Hexan-1-ol

Endpoint summary

Description of key information

The key acute oral toxicity study, conducted according to a guideline similar to the now-deleted OECD Test Guideline 401 but prior to GLP compliance, reports an LD50 value of 3210 mg/kg in rat (Scientific Associates Inc 1965).

The key acute inhalation toxicity study, which was conducted prior to OECD Test Guidelines and GLP, reports an LC50 value of >21 mg/L air (mist) (Scientific Associates Inc. 1977).

The key acute dermal toxicity study, conducted according to a guideline similar to OECD Test Guideline 402 but prior to GLP compliance, reports a LD50 value of 1500-2000 mg/kg bw in rabbit, which is a combined value for intact and abraded skin (Scientific Associates Inc. 1977).

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Test type:

other: LD50

Limit test:

no

Species:

rat

Strain:

other: Holtzman albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Weight at study initiation: 200-265g

- Fasting period before study: Over night

- Housing: Group housing (5 of each sex per cage), in metal cages provided with white pine and cheddar shavings.

- Diet: Purina Laboratory Chow, ad libitum.

- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Exploratory doses were administered to 8 rats to estimate the order of toxicity of the test compound. Based on the preliminary estimation, groups of 10 rats (5M, 5F) were administered the test compound at graded dosage levels designed to blanket the toxicity range.

Doses:

1.17, 1.65, 2.33, 3.28, 4.64 and 6.55 gm/kg

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

- Frequency of observations and weighing: Regular intervals on the day of dosing and daily thereafter for 14 days.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Gross necropsies were performed on all  survivors and any animals which died during the observation period. Body weights of survivors were recorded prior to sacrifice.

Statistics:

Confidence Interval 2.85 ml (2.35 gm) to 5.34ml (4.39gm)/kg body weight. Slope function 1.88, with confidence interval of 1.26 to 2.80.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 210 mg/kg bw

Mortality:

All deaths occurred within 24 hours of dosing. See table. 

.

Clinical signs:

other: Animals at all dose levels exhibited weakness and ataxia. They became comatose and breathing was laboured while comatose.  Animals  which survived appeared normal within 24 hours other than top dose animals (6.55 g/kg) where the rats appeared unwell up t

Gross pathology:

Necropsy of animals which died showed congestion of  the lungs and adrenals in most animals. In some cases gastric 
congestion  was also observed. There were no remarkable gross findings in animals sacrificed at the end of the observation period.

Other findings:

- Organ weights: Not recorded

- Histopathology: Not available

- Potential target organs: No conclusion drawn

- Other observations: No sex specific differences were reported, mortality represented as a combined value so no independent assesment can be made.

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

 

Dose ml (and gm.) kg./body weight	Mortality (# dead/total)			Time of death (day)
	Male	Female	Combined
1.42 (1.17)			0/10
2.00 (1.65)			1/10	1
2.83 (2.33)			4/10	1
3.99 (3.28)			410	1
5.64 (4.64)			8/10	1
7.96 (6.55)			8/10	1

 

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral toxicity study for hexan-1-ol, conducted according to a guideline similar to the now-deleted OECD Test Guideline 401 but prior to GLP compliance, reports an LD50 value of 3210 mg/kg in rat.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 210 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 available

Principles of method if other than guideline:

Only one dose level, short exposure period, no indication of droplet size.

GLP compliance:

not specified

Test type:

other:

Limit test:

no

Species:

rat

Strain:

other: T23-48:COX-SD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Weight at study initiation: 245-356g

- Housing: 57 litre capacity glass chamber

- Diet: Purina laboratoy chow (ad libitum)

- Water: yes (ad libitum)


IN-LIFE DATES: Not specified.

Route of administration:

other: mist

Type of inhalation exposure:

whole body

Vehicle:

other: atmosphere generated as a mist

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: Devilbiss Nebulizer

- Exposure chamber volume: 57 litres

- Method of holding animals in test chamber: Free to move in the glass chamber

- Source and rate of air: Delivery flow concentration of approximately 21 mg per litre of air, at a flow rate of six litres per minute.



TEST ATMOSPHERE

- Brief description of analytical method used: Prior to the actual exposure period, the test material was introduced into the chambre for ten minutes in order to make sure the test atmospheric concetration could reach theoretical equilibrium.

- Samples taken from breathing zone: no


TEST ATMOSPHERE (if not tabulated)

- Particle size distribution: Droplet size not reported

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

1 h

Concentrations:

21 mg/l

No. of animals per sex per dose:

5 male, 5 female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were observed frequently for gross effects during the exposure and daily thereafter for 14 days.

- Necropsy of survivors performed: yes

Statistics:

No statistical analysis was carried out on the test results.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 21 mg/L air

Exp. duration:

1 h

Mortality:

All animals survived the 14 day observation period.

Clinical signs:

other: During exposure all animals showed hypoactivity and/or ataxia, lethargy and prostration. However within 2 hours of removal from the exposure chamber the animals all appeared and continued to appear normal throughout the observation period.

Body weight:

Final bodyweights showed a  slight weight loss in one animal however the others all exhibited weight gains within expected limits.

Gross pathology:

Gross necropsy revealed moderate pulmonary, adrenal and hepatic congestion in one animal only. The findings in the remaining 9 test animals were unremarkable.

Other findings:

No potential target organs were identified.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation toxicity study, which was conducted prior to OECD Test Guidelines and GLP, reports an LC50 value of >21 mg/L air (mist) following 1-hour whole body inhalation exposure. Since the test atmospheric concentration would in all probablility exceed that to be encountered by humans when the substance is used, hexan-1-ol was found not to be a toxic substance.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

21 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:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

not specified

Test type:

other: LD50

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

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

- test material was applied to intact and abraded skin.

Duration of exposure:

24 hours

Doses:

0.5, 1, 1.5 and 2 g/kg

No. of animals per sex per dose:

2M, 2F

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were observed for clinical signs of intoxication several time during the day of dosing and daily thereafter throughout  the 14 day observation period.  The animals were weighed at sacrifice.

- Necropsy of survivors performed: yes

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 500 - < 2 000 mg/kg bw

Mortality:

- Time of death: Within 48 hours of dosing.
- Number of deaths at each dose: 0/4, 1F/4, 1M/4, 4/4.

Clinical signs:

other: Prior to death generalised weakness and/or unthriftiness, diarrhoea, hypothermia, pallor, loss of corneal and palepebral reflexes, hunched position, flaccidity, slow shallow repsiration and coma. Similar signs of intoxication but less marked were observed

Gross pathology:

Premature decedents showed at gross necropsy, in addition to dermal irritation, severe haemorrhaging and/or bloody,  gelatinous infiltration of the subcutis, depletion of fatty tissue, slight accumulation of clear fluid within the peritoneal cavity, moderate congestion of liver and kidneys and severe haemorrhaging and/or blanching  of the gastric mucosa. Amongst survivors (10), other than residual skin damage, gross necropsy findings were unremarkable in 7 rabbits. In the remaining 3 rabbits there was a slight to moderate accumulation of clear viscous liquid in the peritoneal cavity and/or a dpeletion of visceral fat and mottling or stippling of the renal cortex.

Rabbit dermal LD50 (24 hour occlusive exposure) 1.5 - 2 g/kg. This is a combined value for intact and abraded skin and males/females. 

At 24 hours all animals showed slight to moderate erythema especially of the ventral region. Survivors all showed wrinkling 

and/or coriaceousness, hardening and desquamation of the skin which persisted throughout the observation period.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute dermal toxicity study, conducted according to a guideline similar to OECD Test Guideline 402 but prior to GLP compliance, reports a LD50 value of 1500-2000 mg/kg bw in rabbit, which is a combined value for intact and abraded skin

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 500 mg/kg bw

Additional information

The key acute oral toxicity study for hexan-1-ol, conducted according to a guideline similar to the now-deleted OECD Test Guideline 401 but prior to GLP compliance, reports an LD50 value of 3210 mg/kg in rat (Scientific Associates Inc 1965). In the study, 5 male and 5 female rats were given single oral (gavage) administration of 1.17, 1.65, 2.33, 3.28, 4.64 and 6.55 gm/kg bw of undiluted hexan-1-ol (CAS 111-27-3). The animals were observed for 14 days following administration. Clinical signs and body weights were recorded regularly. Necropsy was performed  at the end of the 14-day observation period. No deaths occurred at 1.17 gm/kg bw group; 1 out of 10, 4 out of 10, 4 out of 10, 8 out of 10 and 8 out of 10 animals died at 1.65, 2.33, 3.28, 4.64 and 6.55 gm/kg bw groups, respectively. All deaths occurred withing 24 hours following test item administration. Clinical signs included weakness and ataxia, all surviving animals appearing normal within 48 hours of dosing. Weight gain amongst survivors was within normal limits. Necropsy of decedents revealed congestion of the lungs and adrenals, as well as gastric congestion in some cases. No remarkable gross findings were observed in animals sacrificed at the end of the observation period.

The result of the key study is supported by a reliability 2 study from Scientific Associates Inc. (1977) which reports the LD50 value of 4420 mg/kg in rat, with clinical signs of hypoactivity, diarrhoea and ataxia, gastric mucosa identified as a potential target organ.

Additionally, several reliability 4 supporting studies report LD50 values of 4000 mg/kg in mouse (Bevan, 2001), 4590 mg/kg in rat (Bevan, 2001), 4870 mg/kg in rat (Bevan, 2001), 3131-3344 mg/kg (species unclear) (IUCLID 2000) and 1950 mg/kg in mouse (RTECS, 2004). Several LD50 values for rat are also reported in IUCLID 2000 ascribed to either Henkel or the Dangerous Properties of Industrial Materials Report between 4000 and 4900 mg/kg.

Further investigation of some data listed in IUCLID 2000 and Sax 'Dangerous Properties of Industrial Materials' has led to a reported LD50 in rat of 720 mg/kg bw (Purchase, 1968). While this is an old study with some methodological and reporting deficiencies, on balance it can be considered reliability 2 data and should be taken into account.

The key acute inhalation toxicity study, which was conducted prior to OECD Test Guidelines and GLP, reports an LC50 value of >21 mg/L air (mist) (Scientific Associates Inc. 1977). In the study 5 male and 5 female rats were exposed for 1 hour via whole body inhalation to the atmosphere generated as mist of hexan-1-ol at concentration of 21 mg/L air. Following exposure, the animals were observed for 14 days. Clinical signs and body weights were recorded on a regular basis. At the end of the 14-day observation period, the animals were subject to necropsy. All animals survived the 14 day observation period. During exposure all animals showed hypoactivity and/or ataxia, lethargy and prostration. However within 2 hours of removal from the exposure chamber the animals all appeared and continued to appear normal throughout the observation period. Final bodyweights showed a  slight weight loss in one animal however the others all exhibited weight gains within expected limits. Gross necropsy revealed moderate pulmonary, adrenal and hepatic congestion in one animal only. The findings in the remaining 9 test animals were unremarkable.  

Two supporting studies of reliability 4 are also provided, with an 8-hour LC50 which was found to be greater than the substantially saturated vapour concentration (Bevan, 2001) and an LC50 >1060ppm (Opdyke, 1975) with very little experimental detail available.

The key acute dermal toxicity study, conducted according to a guideline similar to OECD Test Guideline 402 but prior to GLP compliance, reports a LD50 value of 1500-2000 mg/kg bw in rabbit, which is a combined value for intact and abraded skin (Scientific Associates Inc. 1977). In the study, 0.5, 1, 1.5 and 2 g/kg bw of undiluted hexan-1-ol were applied onto the intact or abraded skin of 2 male and 2 female rabbits per dose for 24 hours under occlusive dressing. Following exposure, the animals were observed for 14 days. Clinical signs and body weights were recorded on a regular basis. At the end of the 14-day observation period, the animals were subject to necropsy. No mortality occurred at 0.5 g/kg bw; 1 out of 4 animals, 1 out of 4 animals and 4 out of 4 animals died at 1, 1.5 and 2 g/kg bw dose groups, respectively. All deaths occurred within 48 hours. Clinical signs prior to death included (but were not limited to) weakness, diarrhoea, slow shallow respiration and coma. Similar, but less marked signs of intoxication were observed in survivors who appeared normal within 96 hours of dosing. Premature decedents showed severe haemorrhaging and/or bloody, gelatinous infiltration of the subcutis, depletion of fatty tissue, accumulation of fluid within peritoneal cavity and moderate congestion of liver and severe haemorrhaging and/or blanching of the gastric mucosa. In the survivors, 7 of the animals showed no remarkable findings at necropsy, but the remaining 3 had a slight to moderate accumulation of clear viscous fluid in the peritoneal cavity and/or depletion of visceral fat and mottling or strippling of the renal cortex.

A supporting, reliability 2 study by Scientific Associates Inc. (1980) reported a rabbit dermal LD50 value of 2330 mg/kg body weight with clinical signs and necropsy findings similar to the key study. The remaining reliability 4 data reports LD50 values of 2530 mg/kg and >5000 mg/kg (Bevan, 2001; Opdyke, 1975). Other LD50 values reported in IUCLID 2000 were ascribed to either Henkel or the Dangerous Properties of Industrial Materials were within the range of 2530-2500 mg/kg.

As shown above, the key dermal result falls within the classifiable range and would be consistent with CLP classification. This appears to be the most sensitive result from a consistent range ca. 1500-2600 mg/kg. The consistency of findings between the key result and others available suggests the findings of the 1977 study were not aberrant.

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. 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 EC Regulation 1272/2008. The only exception to this is hexan-1-ol, which finds that the acute data for the test substance are consistent with acute dermal toxicity category 4 and acute oral toxicity 4 H302, the acute oral toxicity classification is in line with the Annex VI entry.

Justification for classification or non-classification

Based on the available data, hexan-1-ol is classified for acute oral toxicity Category 4, H302 "Harmful if swallowed", in Annex VI of Regulation (EC) No 1272/2008. The available data indicate that classification for acute dermal toxicity Category 4, H312 " Harmful in contact with skin", is required according to Regulation (EC) No 1272/2008.