2-ethylhexyl nitrate

Endpoint summary

Description of key information

No repeat dose toxicity studies conducted via the oral route are currently available for 2 -EHN. However, it is worth nothing that in an OECD 421 Reproduction / Developmental Toxicity Screening Test, 2 -EHN was administered daily by oral gavage to male and female Sprague-Dawley rats at doses of 20, 100 or 500 mg/kg/day and the NOAEL for parental toxicity was considered to be 20 mg/kg/day (see the section on Toxicity to reproduction for further details).

In the key study for inhalation exposure using the read-across substance 2 -ethylhexan-1ol, no substance related adverse effects of the test item were observed at the highest vapour concentration achievable. A NOAEL of 863 mg/m³ air was derived for 2 -EHN, based on equimolar conversions and 2 -EHN is considered to be non-toxic at saturated vapour concentrations. However, this strategy of reading across from 2 -ethylhexan-1 -ol has been rejected (Decision TPE-D-0000002102 -92 -05/F). A sub-chronic repeated dose toxicity study (90 -day with 28 -day recovery period; according to OECD Test Guideline 413) with exposure to 2 -EHN via the inhalation route in rats is currently in progress, according to Decision TPE-D-0000002102 -92 -05/F. The dossier will be updated with the study results once these become available. In the 14-day dose range finding study that was completed prior to the 90-day study, a NOAEC of 1.071 mg/l air was identified.

In a 3 -week study, 2 -EHN was applied dermally under semi-occlusion to rabbit skin for 5 days/week. The systemic NOAEL was 500 mg/kg/day based on the lack of systemic effects at any dose. A NOAEC of 0.22 mg/cm² was derived for local effects based on skin cracking, erythema and edema (derivation detailed under the Irritation section).

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study performed with the rapidly formed hydrolysis product of the target chemical following internationally validated test guidelines and GLP requirements, reported in sufficient detail; publication meets generally accepted standards

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Version / remarks:

1981

Deviations:

no

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: supplied by Dr. K. Thomae GmbH, D-88400 Biberach/Riss, Germany
- Age at study initiation: About 7 weeks old on delivery
- Weight at study initiation: Mean body weight males ca. 238 g (standard error of the mean max. ± 2.3 g), females 170 g (standard error of the mean max.± max. 2.2 g)
- Housing: The test animals were individually kept in wire cages placed in the inhalation chambers
- Diet: KLIBA rat/mouse laboratory diet 24-343-4 (Klingentalmühle, AG, CH-4303 Kaiseraugst, Switzerland) ad libitum in the exposure-free periods
- Water: Ad libitum in the exposure-free periods
- Acclimation period: 5 days before exposure

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: Day 1 To: Day 93

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Remarks:

inhalation chamber

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Horizontal-flow whole-body exposure system, chamber volume ca. 1.1 m³ (manufactured using glass & steel by BASF AG, Ludwigshafen, Germany)
- Method of holding animals in test chamber: Individually in wire cages
- Source: Ambient air for 15 ppm exposure, compressed air for 40 and 120 ppm concentrations, exchange rate not stated
- Method of conditioning air: Warmed air of the control group (45.7 °C) and the vapour/air mixture of the treatments were mixed with the overall stream generated by underpressure
- Temperature, humidity, pressure in air chamber: 21.3 to 23.8 °C (measured continuously), 41.8 to 46.2 % (recorded once daily), overpressure 10.1 Pa in the treatments and -10.2 underpressure in the controls

TEST ATMOSPHERE
- Brief description of analytical method used: GC-FID
- Samples taken from breathing zone: Yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of the inhalation atmospheres were analysed at intervals of about 15 min by gas chromatography (Hewlett Packard gas chromatograph Model HP 5880 A with automatic sampler HP 7671 A, FID, column: 1m ∙ 2 mm with 10 % Triton x 305 on Supelcoport, 102/120 mesh, oven temperature: 120°C. C15-parafin used as the internal standard).

Duration of treatment / exposure:

90 days (sacrifice on Day 94)

Frequency of treatment:

6 h per day, 5 days per week (65 exposures)

Remarks:

Doses / Concentrations:
0, 15, 40 and 120 ppm
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
0, 15.0±0.6, 39.9±1.33 and 120±4.8 [ppm±SD]
Basis:
analytical conc.

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The highest test concentration of 120 ppm corresponds to the calculated saturated vapour concentration at 20 °C. Higher concentrations obtainable as aerosols were considered irrelevent for occupational exposure. The remaining concentrations were included to potentially establish a concentration-effect function.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, clinical signs and findings were recorded
- Time schedule: During exposure and daily at exposure free times

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Before start and after end of exposure

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were determined weekly from test start to end, additionally at the beginning of the pre-flow period (i.e. 5 days before test start) and 1 day before start of exposure

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to beginning of the preflow-period and after termination
- Dose groups that were examined: All treatments.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was taken from all animals at the end of the 3–month exposure period, Day 94
- Parameters examined: White blood cells, red blood cells, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets, differential blood count and clotting time


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood was taken from all animals at the end of the 3–month exposure period. Day 94
- Animals fasted: No
- Parameters examined: sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and cyanide-insensitive palmitoyl-CoA oxidation, a marker for peroxisome proliferation

Sacrifice and pathology:

Sacrifice at Day 94
GROSS PATHOLOGY: complete necropsy of all animals including weighing of certain organs, including lungs, liver, kidneys, adrenal glands and testes and a gross–pathologic evaluation was performed.
HISTOPATHOLOGY: selected organs/tissues were examined histologically based on OECD testing guideline

Statistics:

Mean values and standard deviation calculated for body weight, body weight change, haematological and clinical biochemistry parameters, absolute and relative organ weights.
Organ weights: Dunnett's test for comparison of treatments with control.
Analysis of variance with subsequent Dunnett's test to compare body weight, body weight change and haematological & clinical biochemistry of treatments with control

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weight gain of female animals of 40 and 120 ppm decreased compared to controls on day 37. Males of the 15 ppm group had a statistically higher increase in bodyweight on day 93 compared to controls. Differences are not treatment related (table 1.)

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Description (incidence and severity):

Differences observed were: (1) 120 ppm group, males: bilirubin = 4.07 mmol/L (controls 2.99 mmol/L); (2) 15 ppm group females: glucose = 6.98 mmol/L (controls 7.81 mmol/L)

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEC

Remarks:

Discriminating level = highest test concentration, 90 days, 6 h per day on 5 days per week, 65 exposures

Effect level:

>= 120 ppm (analytical)

Based on:

test mat.

Remarks:

2-Ethylhexan-1-ol, measured concentration, SD ±4.8 ppm

Sex:

male/female

Basis for effect level:

other: Absence of toxicity at highest achievable vapour concentration with the experimental setting applied (vapour saturation at 20°C),

Dose descriptor:

NOAEC

Remarks:

Discriminating level

Effect level:

>= 639 mg/m³ air

Based on:

test mat.

Remarks:

2-Ethylhexan-1-ol

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEC

Remarks:

Discriminating level

Effect level:

>= 863 mg/m³ air

Based on:

other: conversion to target chemical 2-Ethylhexyl Nitrate, equimolar

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEC

Remarks:

Discriminating level

Effect level:

>= 5 other: mmol/m³ air

Based on:

other: molar concentration of source and target chemical

Sex:

male/female

Basis for effect level:

other: no toxicity at highest achievable vapor

Dose descriptor:

NOAEL

Remarks:

Discriminating dose

Effect level:

>= 125 other: mg/kg bw/day (inhalation-to-oral extrapolation)

Based on:

other: conversion to target chemical 2-Ethylhexyl Nitrate, equimolar

Sex:

male/female

Basis for effect level:

other: With respiratory rate (6 h, rat) 0.29 m³/kg bw (ECHA Guidance Table R. 8-2, 2012), the corresponding dose-level is 863∙0.29∙50 %/100 %=125 mg/kg/day and considering 50 % inhalation and 100 % oral absorption.

Dose descriptor:

NOAEL

Remarks:

Discriminating level

Effect level:

>= 0.71 other: mmol/kg bw/day (inhalation-to-oral extrapolation)

Based on:

other: molar concentration of source and target chemical

Sex:

male/female

Basis for effect level:

other: no toxicity at highest achievable vapor

Critical effects observed:

not specified

Table 1: Body weight measurements

Weighing time point:		Day 1	Day 9	Day 23	Day 37	Day 51	Day 65	Day 79	Day 93
Males/group
0 ppm	m	282.6	326.3	375.2	413.9	443.3	470.1	487.0	501.6
	sd	10.0	19.9	22.0	25.0	25.8	25.9	26.2	29.1
15 ppm	m	287.2	338.7	383.0	426.2	461.8	487.8	512.4	535.5*
	sd	11.6	11.9	13.8	19.1	18.9	20.6	27.5	32.5
40 ppm	m	286.4	333.7	375.6	421.2	452.1	479.1	499.4	520.0
	sd	8.3	14.8	20.3	24.6	33.3	34.5	40.8	37.7
120 ppm	m	285.5	327.3	372.1	409.2	438.9	463.6	483.3	497.0
	sd	7.3	11.0	13.2	15.3	17.6	18.4	21.4	19.4
Females/group
0 ppm	m	192.2	211.8	225.9	248.0	258.6	266.6	274.3	281.3
	sd	9.3	8.4	15.1	14.1	19.0	17.1	22.0	19.1
15 ppm	m	193.9	206.5	224.2	241.5	257.1	264.2	271.2	275.4
	sd	10.1	18.3	16.0	19.4	16.4	20.0	18.2	19.1
40 ppm	m	196.3	212.1	228.6	237.3	257.5	261.1	272.4	275.3
	sd	3.7	6.9	12.3	11.7	14.1	16.1	15.3	15.4
120 ppm	m	195.3	209.7	224.6	234.7	252.8	257.6	265.0	271.5
	sd	4.6	5.7	7.1	7.3	8.8	11.0	11.9	12.1

Statistically significant: *P < 0.05

m = mean value

sd = standard deviation

Conclusions:

No substance-related adverse effects of the test item and source substance observed at the highest vapour concentration achievable, thus NOAEL ≥ 120 ppm (discriminating dose) for male and female rats; considering the significantly lower vapour pressure of the target chemical (27 versus 93 Pa at 20 °C) an equimolar exposure exceeding saturated vapour concentrations of the target chemical 2-Ethylhexyl Nitrate is concluded to be non-toxic.

Executive summary:

The subchronic repeated dose toxicity of the test item and source substance 2-Ethylhexan-1-ol (CAS 104-76-7) via the inhalation route in the rat was measured in a GLP-compliant study using the “Subchronic Inhalation Toxicity: 90-day Study” protocol compliant with OECD TG 413 (1981). The validity criteria were met and the experiment can be considered relevant and adequate for the endpoint. Therefore it is deemed conclusive and was rated „reliable without restrictions“, i.e. “Klimisch 1” according to the scale of Klimisch et al. (1997). The rating of the study for use in an analogue approach is lower compared to equally rated studies on the target substance.

Ten male and female Wistar rats were individually held in inhalation chambers for 90 days (6 hours perday, 5 days a week) and exposed to vapours of the test item via whole body exposure. While the treated chambers were maintained under ca. 10 Pa underpressure to ensure in flow of the prepared air/vapour mixtures, the control chambers had constant overpressure of 10 Pa from a clean air supply to prevent cross contamination. The exposure level were nominal 0, 15, 40 and 120 ppm and analytically determined employing GC-FID to 0, 15.0±0.6, 39.9±1.33 and 120±4.8 [ppm ± SD], which shows good agreement. The highest achievable test concentration of 120 ppm corresponds to the calculated saturated vapour concentration at 20 °C. Higher concentrations obtainable as aerosols were refused because of their considered irrelevance for occupational areas. The examinations performed included cage side and detailed clinical observations, body weights, ophthalmoscopic examination, haematology clinical chemistry, gross pathology and histology.

None of the followed parameters showed any treatment related change in either sex compared with the controls. Differences to the control group were observed in body weight gain and clinical chemistry. In the 40 and 120 ppm treatments the body weight gain of female test animals was decreased compared to the control on Day 37 only. The male rats in the 15 ppm treatment group showed statistically significantly higher increase in body weight on day 93 compared to control. Furthermore 120 ppm group male rats showed bilirubin f 4.07 mmol/L (controls 2.99 mmol/L) and female rats in the 15 ppm group had a glucose level of 6.98 mmol/L (controls 7.81 mmol/L). It was concluded that these differences were not of toxicological significance and were not treatment related.

In conclusion no substance-related adverse effects of the test item were observed at the highest vapour concentration achievable, which is thus considered ≥ NOAEL (discriminating dose) for male and female rats. This level corresponds to 639 mg test item/m³ air or 5 mmol/m³ as a basis for equimolar comparison in read-across approaches.

Reading-across to the target substance 2-Ethylhexyl nitrate (2 -EHN, CAS 27247-96-7) delivers on the same molar concentration an air level of 863 mg/m³ air. Taking the significantly lower vapour pressure of the target chemical (only 27 versus 93 Pa of 2 -EH at 20 °C) into account, an equimolar exposure exceeding saturated vapour concentrations of the target chemical can be concluded to be non-toxic.

• Klimisch HJ, Andreae M, Tillmann U (1997). A Systematic Approach for Evaluating the Quality of Experimental Toxicological and Ecotoxicological Data. DOI 10.1006/rtph.1996.1076 PMID 9056496 Regul Toxicol Pharmacol 25:1-5.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

Read-across substance, 2-ethyl-1-hexanol is the rapidly formed hydrolysis product of the target substance, 2-EHN.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEC

Effect level:

863 mg/m³ air

Based on:

other: conversion to target chemical 2-Ethylhexyl Nitrate, equimolar

Basis for effect level:

other: Absence of toxicity at highest achievable vapour concentration with the experimental setting applied

Critical effects observed:

no

Conclusions:

No substance-related adverse effects of the test item were observed at the highest vapour concentration achievable, which is thus considered ≥ NOAEL (discriminating dose) for male and female rats. This level corresponds to 639 mg test item/m³ air or 5 mmol/m³ as a basis for equimolar comparison in read-across approaches.

Reading-across to 2-Ethylhexyl nitrate (2 -EHN, CAS 27247-96-7) delivers on the same molar concentration an air level of 863 mg/m³ air. Taking the significantly lower vapour pressure of the target chemical (only 27 versus 93 Pa of 2 -EH at 20 °C) into account, an equimolar exposure exceeding saturated vapour concentrations of the target chemical can be concluded to be non-toxic.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

863 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Available studies meet accepted standards and are reported in sufficient detail, but are generally on read-across substances. The studies on read-across substances are considered to be Klimisch 2 and the one study on the target substance itself is Klimisch 4 due to only summaries being available.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study performed with the rapidly formed hydrolysis product of the target chemical following internationally validated test guidelines and GLP requirements, reported in sufficient detail; publication meets generally accepted standards

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Version / remarks:

1981

Deviations:

no

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: supplied by Dr. K. Thomae GmbH, D-88400 Biberach/Riss, Germany
- Age at study initiation: About 7 weeks old on delivery
- Weight at study initiation: Mean body weight males ca. 238 g (standard error of the mean max. ± 2.3 g), females 170 g (standard error of the mean max.± max. 2.2 g)
- Housing: The test animals were individually kept in wire cages placed in the inhalation chambers
- Diet: KLIBA rat/mouse laboratory diet 24-343-4 (Klingentalmühle, AG, CH-4303 Kaiseraugst, Switzerland) ad libitum in the exposure-free periods
- Water: Ad libitum in the exposure-free periods
- Acclimation period: 5 days before exposure

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: Day 1 To: Day 93

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Remarks:

inhalation chamber

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Horizontal-flow whole-body exposure system, chamber volume ca. 1.1 m³ (manufactured using glass & steel by BASF AG, Ludwigshafen, Germany)
- Method of holding animals in test chamber: Individually in wire cages
- Source: Ambient air for 15 ppm exposure, compressed air for 40 and 120 ppm concentrations, exchange rate not stated
- Method of conditioning air: Warmed air of the control group (45.7 °C) and the vapour/air mixture of the treatments were mixed with the overall stream generated by underpressure
- Temperature, humidity, pressure in air chamber: 21.3 to 23.8 °C (measured continuously), 41.8 to 46.2 % (recorded once daily), overpressure 10.1 Pa in the treatments and -10.2 underpressure in the controls

TEST ATMOSPHERE
- Brief description of analytical method used: GC-FID
- Samples taken from breathing zone: Yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of the inhalation atmospheres were analysed at intervals of about 15 min by gas chromatography (Hewlett Packard gas chromatograph Model HP 5880 A with automatic sampler HP 7671 A, FID, column: 1m ∙ 2 mm with 10 % Triton x 305 on Supelcoport, 102/120 mesh, oven temperature: 120°C. C15-parafin used as the internal standard).

Duration of treatment / exposure:

90 days (sacrifice on Day 94)

Frequency of treatment:

6 h per day, 5 days per week (65 exposures)

Remarks:

Doses / Concentrations:
0, 15, 40 and 120 ppm
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
0, 15.0±0.6, 39.9±1.33 and 120±4.8 [ppm±SD]
Basis:
analytical conc.

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The highest test concentration of 120 ppm corresponds to the calculated saturated vapour concentration at 20 °C. Higher concentrations obtainable as aerosols were considered irrelevent for occupational exposure. The remaining concentrations were included to potentially establish a concentration-effect function.

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes, clinical signs and findings were recorded
- Time schedule: During exposure and daily at exposure free times

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Before start and after end of exposure

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were determined weekly from test start to end, additionally at the beginning of the pre-flow period (i.e. 5 days before test start) and 1 day before start of exposure

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to beginning of the preflow-period and after termination
- Dose groups that were examined: All treatments.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was taken from all animals at the end of the 3–month exposure period, Day 94
- Parameters examined: White blood cells, red blood cells, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets, differential blood count and clotting time


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood was taken from all animals at the end of the 3–month exposure period. Day 94
- Animals fasted: No
- Parameters examined: sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and cyanide-insensitive palmitoyl-CoA oxidation, a marker for peroxisome proliferation

Sacrifice and pathology:

Sacrifice at Day 94
GROSS PATHOLOGY: complete necropsy of all animals including weighing of certain organs, including lungs, liver, kidneys, adrenal glands and testes and a gross–pathologic evaluation was performed.
HISTOPATHOLOGY: selected organs/tissues were examined histologically based on OECD testing guideline

Statistics:

Mean values and standard deviation calculated for body weight, body weight change, haematological and clinical biochemistry parameters, absolute and relative organ weights.
Organ weights: Dunnett's test for comparison of treatments with control.
Analysis of variance with subsequent Dunnett's test to compare body weight, body weight change and haematological & clinical biochemistry of treatments with control

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weight gain of female animals of 40 and 120 ppm decreased compared to controls on day 37. Males of the 15 ppm group had a statistically higher increase in bodyweight on day 93 compared to controls. Differences are not treatment related (table 1.)

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Description (incidence and severity):

Differences observed were: (1) 120 ppm group, males: bilirubin = 4.07 mmol/L (controls 2.99 mmol/L); (2) 15 ppm group females: glucose = 6.98 mmol/L (controls 7.81 mmol/L)

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEC

Remarks:

Discriminating level = highest test concentration, 90 days, 6 h per day on 5 days per week, 65 exposures

Effect level:

>= 120 ppm (analytical)

Based on:

test mat.

Remarks:

2-Ethylhexan-1-ol, measured concentration, SD ±4.8 ppm

Sex:

male/female

Basis for effect level:

other: Absence of toxicity at highest achievable vapour concentration with the experimental setting applied (vapour saturation at 20°C),

Dose descriptor:

NOAEC

Remarks:

Discriminating level

Effect level:

>= 639 mg/m³ air

Based on:

test mat.

Remarks:

2-Ethylhexan-1-ol

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEC

Remarks:

Discriminating level

Effect level:

>= 863 mg/m³ air

Based on:

other: conversion to target chemical 2-Ethylhexyl Nitrate, equimolar

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Dose descriptor:

NOAEC

Remarks:

Discriminating level

Effect level:

>= 5 other: mmol/m³ air

Based on:

other: molar concentration of source and target chemical

Sex:

male/female

Basis for effect level:

other: no toxicity at highest achievable vapor

Dose descriptor:

NOAEL

Remarks:

Discriminating dose

Effect level:

>= 125 other: mg/kg bw/day (inhalation-to-oral extrapolation)

Based on:

other: conversion to target chemical 2-Ethylhexyl Nitrate, equimolar

Sex:

male/female

Basis for effect level:

other: With respiratory rate (6 h, rat) 0.29 m³/kg bw (ECHA Guidance Table R. 8-2, 2012), the corresponding dose-level is 863∙0.29∙50 %/100 %=125 mg/kg/day and considering 50 % inhalation and 100 % oral absorption.

Dose descriptor:

NOAEL

Remarks:

Discriminating level

Effect level:

>= 0.71 other: mmol/kg bw/day (inhalation-to-oral extrapolation)

Based on:

other: molar concentration of source and target chemical

Sex:

male/female

Basis for effect level:

other: no toxicity at highest achievable vapor

Critical effects observed:

not specified

Table 1: Body weight measurements

Weighing time point:		Day 1	Day 9	Day 23	Day 37	Day 51	Day 65	Day 79	Day 93
Males/group
0 ppm	m	282.6	326.3	375.2	413.9	443.3	470.1	487.0	501.6
	sd	10.0	19.9	22.0	25.0	25.8	25.9	26.2	29.1
15 ppm	m	287.2	338.7	383.0	426.2	461.8	487.8	512.4	535.5*
	sd	11.6	11.9	13.8	19.1	18.9	20.6	27.5	32.5
40 ppm	m	286.4	333.7	375.6	421.2	452.1	479.1	499.4	520.0
	sd	8.3	14.8	20.3	24.6	33.3	34.5	40.8	37.7
120 ppm	m	285.5	327.3	372.1	409.2	438.9	463.6	483.3	497.0
	sd	7.3	11.0	13.2	15.3	17.6	18.4	21.4	19.4
Females/group
0 ppm	m	192.2	211.8	225.9	248.0	258.6	266.6	274.3	281.3
	sd	9.3	8.4	15.1	14.1	19.0	17.1	22.0	19.1
15 ppm	m	193.9	206.5	224.2	241.5	257.1	264.2	271.2	275.4
	sd	10.1	18.3	16.0	19.4	16.4	20.0	18.2	19.1
40 ppm	m	196.3	212.1	228.6	237.3	257.5	261.1	272.4	275.3
	sd	3.7	6.9	12.3	11.7	14.1	16.1	15.3	15.4
120 ppm	m	195.3	209.7	224.6	234.7	252.8	257.6	265.0	271.5
	sd	4.6	5.7	7.1	7.3	8.8	11.0	11.9	12.1

Statistically significant: *P < 0.05

m = mean value

sd = standard deviation

Conclusions:

No substance-related adverse effects of the test item and source substance observed at the highest vapour concentration achievable, thus NOAEL ≥ 120 ppm (discriminating dose) for male and female rats; considering the significantly lower vapour pressure of the target chemical (27 versus 93 Pa at 20 °C) an equimolar exposure exceeding saturated vapour concentrations of the target chemical 2-Ethylhexyl Nitrate is concluded to be non-toxic.

Executive summary:

The subchronic repeated dose toxicity of the test item and source substance 2-Ethylhexan-1-ol (CAS 104-76-7) via the inhalation route in the rat was measured in a GLP-compliant study using the “Subchronic Inhalation Toxicity: 90-day Study” protocol compliant with OECD TG 413 (1981). The validity criteria were met and the experiment can be considered relevant and adequate for the endpoint. Therefore it is deemed conclusive and was rated „reliable without restrictions“, i.e. “Klimisch 1” according to the scale of Klimisch et al. (1997). The rating of the study for use in an analogue approach is lower compared to equally rated studies on the target substance.

Ten male and female Wistar rats were individually held in inhalation chambers for 90 days (6 hours perday, 5 days a week) and exposed to vapours of the test item via whole body exposure. While the treated chambers were maintained under ca. 10 Pa underpressure to ensure in flow of the prepared air/vapour mixtures, the control chambers had constant overpressure of 10 Pa from a clean air supply to prevent cross contamination. The exposure level were nominal 0, 15, 40 and 120 ppm and analytically determined employing GC-FID to 0, 15.0±0.6, 39.9±1.33 and 120±4.8 [ppm ± SD], which shows good agreement. The highest achievable test concentration of 120 ppm corresponds to the calculated saturated vapour concentration at 20 °C. Higher concentrations obtainable as aerosols were refused because of their considered irrelevance for occupational areas. The examinations performed included cage side and detailed clinical observations, body weights, ophthalmoscopic examination, haematology clinical chemistry, gross pathology and histology.

None of the followed parameters showed any treatment related change in either sex compared with the controls. Differences to the control group were observed in body weight gain and clinical chemistry. In the 40 and 120 ppm treatments the body weight gain of female test animals was decreased compared to the control on Day 37 only. The male rats in the 15 ppm treatment group showed statistically significantly higher increase in body weight on day 93 compared to control. Furthermore 120 ppm group male rats showed bilirubin f 4.07 mmol/L (controls 2.99 mmol/L) and female rats in the 15 ppm group had a glucose level of 6.98 mmol/L (controls 7.81 mmol/L). It was concluded that these differences were not of toxicological significance and were not treatment related.

In conclusion no substance-related adverse effects of the test item were observed at the highest vapour concentration achievable, which is thus considered ≥ NOAEL (discriminating dose) for male and female rats. This level corresponds to 639 mg test item/m³ air or 5 mmol/m³ as a basis for equimolar comparison in read-across approaches.

Reading-across to the target substance 2-Ethylhexyl nitrate (2 -EHN, CAS 27247-96-7) delivers on the same molar concentration an air level of 863 mg/m³ air. Taking the significantly lower vapour pressure of the target chemical (only 27 versus 93 Pa of 2 -EH at 20 °C) into account, an equimolar exposure exceeding saturated vapour concentrations of the target chemical can be concluded to be non-toxic.

• Klimisch HJ, Andreae M, Tillmann U (1997). A Systematic Approach for Evaluating the Quality of Experimental Toxicological and Ecotoxicological Data. DOI 10.1006/rtph.1996.1076 PMID 9056496 Regul Toxicol Pharmacol 25:1-5.

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

Read-across substance, 2-ethyl-1-hexanol is the rapidly formed hydrolysis product of the target substance, 2-EHN.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEC

Effect level:

863 mg/m³ air

Based on:

other: conversion to target chemical 2-Ethylhexyl Nitrate, equimolar

Basis for effect level:

other: Absence of toxicity at highest achievable vapour concentration with the experimental setting applied

Critical effects observed:

no

Conclusions:

No substance-related adverse effects of the test item were observed at the highest vapour concentration achievable, which is thus considered ≥ NOAEL (discriminating dose) for male and female rats. This level corresponds to 639 mg test item/m³ air or 5 mmol/m³ as a basis for equimolar comparison in read-across approaches.

Reading-across to 2-Ethylhexyl nitrate (2 -EHN, CAS 27247-96-7) delivers on the same molar concentration an air level of 863 mg/m³ air. Taking the significantly lower vapour pressure of the target chemical (only 27 versus 93 Pa of 2 -EH at 20 °C) into account, an equimolar exposure exceeding saturated vapour concentrations of the target chemical can be concluded to be non-toxic.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

863 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Available studies meet accepted standards and are reported in sufficient detail, but are generally on read-across substances. The studies on read-across substances are considered to be Klimisch 2 and the one study on the target substance itself is Klimisch 4 due to only summaries being available.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06 October 1980 - 06 April 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Non-GLP, no reporting/interpretation of results, missing data (clinical signs, histopathology findings reported with extremely low detail). Suspected pneumonitis and parasitic infestation of some animals. However the raw data given enable to set local and systemic NOAELs (set by RSS/CSR author) for risk assessment of dermal exposures.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)

Version / remarks:

mentioned as Federal Register, 43 n° 163

Principles of method if other than guideline:

following deviations to OECD 410: only 2 doses (+ control), only 3 rabbits/dose/sex with intact skin, no reporting of conclusions, no data on clinical signs, ornithine decarboxylase not measured, clotting potential only reported semi-quantitatively, insufficient top-dose (below 1000 mg/kg/day and did not cause toxic effects)

GLP compliance:

no

Limit test:

no

Species:

rabbit

Strain:

other: Albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Breeder: H.A.R.E. Rabbits for Research, P.O. Box "X", Hewitt, New Jersey 07421
- Age at study initiation: approximately 10 weeks
- Weight at study initiation: 2.0 - 2.6 kg
- Housing: the rabbits were housed individually or two to a cage in galvanized steel cages with suspended grid flooring
- Diet (e.g. ad libitum): Charles River Rabbit Chow
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 7 days.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: dorsal trunk, clipped and shaved
- % coverage: 10% of body surface
- Type of wrap if used: gauze patch + surgical hypoallergenic adhesive tape + impervious Saran wrap + elastic bandage
- Time intervals for shavings or clippings: "as necessary" (no details)
NB: skin abrasion was carried out on some animals, animals excluded for this RSS, but showing similar results

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with corn oil
- Time after start of exposure: 6h each day

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 and 500 mg/kg/day, no other detail, see calculations at end of RSS by RSS/CSR author

VEHICLE
- none

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, collar during non-exposure times

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

21 days

Frequency of treatment:

Application of the test material on five days per week for three consecutive weeks. 15 treatments.

Remarks:

Doses / Concentrations:
50 mg/kg/day
Basis:
nominal per unit body weight

Remarks:

Doses / Concentrations:
500 mg/kg/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

6 animals per sex and per dose. 3 with intact skin, 3 with abraded skin.

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale:
The dose-levels were selected so that the highest dose-level would show toxicological or pharmacological effects but would not cause more than 10 percent fatalities.

- Rationale for animal assignment (if not random): random

Positive control:

Not applicable.

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes (cage side or detailed: not indicated)
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily according to Draize scale, one hour after end of treatment

BODY WEIGHT: Yes
- Time schedule for examinations: at the beginning of the test and every 3 to 4 days thereafter.

FOOD CONSUMPTION: yes
- Food consumption for each animal determined : Yes
- Time schedule for examinations: at the beginning of the test and every 3 to 4 days thereafter.

FOOD EFFICIENCY: not calculated

WATER CONSUMPTION, OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY, CLINICAL CHEMISTRY: Yes
- Time schedule: at the beginning of the study (before initiation of testing) and at the end of 21-day test period on each animal in the study

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (as required by OECD 410)

ORGANS WEIGHED: Yes (all those required by OECD 410 + many others)

HISTOPATHOLOGY: Yes (all those required by OECD 410 + many others)

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

skin only

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not examined

Details on results:

No data on clinical signs, only mortality reported. Two deaths occured which were likely not related to the test item (one was due to pneumonitis).

Intercurrent diseases : pneumonia (suspicion of Pasteurella) and liver parasitism (suspicion of coccidiosis), non test-item related

Only dermal effects were noted:
- IN-LIFE : see summary details under section 7.3.1; dose and time-related, delayed erythema and edema in all animals (abraded or not), with occasional skin craking; at both dose-levels
- GROSS NECROPSY: skin changes were minimal to slight and infrequent (occasional erythema, thickening/epithelial hyperplasia/roughening, crusts, dermal inflammation, or hyalinized scar in dermis)
- HISTOPATHOLOGY: not assessable from the poorly detailed data reported (no raw data)

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No relevant systemic effect in the study

Dose descriptor:

conc. level: NOAEC local

Effect level:

0.22 mg/cm² per day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on skin cracking, erythema and edema. Derivation detailed under section "Irritation" of IUCLID.

Critical effects observed:

not specified

Executive summary:

For 2EHN applied dermally under semi-occlusion to rabbit skin, 5 days/week for 3 weeks, the systemic NOAEL appeared to be 500 mg/kg/day (highest tested dose; in absence of data of clinical signs, and in view of very limited histopathology data, this is a screening value) and the local NOAEC was derived as 0.22 mg/cm2/day due to erythema, edema and skin cracking appearing in a delayed manner along repeated exposures. NOAEC derivation by RSS/CSR author is explained under section 7.3.1 and in CSR.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

Only one sub-acute dermal study is available, and it has been assigned a reliability rating of 2 but has a number of limitations.

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

06 October 1980 - 06 April 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Non-GLP, no reporting/interpretation of results, missing data (clinical signs, histopathology findings reported with extremely low detail). Suspected pneumonitis and parasitic infestation of some animals. However the raw data given enable to set local and systemic NOAELs (set by RSS/CSR author) for risk assessment of dermal exposures.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)

Version / remarks:

mentioned as Federal Register, 43 n° 163

Principles of method if other than guideline:

following deviations to OECD 410: only 2 doses (+ control), only 3 rabbits/dose/sex with intact skin, no reporting of conclusions, no data on clinical signs, ornithine decarboxylase not measured, clotting potential only reported semi-quantitatively, insufficient top-dose (below 1000 mg/kg/day and did not cause toxic effects)

GLP compliance:

no

Limit test:

no

Species:

rabbit

Strain:

other: Albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Breeder: H.A.R.E. Rabbits for Research, P.O. Box "X", Hewitt, New Jersey 07421
- Age at study initiation: approximately 10 weeks
- Weight at study initiation: 2.0 - 2.6 kg
- Housing: the rabbits were housed individually or two to a cage in galvanized steel cages with suspended grid flooring
- Diet (e.g. ad libitum): Charles River Rabbit Chow
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 7 days.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: dorsal trunk, clipped and shaved
- % coverage: 10% of body surface
- Type of wrap if used: gauze patch + surgical hypoallergenic adhesive tape + impervious Saran wrap + elastic bandage
- Time intervals for shavings or clippings: "as necessary" (no details)
NB: skin abrasion was carried out on some animals, animals excluded for this RSS, but showing similar results

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with corn oil
- Time after start of exposure: 6h each day

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 and 500 mg/kg/day, no other detail, see calculations at end of RSS by RSS/CSR author

VEHICLE
- none

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, collar during non-exposure times

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

21 days

Frequency of treatment:

Application of the test material on five days per week for three consecutive weeks. 15 treatments.

Remarks:

Doses / Concentrations:
50 mg/kg/day
Basis:
nominal per unit body weight

Remarks:

Doses / Concentrations:
500 mg/kg/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

6 animals per sex and per dose. 3 with intact skin, 3 with abraded skin.

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale:
The dose-levels were selected so that the highest dose-level would show toxicological or pharmacological effects but would not cause more than 10 percent fatalities.

- Rationale for animal assignment (if not random): random

Positive control:

Not applicable.

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes (cage side or detailed: not indicated)
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily according to Draize scale, one hour after end of treatment

BODY WEIGHT: Yes
- Time schedule for examinations: at the beginning of the test and every 3 to 4 days thereafter.

FOOD CONSUMPTION: yes
- Food consumption for each animal determined : Yes
- Time schedule for examinations: at the beginning of the test and every 3 to 4 days thereafter.

FOOD EFFICIENCY: not calculated

WATER CONSUMPTION, OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY, CLINICAL CHEMISTRY: Yes
- Time schedule: at the beginning of the study (before initiation of testing) and at the end of 21-day test period on each animal in the study

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (as required by OECD 410)

ORGANS WEIGHED: Yes (all those required by OECD 410 + many others)

HISTOPATHOLOGY: Yes (all those required by OECD 410 + many others)

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

skin only

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not examined

Details on results:

No data on clinical signs, only mortality reported. Two deaths occured which were likely not related to the test item (one was due to pneumonitis).

Intercurrent diseases : pneumonia (suspicion of Pasteurella) and liver parasitism (suspicion of coccidiosis), non test-item related

Only dermal effects were noted:
- IN-LIFE : see summary details under section 7.3.1; dose and time-related, delayed erythema and edema in all animals (abraded or not), with occasional skin craking; at both dose-levels
- GROSS NECROPSY: skin changes were minimal to slight and infrequent (occasional erythema, thickening/epithelial hyperplasia/roughening, crusts, dermal inflammation, or hyalinized scar in dermis)
- HISTOPATHOLOGY: not assessable from the poorly detailed data reported (no raw data)

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No relevant systemic effect in the study

Dose descriptor:

conc. level: NOAEC local

Effect level:

0.22 mg/cm² per day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on skin cracking, erythema and edema. Derivation detailed under section "Irritation" of IUCLID.

Critical effects observed:

not specified

Executive summary:

For 2EHN applied dermally under semi-occlusion to rabbit skin, 5 days/week for 3 weeks, the systemic NOAEL appeared to be 500 mg/kg/day (highest tested dose; in absence of data of clinical signs, and in view of very limited histopathology data, this is a screening value) and the local NOAEC was derived as 0.22 mg/cm2/day due to erythema, edema and skin cracking appearing in a delayed manner along repeated exposures. NOAEC derivation by RSS/CSR author is explained under section 7.3.1 and in CSR.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.22 mg/cm²

Study duration:

subacute

Species:

rabbit

Quality of whole database:

Only one sub-acute dermal study is available, and it has been assigned a reliability rating of 2 but has a number of limitations.

Justification for classification or non-classification

Based on results from the currently available studies, 2 -EHN does not require classification for repeated dose toxicity according to Regulation (EC) No 1272/2008. A sub-chronic repeated dose toxicity study (90 -day with 28 -day recovery period; according to OECD Test Guideline 413) with exposure to 2 -EHN via the inhalation route in rats is currently in progress, according to Decision TPE-D-0000002102 -92 -05/F. Once the study results are available, the dossier will be updated and this conclusion re-evaluated.