N-(butoxymethyl)acrylamide

Endpoint summary

Description of key information

The acute toxicity of the test substance via the oral route was assessed using a limit method similar to OECD Test Guideline 420 using a fixed dose procedure in rats. The LD50 of the test material was > 1000 mg/kg bw.

 

The acute toxicity via inhalation of the read-across substance, acrylamide, was assessed in two studies, both using a method similar to OECD Test Guideline 433. The LC0 for the test material in rats by inhalation is greater than 12 mg/m3.

 

The acute toxicity of the test substance via the dermal route was assessed using a method similar to OECD Test Guideline 402 using a standard acute method. The LD50 of the test material is greater than 2000 mg/kg body weight.

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:

29 June 2006 to 13 October 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: The pre-test body weight range was 209 - 230 g
- Age at study initiation: Approximately 8 weeks
- Fasting period before study: 16 - 20 hours prior to dosing
- Housing: Animals were housed 1 per cage in suspended wire mesh cages. Bedding was placed beneath the cages and changed at least three times/week.
- Diet: Freely available
- Water: Freely available at all times
- Acclimation period: At least three days

ENVIRONMENTAL CONDITIONS
- Temperature: Not reported, the room was temperature controlled
- Photoperiod: 12 hour light / dark cycle

IN-LIFE DATES:
- From: 27 June 2006
- 10 July 2006

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test material was used as received. The dose was based on the sample weight as calculated from the specific gravity.

MAXIMUM DOSE VOLUME APPLIED: 0.24 cc

Doses:

1000 mg/kg

No. of animals per sex per dose:

Five males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: Animals were observed 1, 4 and 24 hours post-dose for mortality, toxicity and pharmacological effects. Mortality was recorded once daily thereafter for six days.
- Necropsy of survivors performed: No. All animals were humanely sacrificed using CO2 following the study termination.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

> 1 000 mg/kg bw

Based on:

test mat.

Mortality:

2 animals died during the test period; the first within 24 hours of administration, the second on Day 2.

Clinical signs:

other: Pre-death observations included lethargy, wetness and red staining of the nose/mouth area, negative righting reflex, convulsions, spasms, tremors, unkempt appearance, few faeces, ataxia and wetness of the anogenital area. Instances of lethargy, wetness an

Table 1: Dose Volume and Body Weight

Animal No.	Sex	Dose Volume (cc)	Body weight (g)
			Day 0	Day7
1	Male	0.24	230	299
2	Male	0.22	216	N/A
3	Male	0.22	209	267
4	Male	0.23	217	N/A
5	Male	0.23	221	280
Mean			219	282
S.D.			7.7	16.1
Number			5	3

N/A = Not applicable – Animal died before observation period

 

Table 2: Systemic Observations

Time Period	Animal No. / Sex
	1/M	2/M	3/M	4/M	5/M
1 hour	B	B	B, R, T	B, R	B, R
4 hours	B	B, 1	B, R, I	B, R, I	B, R, T, I
24 hours		1, 2, K, B, I, P, O, 3, X, E	1	Z (204 G)	1, R, B, 3, X
Day 2		1, 2, R, K, I, P, O, X, E, Z (193 G)			1, R, X
Day 3					2, R
Day 4
Day 5
Day 6
Day 7

No entry indicates that the animal appeared normal at that observation period.

B = Lethargy

E = Ataxia

I = Convulsion

K = Negative righting reflex

O = Tremors

P = Spasm

R = Anogenital area wet

T = Anogenital area soiled

X = Few faeces

Z = Dead

1= Nose/mouth area stained red

2 = Nose/mouth area wet

3 = Unkempt appearance

Interpretation of results:

other: Category 4 in accordance with EU criteria

Conclusions:

Based on the results of this test, the LD50 of the test material was > 1000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 000 mg/kg bw

Quality of whole database:

A single GLP study was available conducted on the target substance in vivo using a method equivalent to a guideline.

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:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

See the Analogue Approach Report attached in Section 13 of the IUCLID dossier.

Reason / purpose for cross-reference:

other: Read across to target substance

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 433 draft (Acute Inhalation Toxicity: Fixed Concentration Procedure) (not officially approved)

Deviations:

not specified

GLP compliance:

no

Remarks:

Pre-GLP

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not specified
- Age at study initiation: not specified
- Weight at study initiation: 265-279 g
- Fasting period before study: not specified
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): room temperature
- Humidity (%): not specified

IN-LIFE DATES: 15/05/1975 to 29/05/1975

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: glass chamber
- Exposure chamber volume: 160 litres
- Method of holding animals in test chamber: restricted chamber volume
- Source and rate of air: 50 litres/minute by positive pressure spray nozzle
- Method of conditioning air: not specified
- System of generating particulates/aerosols: not specified
- Method of particle size determination: Royco particle analyser/light scattering
- Treatment of exhaust air: not specified
- Temperature, humidity, pressure in air chamber: not specified

TEST ATMOSPHERE
- Brief description of analytical method used: nominal
- Samples taken from breathing zone: no

VEHICLE: Substance was tesed as an aqueous solution

TEST ATMOSPHERE
- Particle size distribution: 1.95 microns (mean value) with 99% of particles 6 microns or smaller
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.95

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

1 h

Concentrations:

12 mg of test substance/litre

No. of animals per sex per dose:

6 males (one dose)

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 15/5, 16/5, 19/5, 21/5, 23/5, 28/5, 29/5
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight

Statistics:

None

Preliminary study:

None

Sex:

male

Dose descriptor:

LC0

Effect level:

12.1 mg/m³ air (nominal)

Based on:

test mat.

Exp. duration:

1 h

Mortality:

One animal died as a result of an infection unrelated to chemical exposure.

Clinical signs:

other: No visible lesions could be attributed to the test material.

Body weight:

No effects could be attributed to the test material.

Gross pathology:

Not performed.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The results of this test indicate that the 50.7 % solution of acrylamide is practically non-toxic by the inhalation route with a LC0 of 12 mg/m3.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

12 mg/m³ air

Quality of whole database:

Two studies were available conducted on the read-across substance in vivo using methods equivalent to a guideline. One was conducted to GLP; the other pre-dates GLP

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:

26 June 2006 to 13 October 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: The pre-test body weight range was 2.1 - 2.9 kg
- Housing: 1 per cage in suspended wire cages. Bedding was placed beneath the cages and changed at least three times/week.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: At least three days

ENVIRONMENTAL CONDITIONS
- Temperature: Not reported, the room was temperature controlled
- Photoperiod: 12 hour light / dark cycle

IN-LIFE DATES:
- From: Animals were received 21 June, 05 July, 26 July and 23 August 2006
- To: Not reported; date of last data collection was 04 September 2006

Type of coverage:

other: occlusive at the lower dose levels, semi-occlusive at the highest dose

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
Prior to application of the test article, the back and sides of each animal were clipped free of hair and remained intact.
- Area of exposure: Approximately 10 %
- Type of wrap if used: Test material was applied under a 4 ply porous gauze dressing measuring 10 x 15 cm at the lower dose levels. The top dose was applied to the prepared site on top of the gauze dressing. The torso was wrapped with plastic sheeting in an occlusive manner for animals dosed at 500, 1000 and 1500 mg/kg. Animals dosed at 2000 mg/kg were wrapped in a semi-occlusive manner. Plastic sheeting was secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The test sites were wiped, not washed
- Time after start of exposure: After 24 hours

TEST MATERIAL
Doses were based on the sample weight as calculated from the specific gravity.
- Amount applied:
1.3 to 1.5 cc at 500 mg/kg bw
2.5 to 2.8 cc at 1000 mg/kg bw
3.3 to 3.6 cc at 1500 mg/kg bw.
4.6 to 6.0 cc at 2000 mg/kg bw

VEHICLE
The test material was used as received

Duration of exposure:

24 hours

Doses:

500, 1000, 1500 and 2000 mg/kg

No. of animals per sex per dose:

Initially, five healthy males were dosed at 500 mg/kg of body weight.
At the sponsor's request and to further characterise the test material, three additional groups of five males were dosed at 1000, 1500 and 2000 mg/kg.

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: Animals dosed at 500 mg/kg were observed at 1, 4 and 24 hours post-dose and animals dosed at 1000, 1500 and 2000 mg/kg were observed at 1, 4 and 24 hours post-dose for mortality, toxicity and pharmacological effects. Animals were observed once daily thereafter for six days for mortality only. Body weights were recorded pre-test and at termination.
- Necropsy of survivors performed: No.
- Other examinations performed: The test sites were scored for dermal irritation at 24 hours post-dose and on day 7 using the Numerical Draize scoring code. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction. Additional signs were described.

Erythema and eschar formation:
0: No erythema
1: Very slight erythema (barely perceptible)
2: Well-defined erythema
3: Moderate to severe erythema
4: Severe erythema (beet redness) to slight eschar formation (injuries in depth)

Oedema formation:
0: No oedema
1: Very slight oedema (barely perceptible)
2: Slight oedema (edges of area well-defined by definite raising)
3: Moderate oedema (edges raised approximately 1 millimetre)
4: Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure)

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

None, all animals survived

Clinical signs:

other: All animals appeared normal at post-dose assessments up to 24 hours.

Gross pathology:

Not performed.

Other findings:

- At 500 mg/kg: Dermal effects ranged from very slight to slight on Day 1 and from absent to well-defined on Day 7.
- At 1000 mg/kg: Dermal effects ranged from absent to well-defined on Day 1 and from absent to very slight on Day 7.
- At 1500 mg/kg: Dermal effects ranged from absent to very slight on Days 1 and 7.
- At 2000 mg/kg: Dermal effects ranged from very slight to slight on Day 1 and from absent to very slight on Day 7.

Interpretation of results:

other: Not classified in accordance with EU criteria

Conclusions:

The LD50 of the test material is greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

A single GLP study was available conducted on the target substance in vivo using a method equivalent to a guideline.

Additional information

The acute toxicity of the test substance via the oral route was assessed using a limit method similar to OECD Test Guideline 420 using a fixed dose procedure in rats. Five male rats were administered 1000 mg/kg via oral gavage. Animals were observed 1, 4 and 24 hours post-dose for mortality, toxicity and pharmacological effects. Mortality was recorded once daily thereafter for six days.

Two animals died during the test period; the first within 24 hours of administration, the second on Day 2. Pre-death observations included lethargy, wetness and red staining of the nose/mouth area, negative righting reflex, convulsions, spasms, tremors, unkempt appearance, few faeces, ataxia and wetness of the anogenital area.

Instances of lethargy, wetness and soiling of the anogenital area, wetness and red staining of the nose/mouth area, unkempt appearance and few faeces were noted early in the study in the survivors but they appeared normal from Day 4 through Day 7.

Based on the results of this test, the LD50 of the test material was >1000 mg/kg bw.

 

Two acute inhalation studies were performed on the read-across substance acrylamide.

The first was performed using a method equivalent to OECD Test Guideline 433 using a standard acute method. Six male rats were exposed to the aerosol (nose only) in a 160 L glass test chamber to 12 mg/m3 of the read-across material, acrylamide, for 1 hour. Observations of clinical signs and body weights were conducted for 14 days following exposure. 

One animal died as a result of an infection unrelated to chemical exposure. No visible lesions could be attributed to the test material and there were no effects on body weights attributed to the test material. The results of this test indicate that the 50.7 % solution of the read-across material by the inhalation route has a 1 hour LC0 of 12 g/m3.

In a second study, performed to a method similar to OECD Test Guideline 433, rats were exposed to the read-across material, acrylamide, using a fixed dose procedure. Ten male rats were exposed to the read-across material using a nose-only exposure system for 6 hours at 16 mg/m3. Following exposure, the rats were observed for 24 hours after which gross necropsies were performed.

Following exposure by the inhalation route, there were no mortalities or systemic effects 16 mg/m3, which was the highest air concentration attainable. It can be concluded therefore that the LC0 for the test material in rats by inhalation is greater than 16 mg/m3.

The acute toxicity of the test substance via the dermal route was assessed using a method similar to OECD Test Guideline 402 using a standard acute method in New Zealand white rabbits. Rabbits were exposed to 500, 1000, 1500 or 2000 mg/kg for 24 hours on the back and sides covering approximately 10 % of the area of each rabbit’s skin, which had been clipped free of hair. The test material was applied under an occlusive or semi-occlusive dressing (highest dose level only). The test area was wiped, not washed, 24 hours after the start of exposure.

Animals dosed at 500 mg/kg were observed at 1, 5 and 24 hours post-dose. Animals dosed at 500 mg/kg were observed at 1, 4 and 24 hours post-dose and animals dosed at 1000, 1500 and 2000 mg/kg were observed at 1, 4 and 24 hours post-dose for mortality, toxicity and pharmacological effects. Animals were observed once daily thereafter for six days for mortality only. Body weights were recorded pre-test and at termination. The test sites were scored for dermal irritation at 24 hours post-dose and on day 7 using the Numerical Draize scoring code. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction. Additional signs were described.

All animals appeared normal at post-dose assessments up to 24 hours. Body weight changes were normal at all doses. The LD50 of the test material is therefore greater than 2000 mg/kg body weight.

Justification for classification or non-classification

The LD50 for exposure via the oral route was > 1000 mg/kg bw and the substance is therefore classified as Category 4 for acute exposure via the oral route.

The LC0 for exposure to the read across substance via the inhalation route was 12 mg/m3; acrylamide has a harmonised classification as Category 4 for acute exposure via the inhalation route.

The LD50 for exposure via the dermal route was > 2000 mg/kg bw and the substance is therefore not classified for acute exposure via the dermal route.