[No public or meaningful name is available]

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

The vapour pressure of the test substance was determined using the vapour pressure balance method, according to OECD Guideline 104 and EU Method A.4 (Ford, 2019).

Vapour pressure:

0.008 Pa

at the temperature of:

25 °C

Cross-reference 2

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

The physical state and appearance of the test substance were observed during the testing of other endpoints (XCellR8, 2019, Envigo, 2019).

Physical state at 20°C and 1013 hPa:

solid

Form:

solid: pellets

Colour intensity:

light

(white waxy solid pellets)

Cross-reference 3

Reason / purpose for cross-reference:

data waiving: supporting information

Reference

Based on the available weight of evidence, except for reduction in food consumption and body weight changes, no other toxicologically significant or critical systemic effects are expected for the test substance. For purposes of risk assessment, the NOAEL based on the study with esters is regarded as representative of the test substance considering that the esters make up more than 80% of the composition. Therefore, a NOAEL of 300 mg/kg bw/day, which also corresponds to the lowest NOAEL, determined in a study with Isodecyl oleate has been considered further for hazard/risk assessment.

Toxic effect type:

dose-dependent

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

233.4 mg/kg bw/day

Study duration:

subchronic

Experimental exposure time per week (hours/week):

168

Species:

rat

Quality of whole database:

Guideline compliant studies on constituents

System:

other: no critical adverse effects were observed, except for reduction in food consumption and body weight in the study with isoalkylester constituent.

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Oral:

In absence of repeated dose toxicity study with the test substance, the endpoint has been assessed based on studies for read across substances representative of the main constituents, which can be categorised as phosphate esters (PSE i.e., mono- and di C16 PSE, K+: 10 -40%), alkyl esters (i.e., C16-18 linear and branched fatty acid esters: 39 -87%) and alcohols (i.e., C16 -18 linear or branched alcohol: 10 -30%). The results are presented below:

Constituent: PSE - read across study:

A screening study was conducted to determine the toxicity to reproduction of the read across substance, ‘mono- C12 PSE, Na+’ (purity: 100%, according to the OECD Guideline 422, in compliance with GLP. The read across substance was administered at 0 (control group), 250, 500 or 1000 mg/kg bw to male Sprague-Dawley SPF rats for 14 days before mating, through the mating period, and up to 1 d before necropsy (42 d in total) and to female Sprague-Dawley SPF rats for 14-d before mating, through the mating period and the gestation period, up to Day 4 of lactation (42 to 45 d in total) to investigate the repeated-dose, reproductive and developmental toxicities. In the 0 and 1000 mg/kg bw groups, a 14-d recovery period was allowed after the 42-d administration period to investigate the reversibility of the toxic changes. Administration of the read across substance had no effect on any of the following: general condition, findings on detailed observation of the general condition, results of function tests, grip strength, spontaneous motor activity, body weight, food consumption, results of urinalysis (including water intake), or in the results of haematological or blood chemistry tests. Administration of the read across substance had no effect on any of the following: general condition, findings on detailed observation of the general condition, results of function tests, grip strength, spontaneous motor activity, body weight, food consumption, results of urinalysis (including water intake), or in the results of haematological or blood chemistry tests. Changes in the forestomach may be considered to be adverse, however, they are also considered to be a result of local irritation of the (irritant) test substance (which is brought directly in contact to the mucosa in a massive amount by gavage application) than a true effect of systemic toxicity. Furthermore, in the light of the absence of a forestomach in humans, observed effects on this tissue are of questionable relevance with reference to the extrapolation of the toxic properties of a read across substance in humans. Under the study conditions, only (local) changes of the forestomach mucosa were observed at 250 mg/kg bw/day and above, which are due to the irritant properties of the substance. Therefore, the NOAEL (systemic) is considered to be 1000 mg/kg bw/day (BRC, 2005). Based on the results of the read across study, similar systemic NOAELs can be considered for the phosphate ester constituent of the test substance.

Constituent: Alkyl ester (branched) - read across study:

A screening study was conducted to determine the repeated dose toxicity of the read across substance, 'Isodecyl oleate' (purity: 77.8%), according to OECD Guideline 422, in compliance with GLP. Three groups of ten male and ten female Sprague-Dawley rats received the read across substance daily by oral (gavage) administration before mating, through mating and, for the females, through gestation until Day 3 post-partum. The read across substance was administered as a suspension in the vehicle, corn oil, at dose-levels of 0, 100, 300 or 1000 mg/kg bw/day. Another group of ten males and ten females received the vehicle alone, under the same experimental conditions and acted as a control group. The concentration of the dose formulation was checked start of treatment period; immediately after preparation of the read across substance-vehicle mixtures; 8 and 24 h after storage of the read across substance preparations at room temperature; end of treatment period; during treatment with the read across substance always before administration to the last animal of the dose level group.

The animals were checked at least twice daily during the dosing period for mortality and morbidity and once daily for clinical signs. Detailed clinical observations were performed once a week. Body weight and food consumption were recorded once a week during premating and mating periods (food consumption not during mating), and during gestation on post coital and lactation on Days 1 and 4 post-partum. The animals were paired for mating after 2 weeks of treatment and the females were allowed to litter and rear their progeny until Day 4 post-partum. At the end of the treatment period, Functional Observation Battery, motor activity and laboratory investigations (haematology and blood biochemistry) were carried out on five males and five females. The males were sacrificed after at least 5 weeks of treatment and the females on day 6 post-partum. Final body weights and selected organs weights (adrenals, brain, epididymides, heart, kidneys, liver, spleen, testes and thymus) were recorded and a complete macroscopic post-mortem examination was performed. A microscopic examination was performed on epididymis, gross lesions, mammary gland, ovary, prostate, seminal vesicle, testicle, uterus (incl. cervix and oviducts), vagina (all animals); adrenal gland, bone marrow (os femoris), brain (cerebrum, cerebellum, brain stem), heart (left and right ventricle, septum), intestine, small (duodenum, jejunum, ileum, incl. Peyer's patches, Swiss roll method), intestine, large (colon, rectum), kidney and ureter, liver, lungs (with mainstem bronchi and bronchioles), preserved by inflation with fixative and then immersion, lymph node (1 cervical, 1 mesenteric), nerve (sciatic), oesophagus, spinal cord (3 sections), spleen, stomach, thyroid (incl. parathyroids), thymus, regional lymph nodes, tongue (incl. base), trachea (incl. larynx), urinary bladder from five males and five females in the control and high dose groups.There were no read across substance related deaths and related signs of toxicity were noted during the observational and neurological screenings. A reduction in food intake (-21.7%) during gestation/lactation period and body weight (-9.7%) during the laction period was observed in high dose females. No other read across substance related changes were noted for other parameters including, water consumption, haematology, clinical chemistry, organ weights gross and histopathology. The effects observed at 1000 mg/kg bw/d in the females were considered adverse; thus, the NOAEL for systemic toxicity was determined to be 300 mg/kg bw/day (i.e., equivalent to 233.4 mg ai./kg bw/day) in females and 1000 mg/kg bw/day (i.e., equivalent to 778 mg a.i./kg bw/day) in male rats in this study (Hansen, 2013).Based on the results of the read across study, similar systemic NOAELs can be considered for the alkyl ester constituent of the test substance.

Constituent: Alcohol - read across study:

A screening study was conducted to determine the oral dietary repeated dose toxicity in rats of the read across substance, dodecan-1-ol according to the draft OECD Guideline 422, in compliance with GLP. The rats were fed 1500, 7500 and 30000 ppm read across substance in diet (approximately 100, 500 and 2000 mg/kg bw/day nominally). Animals were observed for mortality, body weight, food consumption, food efficiency, haematology and clinical chemistry. Gross pathology was performed for all animals and histopathology were performed for control and top dose animals. 1-Dodecanol had no influence on body weight, weight gain, food consumption and food efficiency in either sex at the doses employed. There were no treatment related effects were noted during the study period. With the exception of the small effect on white blood cells and biological parameters mentioned above, no toxic effects were observed. There was a significant reduction in plasma triglyceride (TG) at the top dose level and a significant reduction in plasma free cholesterol at the intermediate dose level. The reduced cholesterol level was re-analysed after removing 2 outlying values when the statistical significance was lost. These results may have been confounded by the difference in dietary composition between groups. There were no dose related changes in organ weights. In males only there was a reduction in relative and absolute liver weights at the low dose level and a reduction in relative liver weight at the mid dose, the top dose was comparable to controls. There were no treatment related changes observed in gross pathology and histopathology. Under the conditions of the study, the oral NOAEL for the read across substance was determined to be 2000 mg/kg bw/day (nominal) (Ernst, 1992). Based on the results of the read across study, similar NOAEL can be considered for the alcohol constituent of the test substance.

Supporting study on hexadecan-1-ol from OECD SIDS dossier:

A 28-d study was conducted to determine the sub-acute toxicity of the test substance, hexadeacn-1-ol (purity: >95%) inSprague-Dawleyrats, according to a method similar to OECD Guideline 407, in compliance with GLP. In the study, SD rats (10 each sex/dose + 5 each sex/dose for reversibility) were exposed to the 0, 2, 10 and 20% test substance in olive oil, 5mL/kg bw by oral gavage for 28 d, 5d/week. The actual doses received were calculated to be 0, 100, 500 and 1000 mg/kg bw/day respectively. Clinical signs, mortality and food consumption were observed daily, whereas, body weight and water consumption were analysed weekly. Opthalmoscopic examination was performed at the end of the study. Biochemistry and haematology analysis were performed 21/22 d after daily dosing. There were no treatment related effects on clinical signs, body weight, mortality and food consumption were noted. In haematology analysis, no differences between treated and control animals other than an increase in neutrophils containing rod like bodies observed in top dose females (1000 mg/kg bw/day) were noted. Statistically significant changes in some clinical chemical parameters were noted, where at 500 mg/kg/day, males increased potassium and females increased GGT, cholesterol and chloride, glucose was elevated in top dose males (1000 mg/kg/day). Both absolute and relative organ weights were essentially comparable in treated and control animals. Increases in absolute weight in male kidney at 500 mg/kg/day and male testes at 1000 mg/kg/day were noted. The only change in relative organ weight was an increase in male adrenal weight at 1000 mg/kg/day. Sporadic statistically significant changes in some organ weights and clinical chemical parameters were observed but these were not associated with histopathological changes and were not considered of toxicological significance.Under the study conditions,NOAEL was considered to be >1000 mg/kg/day (i.e., >950 mg a.i./kg bw/day), based on lack of toxicologically significant treatment related effects at this dose level (top dose level)(OECD SIDS, 2006).

Overall, based on the available weight of evidence, except for reduction in food consumption and body weight changes, no other toxicologically significant or critical systemic effects are expected for the test substance, ‘Reaction products of hexadecyl dihydrogen phosphate, dihexadecyl hydrogen phosphate, hexadecan-1-ol, stearic acid, esters of C18 (branched and linear) fatty acids with C18 (branched and linear) alcohols, and potassium hydroxide’. For purposes of risk assessment, the NOAEL based on the study with esters is regarded as representative of the test substance considering that the esters make up more than 80% of the composition. Therefore, a NOAEL of 300 mg/kg bw/day, which also corresponds to the lowest NOAEL, determined in a study with Isodecyl oleate has been considered further for hazard/risk assessment.

Inhalation:

The substance is a solid (white pellets) with a low vapour pressure (0.0079 Pa) at room temperature. Due to its physical state and physical chemical properties it is unlikely that this substance will form inhalable dust, mist or fumes during normal processing and use conditions. In case inhalable forms of the substance are created under particular conditions (e. g. spraying, elevated temperature/pressure), appropriate risk management measures such as closed systems, exhaust ventilation or wearing of respirators are implemented to control exposure. Under such conditions, the risk to humans following inhalation exposure can be considered minimal and further testing involving vertebrate animals may be omitted, in accordance with Annex XI (1.2) of the REACH regulation. Nevertheless, the risk assessment for this route has been carried out based on oral studies available on substances representative of the main constituents, using appropriate route-to-route extrapolation assessment factors as per the ECHA Guidance R.8.

Dermal:

A repeated dose dermal toxicity study is not required because an OECD 422 and 28-day oral studies are available for substances representative of the main constituents. Further, given the physico-chemical properties of the substance, dermal absorption is not expected to be higher than via the oral route. Hence, testing via dermal route will less likely result in any additional hazard identification and further testing involving vertebrate animals may be omitted, in accordance with Annex XI (1.2) of the REACH regulation. Nevertheless, the risk assessment for this route has been carried out based on oral studies available with the read across substances, using appropriate route-to-route extrapolation assessment factors as per the ECHA Guidance R.8.

Based on the available weight of evidence from the studies on the main constituents, the test substance, does not warrant a classification for STOT RE, according to the EU CLP criteria (Regulation 1272/2008/EC).