Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Cross-referenceopen allclose all
Reason / purpose:
data waiving: supporting information
Reference

Based on the available weight of evidence from studies for substances representing the main constituents, the test substance, 'mono- and di- C16 PSE, K+ and C16-OH and isostearyl isostearate' can be considered to have a low acute oral toxicity potential with LD50 value >2000 mg/kg bw.

Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Good quality studies
Endpoint conclusion:
no study available
Endpoint conclusion:
no study available

In absence of acute oral toxicity study with the test substance, the endpoint has been assessed based on studies for substances representative of the main constituents, which can be categorised as phosphate esters (PSE i.e., mono- and di C16 PSE, K+), alcohol (i.e., hexadecanol) and isoalkylester (i.e., isostearyl isostearate). The results are presented below:

Constituent PSE - read across studies:

Study 1: A study was conducted to determine the acute oral toxicity of the read across substance, mono- and di- C16 PSE, K+ (purity: ca. 85%), according to the OECD Guideline 401, standard acute method, in compliance with GLP. Five male and 5 female Fü-albino SPF rats were randomly selected for an acute oral toxicity study. Fasted rats were given a single dose of the test substance suspended in SSV (Standard Suspended Vehicle) by gavage at a dose level of 5000 mg/kg bw. They were observed for 15 d for toxic signs, mortality and body weight changes. All rats were examined for gross lesions. No compound-related deaths occurred. No compound-related incompatibility reactions were observed. No compound-related effect on body weight development appeared. No compound-related gross or microscopic lesions were observed. The LD50 was determined at >5000 mg/kg bw (i.e., equivalent to 4250 mg a.i./kg bw) (Bremer, 1987).

Study 2: A study was conducted to determine the acute toxicity of the read across substance, di- C16 PSE (purity: 100%), according to the notification no. 118 of the Pharmaceuticals Affairs Bureau, 15 Feb 1984, Toxicity Test Guideline (similar to OECD guideline 401). Groups of fasted, 4 to 6 weeks old CFY (Sprague-Dawley origin) rats, 10/sex were given a single oral dose of test substance in distilled water at doses of 0 (control) and 16 g/kg bw and observed for 14 d. No mortality occurred. Piloerection was observed in all animals in the treated group, however, the animals had recovered on Day 3. No effects on body weight were observed. Terminal necropsy findings were found to be normal. Under the study conditions, the oral LD50 in rats for test substance was determined to be >16000 mg/kg bw (Kynoch, 1985).

Constituent alcohol:

A study was conducted to determine the acute oral toxicity of hexadecan-1-ol (purity: >95%), according to OECD Guideline 401, in compliance with GLP. Five male and five female fasted Sprague-Dawley CD rats were exposed to the 2000 mg/kg bw (based on range finding test) of test substance in arachis oil by oral gavage. The rats were observed for clinical signs of toxicity and mortality 30 minutes, 1, 2 and 4 h after dosing and thereafter daily throughout the observation period. Body weights were recorded prior to dosing on Day 0 and then at 7 and 14 d. All animals were subject to gross pathological examination at the end of the observation period. No compound-related deaths occurred. No compound-related target organ toxicity were observed. No clinical signs of systemic toxicity were observed. All animals showed the expected body weight gain over the observation period. No compound-related gross or microscopic lesions were observed. Under the study conditions, the LD50 for the test substance was determined to be >2000 mg/kg bw (i.e., >1900 mg a.i./kg bw) (OECD SIDS, 2006).

Constituent: Isoalkylester:

A study was conducted to determine the acute toxicity of isooctadecyl isooctadecanoate (purity not specified), according to a method adapted from French Pharmacopoeia 9thedition, dose fixed taking account of the OECD Guideline 401. The test substance was administered to 5 female mice at 5000 mg/kg bw orally. The animals were observed for mortality and signs of toxicity for 6 d post-treatment, and the body weight were determined at the start and end of the study period. There was no mortality or no other signs of toxicity which were observed during the study period. No effect on body weight was noted. Under the study conditions, the LD50 of the test substance in mice was determined to be >5000 mg/kg bw (Dufour, 1991).

Overall, based on available weight of evidence from studies for substances representative of the main constituents, the test substance, 'mono- and di- C16 PSE, K+ and C16-OH and isostearyl isostearate', can be considered to have a low acute oral toxicity potential with LD50 value exceeding 2000 mg/kg bw.

Overall based on the available weight of evidence, the test substance, 'mono- and di- C16 PSE, K+ and C16-OH and isostearyl isostearate', does not warrant a classification for acute oral or dermal toxicity, according to the EU CLP criteria (Regulation 1272/2008/EC).

Reason / purpose:
data waiving: supporting information
Reference

Based on the available weight of evidence information from studies for substances representative of the main constituents, the test substance, 'mono- and di- C16 PSE, K+ and C16-OH and isostearyl isostearate' is considered to be non-sensitiser to skin.

Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

In absence of skin sensitisation study with the test substance, the endpoint has been assessed based on studies for substances representative of the main constituents, which can be categorised as phosphate esters (PSE i.e., mono- and di C16 PSE, K+), alcohol (i.e., hexadecanol) and isoalkylester (i.e., isostearyl isostearate). The results are presented below:

Constituent PSE - read across study:

A study was conducted to determine the skin sensitisation potential of the read across substance, 'mono- and di- C16 PSE and H3PO4' (98.5%) according to OECD Guideline 429 and US EPA OPPTS 870.2600 (LLNA), in compliance with GLP. The read across substance concentrations selected for the main study were based on the results of a pre-screen test. In the main study, four experimental groups of five female CBA/J mice were treated with read across substance concentrations of 2.5, 5, 10 or 25% w/w for three consecutive days, by topical application on the ears. Five vehicle control animals were similarly treated, but with the vehicle alone (Liquid petrolatum). A positive control group with a-hexylcinnamaldehyde (HCA - 50%) was also included in the experiment. Five days after the last exposure, all animals were injected with 5-bromo-2'-deoxy-uridine (BrdU) and the draining (auricular) lymph nodes were then isolated and pooled for each animal. Cells were fixed using 70% ethanol and used for the measurement of the cell number and the BrdU determination (percentage of proliferating cells in "S" phase). Flow cytometry was conducted for analysis and stimulation index (SI) was recorded. Mortality/viability, body weights, clinical signs, ear size and irritation (and other local effects) were recorded as well. SI values were similar among the control and test groups and were below 3. Three concentrations (i.e.2.5, 5 and 25%) induced ear swelling. No mortality occurred and no clinical signs of systemic toxicity were observed in the animals of the main study. Body weights and body weight gain of experimental animals remained in the same range as controls over the study period (MBRL, 2005).

Constituent alcohol:

A study was conducted to determine the skin sensitisation potential of hexadecan-1-ol (purity:>95%), according to modified draize test in guinea pigs. Based on a primary irritation screening, 0.25%, 0.1% and 10% test substance solutions (the concentration giving slight barely perceptible irritation with no oedema) were chosen for the intradermal induction, intradermal challenge and topical challenge respectively. For induction phase, 0.1 mL of 0.25% intradermal and 10% topical application were performed. For challenge phase, 14 d after induction, each animal received  0.1% intradermal and 10% topical application of the test substance. Where materials test negative at challenge a repeat set of induction applications was carried out followed by challenge at 14 d and rechallenge (with controls) 7 d later. No positive control were reported. A colour matching lighting unit was used to examine the skin reactions. Each injection reaction was scored based on size, erythema and oedema and considered positive if the total score was greater than the total average of the control scores. Application reactions were scored on a scale of 0 to 3 and considered positive if individual reactions were ≥1 and there was no erythema in the controls. No sensitisation reactions at challenge or rechallenge following a second induction procedure were observed. There were no clinical signs were noted in all the animals. The study author had reported the test substance as non-sensitiser, whereas, the individual animal data were not presented. Under the study conditions, the test substance was determined to be non-sensitiser to the skin (OECD SIDS, 2006).

Constituent isoalkylester:

A study was conducted to determine the skin sensitisation potential of the read across substance, octyldodecyl isooctadecanoate (purity: assumed to be 100%), using guinea pig maximisation test (GPMT), according to OECD Guideline 406 and EU Method B.6, in compliance with GLP. The test was performed in 15 (10 test and 5 control) female albino Himalayan guinea pigs. Based on the preliminary study, undiluted substance (100%) was considered as induction and challenge phase concentration. In the main test, one treated group of ten females received 3 pairs of intradermal injections (0.1 mL/site) [i.e., Injection 1: a 1:1 mixture (w/w) Freud’s Complete Adjuvant (FCA)/water for injection, Injection 2: undiluted test substance, Injection 3: undiluted test substance in a 1:1 mixture (w/w) with FCA (final concentration is 50% test substance)] on Day 1. 48 h after intradermal injection (i.e., on Day 3), the degree of erythema and edema was evaluated. On Day 7, the scapular area between the injection sites was clipped and subsequently rubbed with 10% sodium dodecyl sulfate (SDS) in Vaseline using a spatula. This concentration of SDS provoked a mild inflammatory reaction. On Day 8, 0.5 mL undiluted read across substance was applied to the SDS-treated skin area under semi-occlusive conditions for 48 h. The degree of erythema and edema was evaluated directly after cleaning the skin area with water (Day 10). Similar procedure was followed for control substance (corn oil). For challenge phase, on Day 21, 0.5 mL of undiluted read across substance or control substance was applied to approximately 20 mm x 30 mm, on one flank of the animals and evaluation was made 24 and 48 h after the challenge ended. The animals were observed for mortality twice daily and for signs of toxicity at least once daily. The body weight of the animals was determined on Day 1 (prior to exposure) and at the end of the study period (Day 24).A reliability check was carried out by the lab at regular intervals with alpha-hexylcinnamic aldehyde to check the sensitivity of the test system and the reliability of the experimental methods.48 h after intradermal induction of the test substance, slight to severe erythema was noted at all of the sites injected with FCA/water and FCA/test substance in 10/10 treated and 5/5 control animals. 4/5 control animals also exhibited necrosis at the FCA/test substance injection site. In 3/10 treated animals slight to well-defined erythema was observed at the injection site of the test substance. Following the topical induction, severe erythema and scabs were observed at the test site in 3/10 treated animals. A further 4/10 (in total 7/10) treated and 4/5 control animals exhibited only scabs. No edema was observed. 48 and 72 h after the challenge, no sensitisation was observed in the treated animals. There was no mortality, no signs of toxicity and no treatment-related effects on body weight. Under the study conditions, the read across substance was determined to be non-sensitiser to the skin (Notox, 1998).

Overall, based on the available weight of evidence information from studies for substances representative of the main constituents, the test substance, 'mono- and di- C16 PSE, K+ and C16-OH and isostearyl isostearate' is considered to be non-sensitising to skin.

Endpoint conclusion:
no study available

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

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion