-Ratus Breeder, Brunntal, Germany
- Age at study initiation: approx. 40 days
- Weight at study initiation: males, 130 g; females, 118 g
- Housing: males were housed in groups of 2 to 3 animals and females in groups of 5 per cage
- Diet: Altromin pelleted diet (Altromin R- Pressling-Haltungsdiät Nr. 1324), ad libitum
- Water: tap water, ad libitum
- Acclimatization: 8 days

- Temperature (°C): 21 - 23
- Humidity (%): 50 - 55
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
CMC (carboxymethyl cellulose)
Details on oral exposure:
The test solution consisted of an emulsion of the test material using 1% CMC as vehicle and was prepared freshly each day.
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
12 - 13 weeks
Frequency of treatment:
5 days/week
Doses / concentrations
Doses / Concentrations:
250 mg/kg bw/day
actual ingested
No. of animals per sex per dose:
The test group consisted of 20 male and 20 female animals; additionally, 10 animals of each sex were added as satellite group.
The control group consisted similarly of 20 + 10 animals per sex.
An additional control group consisted of 20 animals per sex; these animals were used for blood sampling.
Control animals:
yes, concurrent vehicle
Details on study design:
Each animal of the test group received a single dosage of the test solution by gavage on 5 days per weeks. Similarly, each animal of the vehicle control groups received a single dosage of 1% CMC by gavage. The application volume was 10 mL/kg bw.


Observations and examinations performed and frequency:
The rats were checked daily for mortality and clinical symptoms. The body weights were recorded once a week. No further parameters were considered.
At test initiation, blood samples were collected from the additional control group, and at test ending, blood samples were collected from all animals. Following haematological parameters were considered:leukocyte count (WBC), erythrocyte count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), and differential blood count. Referring to clinical chemistry, following parameters were considered: sodium, potassium, urea, calcium, alkaline phosphatase, aspartate aminotransferase (GOT), alanine aminotransferase (GPT), glucose, and total protein.
At test initiation, urine was collected from the additional control group, and at test ending, urine was collected from all animals. For this purpose, the animals were placed individually in metabolism cages for 24 hours and received feed and water ad libitum. Following parameters were considered: volume, pH, protein, glucose, ketones, urobilinogen, blood, specific gravity, and sediment.
The amount of excreted feces during holding of the animals in the metabolism cages was recorded.

Sacrifice and pathology:
At test ending, all animals were sacrificed for the purpose of necropsy. The organs were macroscopically examined for gross pathological lesions or changes. The main organs were collected for determination of absolute weight. Following organs were fixed in formalin for the purpose of histopathological examination:
eyes, tongue, salivary glands, oesophagus, trachea, lungs, aorta, heart, lymph nodes, thymus, liver, pancreas, spleen, kidneys, fore stomach, glandular stomach, duodenum, colon, urinary bladder, testes, epididymides, adrenals, seminal vesicle, prostate, uterus, ovaries, thyroid, parathyroid, brain, skeletal muscle, skin, sciatic nerve
These organs/tissues were paraffin embedded, sectioned, and the sections were stained for purpose of light microscopy with hematoxylin and eosin. The organs and tissues of 6 animals per sex and group were finally subjected to histopathological examination.
Calculation of means and standard deviations, statistical assessment of the significance by means of the t-test and the U-test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
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:
effects observed, treatment-related
Description (incidence and severity):
changes in GPT and GOT in treated females only
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:
Neither mortalities nor clinical symptoms indicating toxicity were noticed.
The body weight and body weight gain of the treated males over the testing period was similar to control, and thus, showed not treatment-related changes. For the treated females, a weak and transient decrease in body weight was noticed on week 11 of treatment, but was not considered to be due to treatment.
At test ending the haematocrit value for the treated male animals was significantly increased compared to control and both, treated males and females showed an increase in MCV. Nevertheless, the measured values still were within the range considered as normal for the strain used and the age of the animals. Thus, the findings were not considered to be adverse effects due to treatment.
The treated female animals showed a weak increase in alanine aminotransferase (GPT), which however was not to be considered as an adverse effect. In five treated females, a clear increase in aspartate aminotransferase (GOT) was noticed, which was considered to be treatment-related. The alkaline phosphase (AP) also was significantly increased in the treated female animals, however, this was almost due to one animal showing a high AP level. The alkaline phosphase (AP) also was increased in the treated males, but the finding was considered to be incidental and not due to treatment since the measured values did not indicate that the finding was adverse. The treated female animals further showed a significant decrease in sodium level.
In both, the treated and control groups, some animals of both sexes showed slight increased protein content and ketones in the urine, and occasionally blood cells were found. These findings were incidental and related to the strain used and the age of the animals; they were not treatment-related.
No difference in excretion was noticed between treated and control animals.
At necropsy, neither organ weighing nor the gross and histological examination of organs and tissues revealed any treatment-related changes.
In fact, it was reported that at necropsy all animals showed signs of respiratory infection such as tracheitis. Furthermore, it was noticed that in the liver of nearly all animals, signs of lysis (almost low grade) of the hepatocytes were observed, and more often in females, intrahepatocytic pigment accumulation also was seen. In addition, some animals further displayed subcapsular lymphohistiocytic granuloma. Nevertheless, all these findings were equally distributed between treated and control animals, and thus, no relationship to treatment could be evidenced.

Effect levels

Dose descriptor:
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: no clear treatment-related effects could be evidenced at the dose level of 250 mg/kg bw/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion