DL-hexane-1,2-diol

Endpoint summary

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:

June - July 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well performed but results for three female animals dosed at 2043 mg/kg bw only qualitatively reported, pre-GLP study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

study was based on draft OECD guideline

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Age of animals at start of test: Females 45-53 days, males 36-43 days
Weight of animlas at start of test: Females 0.127-0.169 kg, males 0.127-0.169 kg
Source of animals: Hagemann, Externtal
Acclimatisation prior to test: 10 days
Animals used per dose: 5-10
Animals used in total: 63
no food was supplied 16 hour prior to test start
Animals were kept in groups of 5 in makrolon cages, type III
standardized food (Altromin) was given and water ad libitum
Room temperature 21 ±2 °C, relative humidity 50-60 %
10 hour light/14 hours dark cycle per day

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

volumina applied were 4.64-10.0 ml/kg bw for females and 2.15-10.0 mg/kg for male rats, equivalent to 4408-9500 mg/kg bw (females) respectively 2043-9500 mg/kg bw (males). The substance was applied pure and undiluted without vehicle by oral gavage.

Doses:

doses applied were 2043 mg/kg, 4408 mg/kg, 5339 mg/kg, 6470 mg/kg, 7838 mg/kg and 9500 mg/kg

No. of animals per sex per dose:

3 males at 2043 mg/kg
5 males and 5 females at 4408 mg/kg
5 males and 5 females at 5339 mg/kg
5 males and 10 females at 6470 mg/kg
5 males and 10 females at 7838 mg/kg
10 females at 9500 mg/kg

Control animals:

not specified

Details on study design:

Observation period after test substance administration was 14 days

Statistics:

the LD50 was determined by Probit analysis for males and graphically for females.

Sex:

male

Dose descriptor:

LD50

Effect level:

6 166 mg/kg bw

Based on:

test mat.

95% CL:

>= 5 197 - <= 7 410

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 5 339 - <= 6 470

Based on:

test mat.

Remarks on result:

other: graphically determined

Mortality:

No mortality was observed at 2043 and 4408 mg/kg bw. At the dose of 6339 mg/kg mortality was observed (1 out of 5 males after 24 h and 3 out of 5 females at 0.5, 2 and 24 hours following exposure). At the highest dose (7838 mg/kg for males) 4 out of 5 animals died after 4 hours, respectively 5 out of 10 females at 9500 mg/kg (two 0.5 hours following exposure, one 2 hours after exposure and two 24 hours after exposure)

Clinical signs:

other: First signs of toxicity were reduction of muscular tonicity and effects on coordination capability, increasing with doses as aplied whereas mortality was described as general paralysis.

Gross pathology:

gross pathology revealed no substance specific effects in organs examined post mortem.

doses [mg/kg]	gender	mortality		0.5 h	1 h	2 h	4 h	8	24 h
4408	males	0/5	0%
6339	males	1/5	20%						1
6470	males	4/5	80%	1					3
7838	males	4/5	80%			4
4408	females	0/5	0%
6339	females	3/5	60%	1		1			1
6470	females	4/10	40%				2		2
7838	females	5/10	50%	3		1	1
9500	females	5/10	50%	2		1			2

results with 3 males dosed at 2043 mg/kg were not reported in value tables!

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

1,2-Hexanediol has an LD50, determined by OECD401 alike methodology, of 6166 mg/kg bw (males) respectively 5339-5470 mg/kg bw (females).
The value for males 6166 mg/kg bw, determined by probit analysis, is taken forward for hazard and risk assessment.

Executive summary:

In this study acute toxicity 1,2-hexanediol was investigated at high doses (4408 up to 9500 mg/kg bw). The LD50 was determined being greater 5000 mg/kg for male and female rats and thus outside boundaries for classification even under GHS (Globally Harmonized System for Classification and Labelling of Chemicals). Symptoms seen at concentrations as of 2043 mg/kg bw were reduced muscular tonicity and effects on coordination capability of animals. As only the LD50 for male rats was determined by probit analysis (LD50 of 6166 mg/kg bw), this value is considered being more reliable and taken forward for hazard and risk assessment.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

6 166 mg/kg bw

Quality of whole database:

Although the study dates pre-OECD protocols draft protocols were already available at that time and used as basis for study design. Even though the study has slight reporting deficiencies the number of animals was high (in total 63 animals used) and dose/response relationship was satisfactory, even at such high doses used in this study (up to 10 ml/kg i.e. 9500 mg/kg bw).

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Study period:

April & May 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study fulfills scientific principles and was conducted according to OECD 403 (1981) but pre-dates GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

1981

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Tif: RAI f (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Husbandry: Young adult rats of both sexes (Tif: RAI f (SPF) strain), weighing 223 ± 8 g (males) and 210 ± 14 g (females), respectively, bred and raised on the premises, were used in the experiment. Before and after the inhalation exposure, the animals were maintained in an animal room at a temperature of 22 ± 2 °C, a relative humidity of 55 ± 10 % and on a 12 hour/day light cycle. The rats, segregated by sex, were group-housed (5 animals per cage) in Macrolon cages, type 4 - (Ehret, 783 Emmendingen/Germany). Rat chow (NAFAG 890 Tox, NAFAG, Gossau/SG, Switzerland)- and water were provided ad libitum.
Group Size: Each of the 2 dosage groups consisted of 20 rats (10 males and 10 females), which were approximately matched in weight. Within the groups, the animals of either sex were identified with numbers from 1 to 10 using picric acid stain on the fur. After exposure, the animals were placed in their cages, which were marked with a cage card containing the date of exposure and the characteristics of the experiment and dose group. A control group (of equal size) was exposed to an inhalation of purified air under the same condition as were used in the test material exposure.
The following environmental parameters within the inhalation chamber were monitored at approximately the same intervals as the concentration determinations:
- Temperature (with a Therm 2104 Contact Thermometer, Ahlborn Mess- und Regeltechnik, Bolzkirchen/Germany)
- Relative humidity (with a Vaisala Humidity Indicator am 11, Belag AG, 8051 Zuerich/Switzerland)
- Oxygen content (with a Draeger E 15 Stationary Control System, Draegerwerk AG, Luebeck/Germany)

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

Chamber: All exposures were conducted according to the procedure of Sachsse at al. in a nose-only exposure system with a plexiglass exposure chamber holding approximately 100 liters. For the inhalation period, the rats were placed in individual PVC-tubes positioned radially around the exposure chamber, so that only the snouts and nostrils of the animals were exposed to the aerosol. The chamber was maintained at a slightly negative pressure to prevent leakage of the aerosol from the system. The exhaust air was decontaminated by subsequent passage through two gas washing bottles containing 5 % NaOH.
Aerosol: The aerosol was generated by injecting the liquid test substance with a Perfusor IV Syringe System (Bender and Hobein, 8051 Zuerich, Switzerland) at a rate of 60 and 180 ml/h into a spray nozzle (JATO, Luzern, Switzerland). Through the nozzle, compressed filtered air (2 atmospheres, 10 1/min) was discharged into the inhalation chamber. The control animals were exposed to filtered air under the same conditions as described above.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The air flow through the chamber was measured with a Brooks Sho-Rate flow meter.

Duration of exposure:

4 h

Concentrations:

The aerosol concentration in the chamber was determined 5 times (after 30 minutes, 1, 2, 3, and 4 hours of exposure) by gravimetric sampling of the test atmosphere through a Selectron filter of 50 mm diameter and a pore size of 0.2 um. The air flow rate for the sample collection was 10 1/min. The means and
standard deviations of the aerosol concentration for each exposure were calculated.
Two concentrations 3380 and 7015 mg/m3 were tested next to control with clean air.

No. of animals per sex per dose:

10 males and 10 females per dose group

Control animals:

yes

Details on study design:

Animals were examined for clinical symptoms and mortalities during the exposure at 1, 2, and 4 hours, as well as 2 hours after the exposure and daily thereafter for 14 days. Body weights were recorded immediately prior to exposure and on days 7 and 14 of the observation period. Gross pathological examinations were performed on all animals dying within the 14 day observation period as well as the survivors which were killed after 14 days by asphyxiation with CO2. Particular attention was given to the respiratory tract.

Statistics:

Inhalation LC50 values including their 95% confidence limits during the 4-hour treatment and the 14 days post-exposure period could not be calculated, because no mortalities were elicited by the test substance. The body weights of the treated animals and the controls were compared by analysis of variance.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 7 015 mg/m³ air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortalities occurred during exposure and during the 14 day observation period. As the limit set in the OECD guidelines (5000 mg/m3) was
exceeded, no attempt was made to generate even higher concentrations of CGA-143816.

Clinical signs:

other: Exposure to 3380 mg/m3 resulted in slight, to 7015 mg/m3 in moderate dyspnoea. Ruffled fur and curved body position were seen at both concentrations during the exposure and one day thereafter. All animals exposed to the test material recovered within 1 da

Body weight:

The body weight gains of both sexes showed a significant increase during the first observation period (day 1-7). During the second observation period, they were within normal limits.

Gross pathology:

Some of the animals exposed to the test substance exhibited mottled or reddish lungs. No other treatment-related deviations were seen.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LC50 to both sexes:greater than 7015 mg/m3 air
According to the OECD guidelines, this study may be considered a limit test, as a concentration greater than 5000 mg/m3 did not produce any mortality.

Executive summary:

Upon a 4 hour aerosol exposure and a 14 day post-treatment observation period, no mortalities could be elicited upon exposure to

CGA-143816 techn., even at the highest particle concentration tested (7015 mg/m3). It can be assumed from the absence of mortalities and the weak symptoms observed that LC50 to both sexes is greater than 7015 mg/m3 air.

According to the OECD guidelines, this study may be considered a limit test, as a concentration' greater than 5000 mg/m3 did not produce any mortality.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Study period:

March & April 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study fulfills scientific principles and was conducted according to OECD 402 (1981) but pre-dates GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

1981

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: TIF:RAIf(SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source: CIBA-GEIGY LTD. Tierfarm, 4334 Sisseln, Switzerland
Initial Body Weight Range: 184-214 g
Initial Age: 7-8 weeks
Individual Identification: By cage number
Husbandry: The animals were kept under conventional laboratory conditions. They were caged individually in Macrolon cages type 2 with standardized soft wood bedding (Societe Parisienne des sciures, Pantin). The animal room was air conditionned: temperature 22 ±3 ° C, relative humidity 55 ±15%, 12 hours light/day, approximately 15 air changes/h.
Diet: Rat food, NAFAG No. 890, NAFAG AG, Gossau, SG (Switzerland), and water were provided ad libitum.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Volume (ml/kg body weight) applied: 2
Pretreatment: The animals were allocated to the different dose groups by random selection. Approximately 24 hours before treatment an area on the back of the rat of at least 10% of the body surface was shaved with an electric clipper.
Administration: The required amount of the test substance was evenly dispersed on the skin.It was covered with a gauze lined occlusive dressing, which was fastened around the trank with an adhesive elastic bandage. After an exposure period of 24 hours the dressing was removed and the skin was cleaned with lukewarm water. Thereafter the reaction of the skin was appraised repeatedly.
Observation Period: 14 days or until all symptoms have disappeared, whichever lasts longer

Duration of exposure:

24 hours exposure and 14 days observation period

Doses:

2 mL /kg bw

No. of animals per sex per dose:

5 male and 5 female

Control animals:

not required

Details on study design:

Mortality was checked twice dails during working days and symptoms were recorded once daily, Body weight was recorded at days 1, 7, 14 and at death (if applicable).

Statistics:

From the Body weights, the group means and their standard deviations were calculated.
Where feasable, the LD50 including the 95% confidence limit were computed by the logit method (J. Berkson, J. Am. Stat. Ass. 39. 357-65, 1944).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed in this study during exposure and observation period.

Clinical signs:

other: Systemically no specific symptoms were seen. At the application site, slight erythema, which lasted for three days, was present.

Gross pathology:

At autopsy no compound related gross organ changes were observed.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

1,2-Pentanediol caused no mortality and only weak fully reversible erythema upon dermal application of 2000 mg/kg bw. Thus the LD50 was set to > 2000 mg/kg bw in this study.

Executive summary:

10 rats (5 male and 5 female) were dermally exposed to 2000 mg/kg bw 1,2-pentanediol for 24 hours occlusively and thereafter observed for 14 days according to OECD 402. No Clinical signs and symptoms were noted except erythemy which fully reversed within three days. No mortality was observed and weight gain was seen in males and females. At autopsy no treatment-related observations were recorded.

Thus, in this limit test no significant toxicity was observed and the LD50 was set to >2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Oral:

In an oral acute toxicity study with 1,2-hexanediol at high doses (4408 up to 9500 mg/kg bw) the LD50 was determined being greater 5000 mg/kg for male and female rats and thus outside boundaries for classification even under GHS (Globally Harmonized System for Classification and Labelling of Chemicals). Symptoms seen at concentrations as of 2043 mg/kg bw were reduced muscular tonicity and effects on coordination capability of animals. As only the LD50 for male rats was determined by probit analysis (6166 mg/kg bw), this value is considered being more reliable and taken forward for hazard and risk assessment.

Dermal:

10 rats (5 male and 5 female) were dermally exposed to 2000 mg/kg bw 1,2-pentanediol for 24 hours occlusively and thereafter observed for 14 days according to OECD 402. No Clinical signs and symptoms were noted except erythema which fully reversed within three days. No mortality was observed and weight gain was seen in males and females. At autopsy no treatment-related observations were recorded. Thus, in this limit test no significant toxicity was observed and the LD50 was set to >2000 mg/kg bw. For read-across justification see below.

Inhalative:

Upon a 4 hour aerosol exposure to 1,2-pentanediol and a 14 day post-treatment observation period, no mortalities could be elicited upon exposure to CGA-143816 techn., even at the highest particle concentration tested (7015 mg/m3). It can be assumed from the absence of mortalities and the weak symptoms observed that the LC50 to both sexes is greater than 7015 mg/m3 air. According to the OECD guidelines, this study may be considered a limit test, as a concentration' greater than 5000 mg/m3 did not produce any mortality. For read-across justification see below.

Hypothesis for the analogue approach from pentane-1,2-diol to hexane-1,2-diol

Both, pentane-1,2-diol and hexane-1,2-diol are two corresponding members of a homologue series of linear 1,2-alkyldiols, starting with 1,2-propandiol, 1,2-butandiol, 1,2-pentanediol, 1,2-hexanediol etc. Based on very similar physico-chemical properties, common functional groups (vicinal diol) and common toxicokinetik behavior, data for 1,2-pentanediol on acute dermal and inhalative toxicity can be used as surrogate data for 1,2-hexanediol.

Source Chemical and Target chemical

	Pentane-1,2-diol (data as shown in REACH registration dossier on Pentane-1,2-diol)	Hexane-1,2-diol
CAS No	5343-92-0	6920-22-5
EC No	226-285-3	230-029-6
Mol. weight	104.15	118.18
Smiles code	OC(CCC)CO	OCC(O)CCCC
Appearance	Clear colourless liquid	Clear colourless liquid
Water solubility	Very soluble (1000 g/L)	Fully miscible (>9 g/g)
logPOW	0.06	0.58
Vapour pressure	1.5 Pa at 20 °C	0.58 Pa at 20 °C
Melting point	-40 °C	2 °C
Boiling point	209.4 °C at 1 atm	228.3 °C
Density	0.98 g/cm3 at 20 °C	0.95 g/cm3 at 20 °C
Purity	Typically >99 %	Typically >99 %
Acute oral toxicity	LD50 (rat) >5000 mg/kg bw	LD50 (rat) >5000 mg/kg bw
Acute dermal toxicity	LD50 (rat) >2000 mg/kg bw	gap
Acute inhal. toxicity	LC50 (rat) >7015 mg/m³air	gap
Corrosion/Irritation	Skin non-irritating Eye irritating	Skin non-irritating Eye irritating
Skin sensitization	Not sensitising	Not sensitising
Repeated dose toxicity	Oral NOAEL(90d) 1000 mg/kg bw/d (read across from 1,2-butanediol) Dermal NOAEL(90d) 700 mg/kg bw/d (read across from 1,2 hexane diol)	Oral NOAEL(14d) 500 mg/kg by/d Dermal NOAEL(90d) 700 mg/kg bw/d
Genetic toxicity	Negative Ames (+/-) Chrom. Ab. (+/-) Mouse lymphoma (L5178Y) (+/-)	Negative Ames (+/-) Chrom. Ab. (+/-) Mouse HPRT (V79) (+/-)
Carcinogenicity	No data	No data
Reproductive toxicity	NOAEL (OECD414) 300 mg/kg bw/d (highest tested dose) (read across from 1,2-hexanediol) NOAEL(OECD422) 1000 mg/kg bw/d (read across from 1,2-butanediol)	NOAEL (OECD414) 300 mg/kg bw/d (highest tested dose) NOAEL(OECD416) >14400 mg/kg bw/d (read across from 1,2-propanediol)

Purity / Impurities

Read across is possible provided that there is no impact of impurities on the toxicological properties of the target and source chemicals. For both, impurities are comparable or not present.

Analogue Approach Justification

Both, pentane-1,2-diol and hexane-1-2-diol are two corresponding members of a homologue series of linear 1,2-alkyldiols, starting with 1,2-propandiol, 1,2-butandiol, 1,2-pentanediol, 1,2-hexanediol etc. 

Both substances do show very similar physico-chemical properties (see above) in particular regards water solubility (fully miscible with water) and low log POW values; consequently, similar oral and dermal absorption is assumed whereas inhalative exposure and absorption is unlikely due to the low vapour pressure of both.

Sharing the same functional group(s) being an alkyl chain with a primary alcohol function and directly associated a secondary alcoholic function (vicinal diol, glycol) following absorption and distribution through blood within the body occurs rapidly and both do share a common metabolism starting with oxidation by alcohol dehydrogenase and thereafter either by further alcohol dehydrogenase to glyoxal derivatives or by aldehyde dehydrogenase to lactates (major pathway). Distribution and following efficient de-toxification pathways via urine as lactates or their glucuronides excretion also is efficient. Bioaccumulation in the body therefore is not apparent (see toxicokinetic assessment in this dossier).

When comparing available toxicological data (see matrix above) acute and repeat toxicity data are in the same range and no significant differences are seen as expected.

Conclusion on bioavailability and metabolism of source and target substance

Both, 1,2-pentanediol and 1,2-hexanediol are well absorbed, rapidly distributed and efficiently metabolized to become excreted as glucuronides mainly via urine. Thus, both substances show a common ADME-pattern as expected. This is supported by comparable acute and repeat dose toxicity data. In addition, genetic toxicity and reproductive toxicity do not show and indications for concern (see matrix above). As a consequence it can be reasonably assumed that acute data on dermal and inhalative toxicity on pentane-1,2-diol can be used to predict acute dermal and inhalative toxicity of hexane-1,2-diol and such read-across approach is valid.

Conclusion on Classification and Labelling / Risk and Hazard Assessment

Data for acute dermal and inhalative toxicity of pentane-1,2-diol used are reliable with restriction (Klimisch 2) as they were performed according to OECD 404 respectively OECD 403 (version 1981) in 1982, pre-dating GLP standards but both do fulfill the criteria as present at time of performing the studies fulfilling basic scientific principles. Their results are adequate for deciding upon classification and labeling as well as for concluding upon hazard and risk assessment for these pathways as in both studies at the highest tested concentration no toxicity was observed and the doses tested were above classification thresholds.

Justification for selection of acute toxicity – oral endpoint
One study was available which was considered reliable with restrictions. Since the LD50 was higher than the limit dose of 2000 mg/kg, the conclusion "no adverse effect observed" was entered above.

Justification for selection of acute toxicity – inhalation endpoint
Reliable inhalative acute study using rats according to OECD 404 on structurally next homologue 1,2-pentanediol.

Justification for selection of acute toxicity – dermal endpoint
Reliable dermal acute study using rats according to OECD 402 on structurally next homologue 1,2-pentanediol.

Justification for classification or non-classification

Due to the findings described above (LD50 oral in rats 6166 mg/kg bw) 1,2-hexandiol has not to be classified as acute orally toxic according to the criteria laid down in the EU Dangerous Substances Directive (67/548/EEC) and in the EU Classification Labelling and Packaging Regulation (1272/2008/EC). Based on results from the next homologue in the series of 1,2-alkanediols, 1,2-pentanediol, by dermal (LD50 > 2000 mg/kg bw) and inhalative exposure (LC50 > 7015 mg/m3), also classification for dermal or inhalative toxicity is not required.

The substance does not have to be classified for specific target organ toxicity – single exposure according to Regulation (EC) No 1272/2008, as no specific toxic effects were observed after acute exposure.