Reaction mass of hexadecyl dihydrogen phosphate and cetyl alcohol (mono- C16 PSE and C16-OH)

Endpoint summary

Description of key information

Based on the available weight of evidence from studies on the main constituents, the test substance can be considered to have a low acute oral toxicity, with LD50 values exceeding 2000 mg/kg bw,

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

From June 02, 1987 to June 17, 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

KL2 due to RA

Justification for type of information:

Refer to section 13 of IUCLID for details on the read-across justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Ibm: RORO (SPF), also known as Fü-albino SPF rat

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals
- Age at study initiation: about 6 weeks
- Weight at study initiation: female 114-117 g; male 116-124 g
- Fasting period before study: 18 h
- Housing:
- Diet: NAFAG standard rat maintenance diet, No. 850 (cubic), ad libitum
- Water: tap water, ad libitum
- Acclimatisation period: seven days under laboratory conditions

Environmental conditions
- Temperature: 20-24°C
- Humidity: 45-65 %
- Air changes: air-conditioned room
- Photoperiod: 12/12 h dark / light

Route of administration:

oral: gavage

Vehicle:

other: Standard Suspending Vehicle (SSV), please see below in " Details on oral exposure"

Details on oral exposure:

Vehicle
The test article was suspended in Standard Suspending Vehicle (SSV)
1000 mL SSV contain:
5 g sodium carboxy methyl cellulose of median viscosity,
4 mL Tween 80,
5 mL benzylalcohol pro analysis,
9 g sodium-chloride pro analysis,
aqua destillata ad 1000 mL.

- Amount of vehicle: 10 mL/kg bw

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

5 animals per sex

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 d
- Frequency of observations and weighing: daily for clinical signs and weighing on Day 1, 4, 8, 11, 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (respiratory distress, crust around nose, hunched posture, crust around eyes, exitability), body weight, histopathology

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: i.e., equivalent to >4250 mg a.i./kg bw

Mortality:

No compound-related deaths occurred.
One male was found dead early in the morning of Day 8. This case of death was considered to be a result of an application injury. This male rat showed a marked respiratory distress and a marked loss of weight. The histopathological examination of the lung of this animal revealed aspiration pneumonia.

Clinical signs:

other: The main symptom was respiratory distress seen in 3 males and 1 female. This symptom developed in consequence of aspiration of a little test suspension. The other findings were of no toxicological significance.

Gross pathology:

In the urinary bladder of male rat 2694, gritty contents were observed. This finding was of a spontaneous nature. No other macroscopic organ changes were seen.

Other findings:

Histopathology: Bronchopneumonia caused the respiratory distress and itself was caused by aspiration of test suspension (by the male rat that died at Day 8).

Interpretation of results:

other: not classified based on EU CLP Criteria

Conclusions:

Based on the results of the read across study, LD50 for the test substance, is considered to be >4250 mg/kg bw.

Executive summary:

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) (XXXX, 1987). Based on the results of the read across study, similar absence of toxicity and oral LD50 value can be expected for the test substance, mono- C16 PSE and C16-OH.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

From August 30, 1985 to September 13, 1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

Refer to section 13 of IUCLID for details on the read-across justification. The study with the read across substance is considered sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: notification No. 118 of the Pharmaceuticals Affairs Bureau, 15 Feb 1984, Toxicity Test Guideline

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

not specified

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

other: CFY (Sprague-Dawley origin)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals
- Source: Interfauna UK Limited, Huntingdon, Cambridgeshire, England
- Age at study initiation: 4 to 6 weeks
- Weight at study initiation: 109 to 150 g
- Fasting period before study: yes; overnight prior to and 4 h after dosing
- Housing: in groups by sex in metal cages with wire mesh floor
- Diet (e.g. ad libitum): standard laboratory rodent diet (Labsure LAD 1), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum 8 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 23°C
- Humidity (%): 62% mean
- Air changes (per hr): ca. 15/h
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on oral exposure:

Vehicle
- Concentration in vehicle: 80%
- Amount of vehicle (if gavage): 20 mL/kg bw

Doses:

0, 16.0 g/kg bw

No. of animals per sex per dose:

preliminary study: 2
main study: 10

Control animals:

yes

Details on study design:

- Duration of observation period following administration: preliminary study 5 d; main study 14 d
- Frequency of observations and weighing: (a) bodyweights: Day 1 (day of dosing), 4, 8, 15 (b) clinical signs: soon after dosing, then at frequent intervals for the remainder of Day 1. On subsequent days the animals were observed at least once in the morning and once at the end of the experimental day (on Saturdays and Sundays app. 11:30 a.m.)
- Necropsy of survivors performed: yes

Statistics:

none

Preliminary study:

0/4 animals died in the preliminary test.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 16 000 mg/kg bw

Based on:

test mat.

Mortality:

0/20 animals died in the main study

Clinical signs:

other: - Piloerection in 20/20 animals in treated group; recovery on Day 3 - No clinical signs in control group

Gross pathology:

- Terminal autopsy findings were normal

Other findings:

None

Interpretation of results:

other: Not classified based on EU CLP criteria

Conclusions:

Under the study conditions, the oral LD50 in rats for test substance was determined to be >16000 mg/kg bw.

Executive summary:

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 (Huntingdon, 1985). Based on the results of the read across study, similar absence of toxicity and oral LD50 value can be expected for the test substance, mono- C16 PSE and C16-OH.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Sprague-Dawley CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test organism: Rat (Sprague-Dawley)
- Source: Charles River, Margate, Kent, UK
- Age: 5-8 weeks
- Weight at study initiation: males 135-145g, females 127 -137g
- Group size: 5M+5F fasted
- Controls: no

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

Administration: Oral gavage
- Doses: Single dose level of 2000 mg/kg based on a range finding test.
- Doses per time period: single dose
- Volume administered or concentration: 10 mL/kg at a concentration of 200 mg/mL in arachis oil.
- Post dose observation period: 14 d

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Post exposure examination
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.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

There were no deaths.

Clinical signs:

other: No clinical signs of systemic toxicity. All animals showed the expected body weight gain over the observation period.

Gross pathology:

Unremarkable

Other findings:

Potential target organs:
None identified.

Sex specific difference:
None observed.

Interpretation of results:

other: not classified based on EU CLP criteria

Conclusions:

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) .

Executive summary:

A study was conducted to determine the acute oral toxicity of the test substance, hexadecan-1-ol (purity: >95%), according to the 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).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral:

In absence of acute oral toxicity study with the test substance, the endpoint has been assessed based on studies for substances representative of the two main constituents, which can be categorised as phosphate esters (PSE) and alcohol. The results are presented below:

Constituent 1: PSE - read across study:

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 (Huntingdon, 1985).

Constituent 2: Alcohol:

A study was conducted to determine the acute oral toxicity of hexadecan-1-ol (purity: >95%), according to the 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 read across substance was determined to be >2000 mg/kg bw (i.e., >1900 mg a.i./kg bw) (OECD SIDS, 2006).

Overall, the test substance can be considered to have a low acute oral toxicity, with LD50 values for its main constituents >2000 mg/kg bw..

Dermal:

As per Annex VIII (8.5.3), the acute dermal toxicity testing is not needed as the substance does not meet the criteria for classification for acute toxicity and STOT SE for the oral route (based on read across studies). This is also supported by the absence of any systemic effects in thein vivoskin sensitisation study available with the read across substance, ‘mono- and di- C16 PSE, K+ and H3PO4’. Moreover, given the physico-chemical properties of the test substance, the dermal LD50 value is less likely (due to lower absorption potential of dermal route) to be lower than oral LD50 or the oral doses showing clinical signs. Hence, testing via dermal route will less likely result in any additional hazard identification and testing is therefore considered unnecessary. No systemic toxicity was observed in thein vivoskin sensitisation study available with the read across substance.

Inhalation:

The substance is a solid powder (particle size exceeding 2000 µm) 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

Justification for classification or non-classification

Overall, based on the available weight of evidence from studies on the main constituents, the test substance, 'mono- C16 PSE + C16-OH', does not warrant classification for acute toxicity according to EU CLP (Regulation 1272/2008/EC).