Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
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Reason / purpose:
data waiving: supporting information
Reference

The vapour pressure of the test substance was determined experimentally using static method, according to EU Method A.4 (Chilworth, 2017) as well using QSAR models EPI Suite and T.E.S.T (US EPA, 2018).

Vapour pressure:
0.002 Pa
at the temperature of:
25 °C

- Experimental VP: 277 Pa (using static method); the VP value is suspected to be influenced by trapped gases/impurities.

- Weighted average QSAR based VP: 0.00072 Pa at 25°C (using EPI Suite v.4.11) and 0.0021 Pa at 25°C (using T.E.S.T. v4.2.1). The estimates for the major constituents are considered to be reliable with restrictions, as they do not completely fall within of the applicability domain.

- VP values for the main constituents, phosphate esters (PSE), alcohol and isoalkyl esters: 0.00289 Pa at 20°C (using effusion method) for mono- and di- C16 PSE, K+ (ECHA REACH dossier on CAS 19035-79-1); 0.0014-0.0016 Pa at 25˚C for hexadecane-1-ol (OECD SIDS, 2006); 9.79E-12 at 20 °C (Estimated using SPARC v.4.6) for isostearyl isostearate (ECHA REACH dossier on CAS:41669-30-1) respectively.

 

Overall, based on the above information, the test substance can be considered to have low volatility potential. In absence of a reliable experimental value for the overall test substance, the relatively higher QSAR based VP value of 0.0021 Pa has been considered further for hazard/risk assessment as a conservative approach.

Reason / purpose:
data waiving: supporting information
Reference

The physical state and appearance of the test substance were observed during the testing of other endpoints (Chilworth, 2017).

Physical state at 20°C and 1013 hPa:
solid

(white solid pellets)

Reason / purpose:
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,'mono- and di- C16 PSE, K+ and C16-OH and isostearyl isostearate'. However, as a conservative approach,the lowest NOAEL value of 300 mg/kg bw/day (or 233.4 mg a.i./kg bw/day; based on read across to isoalkylester study) has been considered further for hazard/risk assessment.

Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
233.4 mg/kg bw/day
Study duration:
subchronic
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 substances representative of the three main constituents, which can be categorised as phosphate esters (PSE), alcohol (hexadecanol) and isoalkylester (isostearyl isostearate). 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).

Constituent: Alcohol

A 28-d study was conducted to determine the sub-acute toxicity of hexadeacn-1-ol (purity: >95%) in Sprague-Dawley rats, 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, 5 mL/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, the 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).

Constituent: Isoalkylester - read across study:

A 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 NOAELs can be considered for the test substance,'mono- and di- C16 PSE, K+ and C16-OH and isostearyl isostearate'.

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, 'mono- and di- C16 PSE, K+ and C16-OH and isostearyl isostearate'. However, as a conservative approach, the lowest NOAEL value of 300 mg/kg bw/day (or 233.4 mg a.i./kg bw/day; based on read across to isoalkylester study) has been considered further for hazard/risk assessment.

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.

Inhalation:

The substance is a solid (white pellets) with a low vapour pressure 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.

Based on the available weight of evidence from the studies on the main constituents, the test substance, 'mono- and di- C16 PSE, K+ and C16-OH and isostearyl isostearate', does not warrant a classification for STOT RE, according to the EU CLP criteria (Regulation 1272/2008/EC).

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion