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Description of key information

The key acute oral toxicity study for hexadecan-1-ol, conducted according to the now-deleted OECD Test Guideline 401 and in compliance with GLP, reports an LD50 value of >2000mg/kg (Safepharm Laboratories, 1996; rel 1).

There are no acute inhalation and acute dermal toxicity data for hexadecan-1-ol. Therefore, data are read-across from tetradecan-1-ol.

The key acute inhalation toxicity study with tetradecan-1-ol, conducted prior to OECD Test Guideline and GLP, reports an LC50 of >1.5 mg/L air in rat, following 1-hour whole body inhalation exposure to vapour, which is the equivalent to 0.375 mg/L for a 4-hour exposure

(Scientific Associates, 1977; rel 2).

The key acute dermal toxicity study for tetradecan-1-ol, conducted prior to OECD Test Guideline and GLP, reports an LD50 value of 8000-12000 mg/kg bw in rabbit (Scientific Associates 1977; rel 2).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996/03/06-1996/04/16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
other: LD50
Limit test:
yes
Species:
rat
Strain:
other: Sprague-Dawley CD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Source: Charles River (UK) Ltd., Margate, Kent, UK.

- Age at study initiation: 5-8 weeks

- Weight at study initiation: Males 135-145g, females 127-137g.

- Fasting period before study: Overnight, immediately before dosing.

- Housing: Housed in groups of up to five by sex in solid floor polypropylene cages furnished in woodflakes.

- Diet: Rat and Mouse Expanded Diet No.1, Special Diets Services Limited, Witham, Essex, UK (ad libitum)

- Water: Mains drinking water (ad libitum)

- Acclimation period: Minimum of five days.


ENVIRONMENTAL CONDITIONS

- Temperature (°C): 19-22C

- Humidity (%): 39-60%

- Air changes (per hr): 15

- Photoperiod (hrs dark / hrs light): 12h/12h

Route of administration:
oral: gavage
Vehicle:
other: arachis oil
Details on oral exposure:
VEHICLE

- Amount of vehicle (if gavage): 10 ml/kg at a concentration of 200 mg/ml in arachis oil.

- Lot/batch no. (if required): 2439


MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bodyweight. The volume administered to each animal was calculated according to its fasted bodyweight at the time of dosing.


DOSAGE PREPARATION (if unusual): All animals were dosed once only by gavage using a metal cannula attached to a graduated syringe.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: A range finding study was carried out prior to dosing, using 1 male and 1 female rat which were administered 200 mg/kg of test substance at the concentration of 200 mg/ml in the volume of 10 ml/kg. The animals were observed for deaths and overt signs of toxicity 30 min, 1h, 2h and 4 hrs after dosing and subsequently for five days.
Doses:
2000 mg/kg
No. of animals per sex per dose:
10
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: Individual body weights were recorded prior to dosing on dayy 0 and on days 7 and 14. The animals were observed for deaths or overt signs of toxicity at 30 minutes, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Necropsied animals were examined externally and their abdominal and thoracic cavities opened for the examination of major organs. No tissues were retained. All animals were subject to gross pathological examination at the end of the observation period.
Statistics:
No statistical analysis of the results was carried out in this study.
Preliminary study:
A range finding study was performed to establish a dosing regime as follows: 2000 mg/kg at the concentration of 200 mg/ml in dose volume of 10 ml/kg to 1 male and 1 female rat. The rats were observed for overt signs of toxicity at 30min, 1h,2h and 4hrs after dosing subsequently once daily for five days.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
other: No clinical signs of systemic toxicity. 
Gross pathology:
Necropsy findings were unremarkable
Other findings:
POTENTIAL TARGET ORGANS: None identified.
SEX-SPECIFIC DIFFERENCES: None observed.
Interpretation of results:
GHS criteria not met
Conclusions:
The rat oral LD50 for Kalcol 6098 is >2000 mg/kg. At this dose level there were no signs of toxicity.
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
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Method: other: In house protocol
GLP compliance:
not specified
Test type:
fixed concentration procedure
Limit test:
no
Species:
rat
Strain:
other: COX-SD
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS


- Weight at study initiation: 238-338g

- Housing: A 57 litre capacity glass chamber


ENVIRONMENTAL CONDITIONS

- Air changes (per hr): Air flow rate of 600 litres per hour



IN-LIFE DATES: Not stated
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: produced as a heated vapour
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION


- Exposure chamber volume: 57 litres

- Method of holding animals in test chamber: Animals were contained in a glass chamber.

- Source and rate of air: ALFOL 14 alcohol was introduced by passing an air flow over the test material as it was heated in a 60C at an ambient chambre concentration of approximately 1.5mg per litre of air at a flow rate of ten litres per minute for a period of one hour.


TEST ATMOSPHERE


- Samples taken from breathing zone: Prior to the actual test period, the test material was introduced into the chambre for six minutes, in order that the test atmospheric concentration could reach theoretical equilibrium.


VEHICLE

- Lot/batch no. (if required): 8714J



CLASS METHOD (if applicable)

- Rationale for the selection of the starting concentration: The 1.5mg/litre test concentration was chosen since the level does not exceed any to which man could be subjected to in any foreseeable use of the material.
Analytical verification of test atmosphere concentrations:
no
Duration of exposure:
1 h
Concentrations:
1.5 mg/l
No. of animals per sex per dose:
5 female, 5 male
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Final body weight records of the ten animals at termination (14 days) showed weight gains within expected limits of that expected in all ten animals. The animals were observed frequently on the day of exposure and daily thereafter. Survivors were weighed and necropsied at the end of  the exposure period.

Statistics:
No statistical test was performed.
Key result
Sex:
male/female
Dose descriptor:
other: Inhalation
Effect level:
> 1.5 mg/L air
Exp. duration:
1 h
Mortality:
There were no mortalities during the exposure itself or in the 14 day observation period.
Clinical signs:
other: There were no clinical signs of toxicity present at any point of the study.
Body weight:
Body weight gain remained within expected limits for all ten animals.
Gross pathology:
Gross necropsy of the animals sacrificed at termination (14 days) showed no remarkable findings.
Other findings:
There were no other observations.

Table 1: Concentrations, exposure conditions and number of evident toxicity per animals treated

Nominal

Conc. (mg/L)

MMAD

µm

GSD

 

Number with evident toxicity (#/total)

Males

Females

Combined

 1.5mg/L

 

 

0 /5

0/5

0/10

 

Interpretation of results:
GHS criteria not met
Conclusions:
The rat 1 hour inhalational LC50 for tetradecan-1-ol is >1.5 mg/l. There were no signs of toxicity and findings at gross necropsy were unremarkable.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
1 500 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Method: other: Contract laboratory protocol
GLP compliance:
not specified
Test type:
fixed dose procedure
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Weight at study initiation: 2.3 to 2.9 kg

- Housing: The rabbits were individually housed in metal cages elevated above the droppings.

- Diet: Purina rabbit Chow (ad libitum)

- Water: Tap water (ad libitum)


IN-LIFE DATES: Not stated.
Type of coverage:
occlusive
Vehicle:
other: 50% w/w dilution tetradecanol in 1 % w/w gum tragacanth
Details on dermal exposure:
TEST SITE

- Area of exposure: The skin of the trunk which was clipped free of hair.

- Type of wrap if used: plastic binder


REMOVAL OF TEST SUBSTANCE

- Washing (if done): The binder was removed and the amount of unabsorbed substance estimated. The animals were then washed and the carefully blotted dry with absorbent hand towels.

- Time after start of exposure: The test compound was removed after 24 hours of exposure.


TEST MATERIAL


- Amount(s) applied (volume or weight with unit): The animals were distributed evenly as to sex in each of three dosage groups as follows: 2M+2F (1M+1F each intact and abraded) and dosed 2.0, 4.0 and 8.0 g/kg of the test substance.


- Concentration (if solution): A 50% w/w dilution of ALFOL 14 alcohol in 1% w/w gum tragacanth.



VEHICLE

- Amount(s) applied (volume or weight with unit): 1% w/w gum tragacanth.



Duration of exposure:
24 hours
Doses:
2, 4 and 8 g/kg
No. of animals per sex per dose:
2
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were observed for gross effects at regular intervals on the day of dosing and daily thereafter for fourteen days.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Body weights were recorded prior to dosing and on observation day 14.
Statistics:
No statistical analysis was carried out.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
8 000 mg/kg bw
Based on:
test mat.
Mortality:
100% of the animals with abraded skin died between 8 and 10 days of the exposure period. The animals with intact skin survived.
Clinical signs:
other: At twenty-four hours following test application, all animals showed slight to moderate erythema, desquamation, wrinkling and dryness of the skin at the treatment site. In all surviving animals, desquamation and wrinkling of the skin occurred and persisted
Gross pathology:
Gross necropsy of animals which succumbed showed depletion of visceral fatty tissue (one animal), moderate dermal irritation and desquamation at the treatment site (two animals). Gross necropsy of the animals which survived the 14 day observation period and were sacrificed, showed one animal with slight accumulation of clear viscous fluid within the peritoneal cavity and crazing over cortex of both kidneys. Eight animals showed no signs of gross systemic abnormalities.

Table 1: Number of animals dead within the 14 day observation period.

Dose
(g/kg
bw)

Mortality (# dead/total)

Time range of deaths (day)

Male

Female

Combined

2.0

 0/2

0/2

0/4 

 -

4.0

 0/2

0/2

0/4 

 -

8.0

 1/2

1/2 

2/4 *

 9 and 11

*thedead animals were from the group with skin prepared with abrasion.

 

Interpretation of results:
GHS criteria not met
Conclusions:
The rabbit dermal LD50 (24 hour occluded) for Alfol 14 was approx. 8000 mg/kg. All survivors showed skin irritation at the application site throughout the observation period. Signs of intoxication included weakness, emaciation and pallor. The result is read across from tetradecan-1-ol (CAS 112-72-1).
Executive summary:

In the acute dermal toxicity study, 2, 4 and 8 g/kg of test material was applied to the flanks of 2 male and 2 female rabbits per dose, kept in contact to the skin under occlusive dressing for 24 hours. The experiement was performed on intact and abrated skin. Body weight changes and clinical signs of toxicity were noted regularly. Necropsy was performed at the end of the 14 -day study period.

100% of the animals with abraded skin died between 8 and 10 days of the exposure period. The animals with intact skin survived. At twenty-four hours following test application, all animals showed slight to moderate erythema, desquamation, wrinkling and dryness of the skin at the treatment site. In all surviving animals, desquamation and wrinkling of the skin occurred and persisted in varying degrees throughout the 14 -day study period. At the highest dosage level (8 g/kg body weight, two of the surviving animals showed signs of weakness, emaciation and pallor; however all appeared systematically normal within 96 hours following exposure. Final body weight records of the surviving animals at termination, showed a slight loss in one animal, a constant weight in one animal and gains within expected limits in the eight remaining animals. At necropsy, there was one animal with slight accumulation of clear viscous fluid within the peritoneal cavity and crazing over cortex of both kidneys. Eight animals showed no signs of gross systemic abnormalities.

An LD50 value of 8000 mg/kg bw was reported. The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
8 000 mg/kg bw

Additional information

The key acute oral toxicity study for hexadecan-1-ol, conducted according to the now-deleted OECD Test Guideline 401 and in compliance with GLP, reports an LD50 value of >2000mg/kg (Safepharm Laboratories, 1996; rel 1).

In the study, 2000 mg/kg bw of hexadecan-1-ol in arachis oil were administered to 10 rats via oral gavage route. The animals were  observed for deaths or overt signs of toxicity at 30 minutes, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days. Individual body weights were recorded prior to dosing on day 0 and on days 7 and 14. Necropsied animals were examined externally and their abdominal and thoracic cavities opened for the examination of major organs. No tissues were retained. All animals were subject to gross pathological examination at the end of the observation period. No deaths occurred during the 14-day observation period. No clinical signs of systemic toxicity were noted. All animals showed the expected body weight gain over the observation period. Necropsy findings were unremarkable.

Two high reliability supporting studies for acute oral toxicity support the key findings, reporting LD50 values of >5000mg/kg bw (Henkel 1981; rel 1) and 7960 mg/kg (Scientific Associates, 1965; rel 2).

There are no acute inhalation and acute dermal toxicity data for hexadecan-1-ol. Therefore, data are read-across from tetradecan-1-ol.

The study for acute inhalation toxicity was selected as read-across from tetradecan-1-ol as it was the closest structural analogue substance available with the most recent and reliable information.

The key acute inhalation toxicity study with tetradecan-1-ol, conducted prior to OECD Test Guideline and GLP, reports an LC50 of >1.5 mg/L air in rat (Scientific Associates, 1977; rel 2). In the study, 5 male and 5 female rats were exposed to tetradecan-1-ol vapour at a concentration of 1.5 mg/L by whole body inhalation exposure for 1 hour. The animals were observed frequently on the day of exposure and daily thereafter for 14 days. Survivors were weighed and necropsied at the end of the exposure period. There were no mortalities during the exposure itself or in the 14-day observation period. There were no clinical signs of toxicity present at any point of the study. Body weight gain remained within expected limits for all ten animals. Gross necropsy of the animals sacrificed at termination (14 days) showed no remarkable findings.

The LC50 value for the study is below the concentration necessary for classification purposes. Furthermore, the saturated vapour concentration (calculated by the reviewer using the ideal gas equation on the basis of the physicocemical properties of tetradecan-1-ol) demonstrates that the highest theoretically achievable vapour concentration would have been reached or exceeded in this study (4h LC50 value of 0.375 mg/l). Therefore the recorded concentration in the key study represents the highest possible exposure concentration and can be considered for classification purposes.

The key acute dermal toxicity study for tetradecan-1-ol, conducted prior to OECD Test Guideline and GLP, reports an LD50 value of 8000-12000 mg/kg bw in rabbit (Scientific Associates 1977; rel 2). In the study, 2000, 4000 and 8000 mg/kg bw of 50% w/w dilution tetradecanol in 1 % w/w gum tragacanth were applied onto the abraded or intact skin of 2 male and 2 female rabbits for 24 hours under occlusive dressing. The animals were observed for gross effects  at regular intervals on the day of dosing and daily thereafter for 14 days. The animals were weighed at the beginning and end of the study period. Necropsy was performed at the end of the 14-day observation period. All the animals with abraded skin died between 8 and 10 days of the exposure period. The animals with intact skin survived. At 24 hours following test application, all animals showed slight to moderate erythema, desquamation, wrinkling and dryness of the skin at the treatment site. In all surviving animals, desquamation and wrinkling of the skin occurred and persisted in varying degrees through determination (14 days). At the highest dosage level (8000 mg/kg body weight, two of the surviving animals showed signs of weakness, emaciation and pallor; however all appeared systematically normal within 96 hours following exposure. One animal showed signs of moribundity. Final body weight records of the surviving animals at termination, showed a slight loss in one animal, a constant weight in one animal and gains within expected limits in the eight remaining animals. Gross necropsy of animals which succumbed showed depletion of visceral fatty tissue (one animal), moderate dermal irritation and desquamation at the treatment site (two animals). Gross necropsy of the animals which survived the 14-day observation period and were sacrificed, showed one animal with slight accumulation of clear viscous fluid within the peritoneal cavity and crazing over cortex of both kidneys. Eight animals showed no signs of gross systemic abnormalities.

A full discussion of the Category and considerations of RAAF Assessment Entities can be found in the Human Health Alcohols C6-24 Category report (PFA, 2016).

Discussion of trends in the Category of C6-24 linear and essentially-linear aliphatic alcohols:

Acute toxicity tests of the linear and essentially linear alcohols do not indicate any potential hazard for acute, dermal or inhalation toxicity. The available data for the Category have been reviewed with the conclusion that the long chain alcohols are of a low order of acute oral and dermal toxicity, and the inhalation LC50 is expected to be greater than the substantially saturated vapour concentration (Veenstra G, Webb C et al., 2009). Tests on various substances included in this category are all supportive of these results and do not warrant classification for most of the acute toxicity endpoints under GHS criteria. The majority of the substances are therefore not classified for acute toxicity in accordance with Regulation (EC) No 1272/2008. The only exception to this is hexan-1-ol, which finds that the acute dermal data for the test substance are consistent with Acute dermal tox category 4 and Acute oral tox 4 H302/R22, in line with the Annex VI entry.

Justification for classification or non-classification

Based on the available data, hexadecan-1-ol does not require classification for acute toxicity according to Regulation (EC) No 1272/2008.