1,4-dioxane

Endpoint summary

Description of key information

Based on all data available (including human experience) it can be concluded that 1,4-dioxane is irritating to the eye and the respiratory tract, but not to the skin. However, being a fat solvent, 1,4-dioxane can cause eczema upon prolonged or repeated contact.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

study was conducted before OECD 404 TG was established

Principles of method if other than guideline:

BASF Test
Before OECD Guideline 404 was established in 1982, skin irritation was tested using an internal method (BASF test). Two white Vienna rabbits were treated for 1, 5 and 15 minutes and for 20 hours using occlusive conditions.

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Weight at study initiation: male 3.11 kg; female 3.18 kg


ENVIRONMENTAL CONDITIONS
no data

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: approx. 1 mL

Duration of treatment / exposure:

1, 5, 15 min and 20 h

Observation period:

8 days

Number of animals:

2

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- Type of wrap if used: patch, no further data


REMOVAL OF TEST SUBSTANCE
- Washing: yes (exposure 1, 5, 15 min) first with undiluted Lutrol 9, then with an aqueous Lutrol solution (50 %); no (exposure 20 h)
- Time after start of exposure: 1, 5, and 15 min, respectively


SCORING SYSTEM:
The original BASF grading was converted into the numerical grading according to the OECD Draize system.

Irritation parameter:

erythema score

Remarks:

Exposure time: 15 min

Basis:

mean

Remarks:

(2 animals)

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: desquamation, parchment-like necrosis

Irritation parameter:

edema score

Remarks:

Exposure time: 15 min

Basis:

mean

Remarks:

(2 animals)

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effects

Irritation parameter:

erythema score

Remarks:

Exposure time: 20 h

Basis:

mean

Remarks:

(2 animals)

Time point:

24/48/72 h

Score:

1.34

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: desquamation, parchment-like necrosis

Irritation parameter:

edema score

Remarks:

Exposure time: 20 h

Basis:

mean

Remarks:

(2 animals)

Time point:

24/48/72 h

Score:

0.84

Max. score:

4

Reversibility:

fully reversible within: 8 days

Table 1 Mean erythema score after 24, 48 and 72 h (2 animals)

Exposure time	24 h	48 h	72 h	mean
1 min	1/1	0/1	0/1	0.33/1
5 min	0/1	0/1	0/1	0/1
15 min	0/2*	0/2**	0/2**	0/2
20 h	1/2*	0/2*	1/2	0.67/2

* brownish

** parchment-like

*** leather-like necrosis

 

Table 2 Mean edema score after 24, 48 and 72 h (2 animals)

Exposure time	24 h	48 h	72 h	mean
1 min	0/0	0/0	0/0	0/0
5 min	0/0	0/0	0/0	0/0
15 min	0/0	0/0	0/0	0/0
20 h	0/2	0/3	0/0	0/1.67

 

 

Table 3 Findings after 8 days (2 animals)

Exposure time	Skin finding
1 min	no skin findings*/desquamation
5 min	no skin findings*/desquamation
15 min	no skin findings*/desquamation, parchment-like necrosis fallen off
20 h	no skin findings*/desquamation, parchment-like necrosis

*transient desquamation observed 6 days after application

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1973

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Application volume 50 µL, 2 animals, 8 days observation period

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Gaukler, Offenbach, Germany
- Weight at study initiation: 2.99 kg (male); 3.21 kg (male)

ENVIRONMENTAL CONDITIONS
no data

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 50 µL

Duration of treatment / exposure:

eye remaind unwashed after application

Observation period (in vivo):

8 days

Number of animals or in vitro replicates:

2

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: no washing

SCORING SYSTEM:
Discriptive scoring system comparable to draize

TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.67

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.3

Max. score:

3

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal: #1 & #2

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Irritant / corrosive response data:

Mucous deposits on the eye were observed the 1st day after application.

Descriptive scores of the raw data have been converted to Draize numerical scores.

Animal 1 (male):  day 1: 2.99 kg; day 8: 3.11 kg

Animal 2 (male): day 1: 3.21 kg; day 8: 3.19 kg

Animal	Reading	Opacity	Redness	Chemosis	Comment
1	1 h	1	1	2	mucous deposits
2	1 h	1	1	1	mucous deposits
1	24 h	1	1	2	mucous deposits
2	24 h	1	1	1	mucous deposits
1	48 h	2	2	1	blood and scar (scraching)
2	48 h	1	1	0	blood (scraching)
1	72 h	1	1	1	blood and scar (scraching)
2	72 h	0	0	0
1	8 d	0	1	0
2	8 d	0	0	0
mean	24 - 72 h	1	1	0.8

 

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Very limited human data regarding skin irritation is available. Regarding animal data, the BASF study (1973) was the only study considered acceptable for assessment. The study showed some indication of an irritant property to the intact skin. However, the findings were not considered sufficient to classify the substance for skin irritation. In an epicutaneous study in rabbits (1 male and 1 female) a cotton patch sized 2.5x2.5 cm was soaked with undiluted 1,4 -dioxane (approximately 0.5 mL) and applied to the shaven back ( for 1, 5 and 15 minutes as well as for 20 hours) under occlusive conditions. Application to the skin during 1 -15 minutes caused very slight erythema after 24 hours and slight scale formation after 8 days. This scale formation is most likely caused by the defatting properties of 1,4 -dioxane. 24 hours after the 20 -hour application, slight erythema and slight edema were observed on the back of 1 animal. Seven days later moderate scale formation was seen. The results do not trigger classification for skin irritation (BASF AG, 1973).

 

Regarding eye irritation, an animal study is available (BASF AG, 1973). Two male White Vienna rabbits received an instillation of 0.05 mL undiluted 1,4 -dioxane (eye remained unwashed after application). 24 hours after instillation, slight corneal opacity and conjunctival redness as well as slight to severe chemosis were observed in both rabbits. Additionally, smeary deposition was noted. 8 Days after application, when the study was terminated, slight conjunctival redness was observed in one animal. This finding was expected to would have reversed if the observation period had been prolonged. This animal showed small retraction of the eyelid. Because the chosen dose level is very low in comparison to the current guidelines and only 2 animals were used, 1,4 -dioxane is considered as an eye irritant (BASF AG, 1973).

Human data also indicated that 1,4 -dioxane can cause eye irritation.

Young et al. (1977) reported irritation of the eyes at 50 ppm (180 mg/m³) in 4 healthy volunteers during an inhalation study regarding toxicokinetics (exposure over 6 hours, see section 5.1.2). Eye irritation was a frequent complaint throughout exposure.

Furthermore, in a study by Silverman et al. (1946), twelve subjects were exposed to 1,4 -dioxane for 15 minutes. A concentration of 720 mg/m³ showed to be the highest concentration acceptable. At 1080 mg/m³ irritation of eyes was reported.

Available human and animal acute data regarding the inhalation route of exposure show that 1,4-dioxane can cause respiratory tract irritation. For DNEL derivation human data is used: twelve subjects were exposed to 1,4-dioxane for 15 minutes to observe olfactory fatigue. A concentration of 720 mg/m³ showed to be the highest concentration acceptable. At 1,080 mg/m³ irritation of the nose and throat was reported (Silverman et al., 1946).

 

In addition, 1,4-dioxane is a fat solvent and prolonged and repeated contact can cause eczema.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on all data available (including human experience) it can be concluded that 1,4-dioxane is irritating to the eye, but not to the skin. Therefore, the test item is classified as Eye irritation Cat.2 (H319:"Causes serious eye irritation") according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) 2019/521.

 

Based on practical observations in humans it is concluded that 1,4 -dioxane is irritating to the respiratory system. Therefore, the test item is classified as STOT SE 3 (H335: "May cause respiratory irritation") according to Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation).

 

In addition, being a fat solvent, 1,4-dioxane can cause eczema upon prolonged or repeated contact. However, this property is not covered by the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 and should be indicated as supplemental hazard information as listed in Annex II to the CLP Regulation. In this case Section 1.2.4. EUH066.

The above classifications are also in accordance with harmonised classification of the registered substance according to Annex VI of the CLP Regulation.