Registration Dossier

Administrative data

Description of key information

In accordance with Annex XI of Regulation (EC) No 1907/2006 no study on the repeated dose toxicity with UVCB 400160 was conducted. This is justified for 400160 as several pivotal studies have been performed with relevant structural analogues, i.e. with medium- and long-chain fatty acids as well as with 2-ethylhexanol, the alcoholic moiety of the mono- and diesters included in UVCB 400160, and in view of the comprehensive knowledge of the overall toxicokinetic and toxicological properties of fatty acids. Accordingly, also for animal saving reasons studies on repeated dose toxicity of UVCB 400160 are prevailed. 

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:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Robust summary of study published in official document (Test Plan for fatty acid dimers and trimer) submitted to US EPA. There the study was classified as Klimisch 1. The study was GLP compliant and performed according to OECD guideline 408. As the robust study summary is taken from a secondary source the reliability was downgraded.
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
concentration of 5% in the diet = approximate dose of 5000 mg/kg day
Basis:
other: standard conversion factors (WHO 1990)
Remarks:
Doses / Concentrations:
concentration of 1% in the diet = approximate dose of 1000 mg/kg day
Basis:
other: standard conversion factors (WHO 1990)
Remarks:
Doses / Concentrations:
concentration of 0.1% in the diet = approximate dose of 100 mg/kg day
Basis:
other: standard conversion factors (WHO 1990)
No. of animals per sex per dose:
20
Control animals:
yes
Observations and examinations performed and frequency:
Parameters evaluated included clinical signs, body weight, food and water consumption, ophthalmoscopy, hematology, clinical chemistry, gross pathology, organ weights (brain, heart, liver, kidneys, spleen, testes, adrenal glands), and microscopic pathology (adrenal glands, brain, colon, femur and stifle joint, ileum, larynx, lymph nodes, muscle, ovaries and fallopian tubes, pituitary, sciatic nerve, sternum, thyroid and parathyroids, uterus, aorta, cecum, duodenum, head, jejunum, liver, esophagus, pancreas, prostate, spinal cord, stomach, tongue, bladder, cervix, heart, kidneys, lungs, mammary glands, rectum, spleen, thumus, trachea, epididymides, skin, salivary glands, testes, seminal vesicles, vagina, eyes/harderian glands).
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):
effects observed, treatment-related
Description (incidence and severity):
A statistically significantly decrease in food consumption occurred in the 5% males and females during the first four weeks of study.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Slight changes in hemoglobin (increased in males at 5000 mg/kg/day) and prothrombin time (increased in females at 1000 mg/kg/day and in males and females at 5000 mg/kg/day) were considered not to be toxicologically significant.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
see details on results
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
see details on results
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see details on results
Details on results:
Treatment-related clinical chemistry changes included statistically significant increases in alkaline phosphatase (in males and females at concentrations of 1 and 5% ) and ALT (in males and females at 5% ), and statistically significant decreases in total cholesterol (in males and females at concentrations of 1 and 5% ), triglycerides (at 1% in males and at 5% in males and females), total serum protein and albumin (in males and females at 5% ), and beta-globulin fraction (at 1 and 5% in males). At necropsy, the mesenteric lymph nodes were slightly to moderately enlarged in all dimer treatment groups and the incidence of uterine fluid distension was increased at a concentration of 5%.
Absolute and relative spleen (in males at 1 and 5%) and liver (in males and/or females at 1 and 5%) weights were statistically significantly decreased. In addition, absolute kidney weight was significantly decreased in females at a concentration of 5% and absolute and relative liver weights were significantly decreased in females at 0.1%. The relevance of these decreases in organ weights is not known, since they did not correlate to any microscopic changes.
Histopathology revealed treatment-related findings in the following organs:
mesenteric lymph nodes (aggregation of macrophages in both sexes at 0.1% and higher); spleen (macrophages with brown pigment in both sexes at 1 and 5% and in the females at 0.1%); liver (bile duct proliferation and bile duct sclerosis in males at 5%); adrenals (cortical vacuolation in females at 1 and 5%); and thyroids (follicular epithelial hypertrophy in females at 5%).
Dose descriptor:
NOAEL
Effect level:
ca. 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on increases in clinical chemistry parameters and histopathological findings at the higher doses
Critical effects observed:
not specified
Conclusions:
Although a NOEL was not identified in this study, 0.1% (approximately 100 mg/kg/day) can be considered as NOAEL based on increases in clinical chemistry parameters and histopathological findings at the higher doses.
Executive summary:

Dimer (CAS #61788-89-4) was administered to CD Sprague-Dawley rats (n = 20/sex/group) in the diet at concentrations of 0, 0.1, 1, or 5% for 13 weeks. The approximate doses were 0, 100, 1,000, or 5,000 mg/kg/day, based on standard conversion factors (WHO 1990). Parameters evaluated included clinical signs, body weight, food and water consumption, ophthalmoscopy, hematology, clinical chemistry, gross pathology, organ weights, and microscopic pathology.

 

No deaths occurred and no treatment-related effects on clinical signs, body weight, body weight gain, water intake, or ophthalmoscopy were noted.

Although a NOEL was not identified in this study, 0.1% (approximately 100 mg/kg/day) can be considered as NOAEL based on increases in clinical chemistry parameters and histopathological findings at the higher doses.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study was GLP compliant and performed according to OECD guideline 408. The substance fatty acids, C18-unsaturated dimers (CAS 61788-89-4, the main raw material of 400160) was used in this study.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
no data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Peer-reviewed publication with summarized results. The study was GLP complient and performed according to OECD guideline 413.
Qualifier:
according to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: SPF-Wistar, Chbb: THOM
- Source: Dr. K. Thomae GmbH, D-88400 Biberach/Riss, Germany
- Age: 7 weeks
- Weight at study initiation: mean body weight male: 238 g; female: 170 g
- Housing: individually in wire cages in the inhalation chamber
- Diet (ad libitum): KLIBA rat/mouse laboratory diet 24-343-4 (Klingentalmühle, AG, CH-4303 Kaiseraugust, CH)
- Water (ad libitum): tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
The different 2-Ethylhexanol (2-EH) inhalation chamber concentrations were achieved by conveying the substance via continuously operating metering pumps to evaporators. For 15, 40 and 120 ppm 2-EH the vapour generation was carried out in a thermostated glass container (maintained at 46.4- 50.4°C) with a downstream mixing unit. 40 and 120 ppm atmospheres were generated by means of a two-component atomizer using compressed air and evaporation of the 2-EH-aerosol. The warmed air of the control group (45.7°C) and the vapour-air mixture of the 2-EH groups were then mixed with the overall stream and distributed to a horizontal-flow whole-body exposure system (inhalation chamber glass/steel construction with volumes of approx. 1.1 m³ manufactured by BASF AG, Ludwigshafen, Germany). In the inhalation chamber of the control group, the exhaust air system was set lower (positive pressure), in the 2-EH inhalation chambers the exhaust air system was set higher than the supply air system (negative pressure). Pressure (mean chamber pressure from - 10.2 to 10.1 Pascal) and temperature (mean temperature 23.1°C to 23.8°C) were measured continuously. The relative humidity (mean relative humidity 41.8% to 46.2%) was checked and recorded once daily.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the inhalation atmospheres were analyzed at intervals of about 15 min by gas chromatography (Hewlett Packard gas chromatograph Model HP 5880 A with automatic sampler HP 7671 A, FID, column: 1 m x 2 mm with 10% Triton x 305 on Supelcoport, 102/ 120 rnesh, oven temperature: 120°C. C15-paraffin was used as internal standard).
Duration of treatment / exposure:
6 h on workdays over a period of 90 days (65 exposures)
Frequency of treatment:
5 days/week
Remarks:
Doses / Concentrations:
120 ppm
Basis:

Remarks:
Doses / Concentrations:
40 ppm
Basis:

Remarks:
Doses / Concentrations:
15 ppm
Basis:

No. of animals per sex per dose:
10 m/10 f per group
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
Individual body weights: beginning of the preflow period, 1 day before commencement of the exposure period and weekly throughout the study.
Body weight gain: The difference between the body weight on the day of weighing and that of the preceding weighing was calculated as group mean average.
Clinical signs and mortality: daily
Ophthalmological examinations: prior to the beginning of the preflow period and at the termination of the study using an ophthalmoscope.
Blood for clinical pathology testing was collected in randomized order by retro-orbital bleeding.
Haematology: white blood cells, red blood cells, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets, differential blood count – on day 94 of the study
Clinical chemistry: sodium, potassium, chloride, inorganic phosphate, calcium, urea , creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase - on day 94 of the study
Sacrifice and pathology:
At the end of the 90-day exposure period all animals were necropsied and assessed by gross pathology. The body weight and the weight of the lungs, liver, kidneys, adrenal glands and testes were determined. Organs or tissues required by guidelines to be tested as well as all gross lesions were fixed in a 4% formaldehyde solution.
Histological examination and assessment of findings were carried out after histotechnical processing and staining with haematoxylin and eosin.
Statistics:
Mean values and standard deviation were calculated for body weight and body weight change, haematological and clinical biochemistry parameters as well as for absolute and relative organ weights. The organ weights were statistically evaluated using the Dunnett's test (Dunnett 1955 and 1964) for comparison of the exposure groups with the control group. The analysis of variance (Cochran, 1957) with subsequent Dunnett's test (Dunnett 1955 and 1964) was used to compare body weight, body weight change as well as haematological and clinical biochemistry data of the treatment groups with those of the control group.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
not dose-related and therefore of no toxicological relevance
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Details on results:
Analysis of the daily inhalation chamber concentrations revealed that the values obtained closely fitted with the desired nominal level.
There were no effects regarding clinical signs; mortality; body weight gain; ophthalmoscopic examination; haematology; clinical chemistry; organ weights; histopathology at any dose level.
Under the conditions of the test no treatment-related toxic effects were found in male and female Wistar rats which were exposed to 2-ethylhexanol vapor up to 120 ppm, corresponding to 638.4 mg/m³. The concentration of 120 ppm corresponds to the calculated saturated vapor concentration at 20°C.
Dose descriptor:
NOAEL
Effect level:
120 ppm (analytical)
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight gain; ophthalmoscopic examination; haematology; clinical chemistry; organ weights; histopathology
Dose descriptor:
NOAEL
Effect level:
638.4 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight gain; ophthalmoscopic examination; haematology; clinical chemistry; organ weights; histopathology
Critical effects observed:
not specified
Conclusions:
Based on these results, for male and female Wistar rats the NOAEL of inhaled EH was 120 ppm corresponding to 638.4 mg/m³.
Executive summary:

A 90-day subchronic inhalation toxicity study was performed on Wistar rats in accordance to OECD testing guidelines to evaluate the toxicological profile of 2-ethylhexanol, potential target organs, and a no-observable-adverse-effect-level (NOAEL). 10 males and 10 females per group were exposed to 2-ethylhexanol vapours at concentrations of 15, 40 and 120 ppm (the latter corresponding to the vapour saturation at 20°C) 6 hours/day for 90 days. The respective controls inhaled clean air under the same conditions. No substance-related adverse effects were observed for body weight, body weight gain, mortality, organ weights, clinical biochemistry and haematological parameters including clotting time. There were no findings related to the treatment with 2 -ethylhexanol either at necropsy or at histological examination. The highest concentration tested under these conditions (120 ppm corresponding to 638.4 mg/m³) was found to be the NOAEL for male and female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
638.4 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Peer-reviewed publication with summarized results. The study was GLP compliant and performed according to OECD guideline 413. The substance 2-ethylhexanol was used in this study (a raw material of 400160).

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

Several pivotal studies have been performed with structural analogues of UVCB 400160 (CAS No. 68334-05-4; typically consisting of 16% diesters, 43.3% monoesters, and 40.7% C18–unsaturated fatty acid dimers), in particular with medium- and long-chain fatty acids as well as with 2-ethylhexanol (2-EH), the alcoholic moiety of the mono- and diesters included in 400160.

Fatty acids

Several studies on repeated-dose toxicity of medium- and long-chain fatty acids as structural analogues of the fatty acid components of UVCB 400160 have been performed. These studies lasting up to 47 weeks were conducted in the rat (US EPA 2009; Bibra 1996) and the rabbit (Traul et al. 2000).

Sprague-Dawley rats (20/sex/concentration) were administered fatty acids, C18-unsaturated dimers (CAS 61788-89-4; corresponding to raw material of 400160) via the diet at 0, 0.1, 1 or 5% (corresponding to daily doses of 0, 100, 1000 or 5,000 mg/kg body weight (bw)) for 13 weeks (US EPA 2009). No deaths occurred and no treatment-related effects on clinical signs, body weight, body weight gain or water intake were noted. A transient, statistically significantly decrease in food consumption occurred in both genders during the first four weeks of study at 5,000 mg/kg bw. Treatment-related clinical chemistry effects included decreases in total cholesterol and triglycerides and beta globulin fraction. Increases in alanine aminotransferase activity, total serum protein, albumin levels, and alkaline phosphatase activity were observed; prothrombin time was slightly increased. These effects on clinical chemistry occurred in the two highest concentrations tested. Slight increases in haemoglobin (at 5,000 mg/kg bw) were considered not to be toxicologically significant. Necropsy and histopathological examinations revealed slight to moderately enlarged mesenteric lymph nodes (all concentrations), increased incidence of uterine fluid distension (5,000 mg/kg bw; females), decreased absolute and relative liver weight (100 mg/kg bw, females and 1,000 and 5,000 mg/kg bw, males and/or females), decreased absolute and relative spleen weight (1,000 and 5,000 mg/kg bw males) and decreased absolute kidney weight (5,000 mg/kg bw, females). All effects other than enlarged lymph nodes and fluid distention in the uterus were noted as being statistically significant, although significance levels were not stated. Histopathology revealed aggregation of macrophages in mesenteric lymph nodes at all treatment levels, macrophages in brown pigment of the spleen (all treatment groups of females and at 1,000 and 5,000 mg/kg bw in males), cortical vacuolation in adrenals (1,000 and 5,000 mg/kg bw, females), hepatic bile duct proliferation and sclerosis (5,000 mg/kg bw, males), and thyroid follicular epithelial hypertrophy (5,000 mg/kg bw, females). Although a NOEL was not identified in this study, a NOAEL of 100 mg/kg bw/day was derived based on clinical chemistry parameters and histopathological findings. The LOAEL was 1,000 mg/kg bw/day (US EPA 2009).

In a 18-week dietary study in rats, NOAEL was >5,000 mg/kg/d for lauric acid and >7,500 mg/kg/day for oleic acid, respectively (DHI 2009). In a 90-day toxicity study in rabbits treated with medium-chain triglycerides containing predominantly caprylic acid (C8) and decanoic acid (C10) with less amounts of caproic acid (C6) and lauric acid (C12), no notable toxicity was observed, irrespective of whether the product was administered in the diet (up to 9,375 mg/kg bw/day) or by intramuscular injection in rabbits (up to 0.5 mL/kg/day) (Traul et al. 2000).

A chronic exposure or carcinogenicity study was conducted in 15 male and 15 female Wistar rats, fed with 40% medium-chain triglycerides (C8, C10) diet daily for 47 weeks. Mortality, growth, organ weights and the cellular structure of the liver and intestine were normal. Fat deposition was lower than might be expected on normal fat diets (Bibra 1996). NOAELs of decanoic acid and octanoic acid were equivalent to 2.5 g/kg/day and 7.4 g/kg/day, respectively (DHI 2009).

Moreover, caprylic acid is listed by the FDA as a direct food substance affirmed as generally recognized as safe (GRAS 1974), when used in foods at concentrations ranging from 0.001 to 0.04% (depending upon the food) according to good manufacturing practice (Code of Federal Regulations 2011).

The Joint FAO/WHO Expert Committee on Food Additives established for decanoic acid no specific ADI (Acceptable Daily Intake), because it was expected that the compound’s presence in food would not represent a human health hazard (Bibra 1996). This view was based upon the occurrence of the acid in edible fats and oils with long food-use history as well as data on total daily intakes and the toxicology of the acid (JECFA 1986; Bibra 1996). Decanoic acid was also considered “safe in use” by the EU’s Scientific Committee for food in their consideration of Chemically Defined Flavouring Substances (Bibra 1996).

2- Ethylhexanol (2-EH)

Systemic toxicity of 2-EH was investigated in repeated dose studies lasting up to 24 months in rats and mice (Astill et al. 1996; Klimisch et al. 1998; WHO 1993).

Astill et al. (1996) investigated the subchronic toxicity of 2-EH at daily oral doses up to 500 mg/kg bw in rats and mice over a period of 13 weeks. Effects in rats were limited to dose levels of 250 and 500 mg/kg. Principal effects were mild reductions in weight gain at 500 mg/kg, moderate increases in relative stomach, liver, and kidney weights at 250 and 500 mg/kg, and inflammatory changes in the forestomach at 500 mg/kg. Effects in the mouse were limited to increases in relative stomach weight in males at 250 and 500 mg/kg and a low incidence of inflammatory lesions in the forestomach at 500 mg/kg. No mortalities were observed in this study (Astill et al. 1996).

A 90-day subchronic inhalation toxicity study of 2-EH vapour in rats was conducted by Klimisch et al. (1998). No substance-related adverse effects were observed for body weight, body weight gain, mortality, organ weights, clinical biochemistry and haematological parameters. There were no findings related to the treatment with 2-EH either at necropsy or at histological examination. The highest concentration tested under these conditions (120 ppm corresponding to 638.4 mg/m3) was found to be the NOAEL for male and female rats.

When 2-EH (0, 50, 200, or 750 mg/kg bw/day) was administered by gavage to groups of 50 male and 50 female mice for 18 months, no 2-EH-related changes were observed in mice administered 50 or 200 mg/kg bw. At 750 mg/kg bw, in both genders the following effects were observed: Decreased body weight gain associated with substantial reduction in feed consumption; an increased mortality, treatment-related haematological changes, including slightly increased polymorphonuclear neutrophils and slightly decreased lymphocytes, treatment-related, but not statistically significant, increased focal hyperplasia of the epithelium of the forestomach. Also, a slight increase in the incidence of hepatocellular carcinomas in high-dose females was statistically significant when compared to the incidence in vehicle control females but not when compared to the incidence in water-gavage control females. No statistically significant increase in tumour incidence occurred in male mice. Therefore, 2-EH was not oncogenic in the mouse under the conditions of this study (WHO 1993).

In another study in rats lasting 24 months, 2-EH (0, 50, 100, 150 or 500 mg/kg bw/day) was administered by gavage to groups of 50 male and 50 female Fischer 344 rats five days/week. No compound-related changes were associated with administration of 50 mg/kg bw/day for 24 months; however, body weights and bodyweight gains of rats receiving 50, 150, or 500 mg 2-EH/kg bw/day were decreased in a statistically significant dose-dependent manner compared to vehicle control rats. Feed consumption of male and female rats receiving 500 mg/kg bw/day showed occasional statistically significant decreases compared to both control groups of rats, but no dose-response relationship was observed. A 2-EH-associated increase in mortality was observed for female mice of the high-dose group only (WHO 1993).

According to molecular weight and physicochemical properties the various compounds of UVCB 400160 are able to penetrate mucosa or human skin subsequent to oral or dermal exposure. After absorption, the esters are being partially or completely hydrolysed to the corresponding dicarboxylate acids and 2-EH. Fatty acids are being further metabolized via β-oxidation leading to C2-moieties that finally enter the citric acid cycle for endoxidation.

In accordance with the long history of safe use in foods for fatty acids and glycerides the data summarized above demonstrate low toxicity of fatty acids and their salts after subchronic and chronic administration (HERA 2002). The low toxicity of fatty acids concerning repeated dose administration becomes also evident by considering their safety evaluation with respect to exemption of fatty acids from the obligations to register in accordance with article 2(7)(a) of Annex IV of REACH Regulation (EC) No 1907/2006. Data available on repeated-dose toxicity were considered sufficient to fulfil the Annex IV inclusion criteria. Therefore no concerns were stated with respect to the endpoint repeated-dose toxicity (DHI 2009). The reasons why fatty acids were finally not included in Annex IV were a skin and eye-irritating potential as well as ecotoxicological concerns (Commission of the European Communities 2009; DHI 2009).

2-EH is subjected to extensive oxidative metabolism and glucuronidation followed by rapid excretion, primarily in the urine. Long-term studies in various species did not reveal any significant systemic toxicity even at high dosages.

In conclusion, in accordance with Annex XI of Regulation (EC) No 1907/2006 waiving of the endpoint repeated dose toxicity is justified for UVCB 400160 as several pivotal studies have been performed with relevant structural analogues, i.e. with medium- and long-chain fatty acids as well as with 2-EH, the alcoholic moiety of the mono- and diesters included in UVCB 400160, and in view of the comprehensive knowledge of the overall toxicokinetic and toxicological properties of fatty acids. Accordingly, also for animal saving reasons studies on repeated dose toxicity of UVCB 400160 are prevailed.

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the lowest NOAEL was chosen.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Only one study available

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008 no classification of 400160 is required. The LOAEL observed for 2-ethylhexanol in rats and mice were 250 mg/kg bw/day which is above the guidance value for category 2 classification. The NOAEL for fatty acid dimers in rats was 100 mg/kg bw/day. No significant toxic effects were observed at this concentration, therefore no classification is required.