Propionaldehyde, reaction product with formaldehyde

Endpoint summary

Description of key information

Acute oral toxicity: OECD 423, EU Method B.1 tris: LD50 >5000 mg/kg body weight
Acute dermal toxicity: OECD 402, EU Method B.3: LD50 >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:

from 26 January to 18 August 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP-Study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

17 Dec 2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Species, strain: Rats, Crl:CD(SD).
- Supplier: Charles River Deutschland GmbH, D-97633 Sulzfeld.
- Number and sex: 6 females.
- Age: Approx. 8 weeks at the time of the administration.
- Health conditions: A health inspection was performed prior to the commencement of treatment to ensure that the animals were in a good state of health.
- Hygiene: Optimal hygienic conditions.
- Feed: Ssniff R/M-H maintenance diet for rats and mice (item V1534-300) ad libitum, supplied by Ssniff Spezialdiäten GmbH, 59494 Soest, Germany. Analysis of the feed for ingredients and contaminants is performed randomly by Ssniff.
- Exception: The feed was withdrawn the evening before the administration of the test substance and was offered again about three hours afterwards.
- Water: Tap water from an automatic watering system, ad libitum. Random samples of the water are analysed by the "AGES", A-1226 Vienna, to check, if the water fulfils the requirements for drinking water for humans.
- Identification: Labelling with felt-tipped pen on the tail and on the cage.


ENVIRONMENTAL CONDITIONS
- Room number: EI1-11.
- Room temperature: Ranges from 22 °C +/- 3 °C (continuous control and recording).
- Relative humidity: Ranges from 30 - 70 % (continuous control and recording).
- Air exchange: 12 per hour.
- Light: Artificial light from 6 a.m. to 6 p.m.
- Cages: Single caging in Makrolon cages type III (39 cm x 23 cm bottom area, 18 cm height). Wire mesh lids. Sanitation of cages once a week.
- Bedding material: Aspen wood chips, Fa. ABEDD Dominik Mayr KEG, A-8580 Köflach, autoclaved. Random samples of the bedding material are analysed for contaminants by the supplier. Changes 1 / week.
- Environmental enrichment: Nibbling wood bricks (10 cm x 2 cm x 2 cm) and nesting material, both from the same material and source as the bedding material, were offered to the animals once a week.

Acclimatisation: At least 7 days.

Route of administration:

oral: gavage

Vehicle:

water

Remarks:

deionised

Details on oral exposure:

A peroral administration was performed once in the morning by stomach intubation using a metal gavage.

VEHICLE
- Vehicle: deionised water.
- Amount of vehicle (if gavage): 10 mL per kg body weight.
- Justification for choice of vehicle: The test substance was sufficeiently soluble in water and water shalll be used pfeferagly, according to the guiedelines. The solutions were prepared freshly before administration and were administered within 10 minutes after the preparation.



CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The selection of the starting dose was based on available data on the acute toxicity of a 50 % solution of the test substance, submitted by the sponsor (LD50 > 2000 mg/kg) and on the results of a dose range finding study for a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (internal study code ZSI32), where all animals survived a dose of 1000 mg/kg given on 7 consecutive days. Therefore a LD50, oral > 2000 mg/kg was assumed.
The further proceeding was in accordance with the guideline/directive:
• Step 1: 2000 mg per kg body weight.
• Step 2: 2000 mg per kg body weight.

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

3 per step (6 females per dose)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations were performed within the periods 0 - 0.5, 0.5 - 1, 1 - 2, 2 - 4 and 4 - 6 hours after administration (p.a.) of the test substance and then at least once a day for a total of 14 days.
- Necropsy of survivors performed: yes
- Clinical signs including body weight : Observations included but were not limited to changes in skin, fur, eyes, the occurrence of secretions and excretions, autonomic activity, changes in gait, posture and the presence of convulsions.
The animals were sacrificed by inhalation of 80 % CO2 + 20 % air 14 days p.a. and subjected to a necropsy including a gross pathological examination.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

All animals survived until the scheduled termination of the study.

Clinical signs:

other: All animals showed signs of reduced well-being from 1 h until 6 h p. a. This term encompasses unspecific alterations, like sedation, apathy, piloerection, hunched posture or closed eyes, in single or multiple occurrence.

Gross pathology:

No abnormal findings were made in all animals at the necropsy 14 d p.a.

Table:    Body weights and body weight gain

             Individual data, means and standard deviations SD.

Dose	Animal	Body weight (g)			Body weight gain (g)
mg/kg (Step No.)	No.	before administr.	7 days p.a.	14 days p.a.	death	0-7 days p.a.	7-14 days p.a.
2000	21	193	208	223	-	15	15
(1)	22	189	230	233	-	41	3
	23	188	217	235	-	29	18
	mean	190.0	218.3	230.3	-	28.3	12.0
	SD	2.6	11.1	6.4	-	13.0	7.9
2000	24	187	214	232	-	27	18
(2)	25	183	210	221	-	27	11
	26	187	214	230	-	27	16
	mean	185.7	212.7	227.7	-	27.0	15.0
	SD	2.3	2.3	5.9	-	0.0	3.6

Table:    Observations in life

             A grade of severity was recorded where applicable (low - mid - high).

Findings	Dose (mg/kg), Step No.	Animal Nos.	Observation time (p.a.) first    last
signs of reduced well-being	2000, 1	21, 22, 23	1 h / 6 h
	2000, 2	24, 25, 26	1 h / 6 h

Table:    Necropsy findings

             Number of animals examined: 6 females.

SYSTEM Organ, finding	Dose (mg/kg)	Step No.	Animal Nos.
no abnormal findings	2000	1	21, 22, 23
	2000	2	24, 25, 26

Interpretation of results:

GHS criteria not met

Remarks:

according to EU GHS

Conclusions:

No severe toxic effects are present in the tested animals until a dose of 2000 mg/kg bw. The LD50 oral was concluded to be > 5000 mg/kg bw.

Executive summary:

The aim of the study was to investigate acute toxic effects of the test substance after a single peroral administration to rats in conformance with the OECD Guideline 423, 17 December 2001 and the Council Regulation (EC) No 440/2008, Method B.1 tris in compliance with GLP criteria.

The test substance was administered once orally via gavage as a solution in deionised water to female Crl:CD(SD) rats. The dosing was performed sequentially to groups of 3 animals per step using a starting dose 2000 mg per kg body weight. The dose volume was 10 mL per kg body weight for all groups. Body weights were investigated before administration, 7 and 14 days after the administration (p.a.). Clinical observations were performed at least once per day and animals were sacrificed and necropsied 14 days p.a.

 

Results

Dose (mg/kg)	Step No.	No. of animals			Prominent findings
		exposed	affected	deceased	in life	post mortem
2000	1	3	3	0	signs of reduced well-being	none
2000	2	3	3	0	signs of reduced well-being	none

 

All animals showed signs of reduced well-being from 1 h until 6 h p. a. This term encompasses unspecific alterations, like sedation, apathy, piloerection, hunched posture or closed eyes, in single or multiple occurrence. No animal died and they fully recovered .  All animals gained weight in both weeks p.a.  No severe toxic effects present were recorded in life or post-mortem.

The LD50 oral has been determined to be > 5000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

guideline study

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Endpoint conclusion

Endpoint conclusion:

no study available

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:

from 8 June to 18 August 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP-Study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Species, strain: Rats, Crl:CD(SD).
- Supplier: Charles River Deutschland GmbH, D-97633 Sulzfeld.
- Number of animals and sex: 5 males and 5 females, females were nulliparous and non-pregnant.
- Age: Approximately 8 weeks (males) and 12 weeks (females) at the time of administration.
- Health conditions: A health inspection was performed prior to the commencement of treatment to ensure, that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from any abnormality.
- Hygienic status: Optimal hygienic conditions.
- Feed: Ssniff R/M-H maintenance diet for rats and mice (item V1534-300) ad libitum, supplied by Ssniff Spezialdiäten GmbH, 59494 Soest, Germany. Analysis of the feed for ingredients and contaminants is performed randomly by Ssniff.
- Water: Tap water, from an automatic watering system, ad libitum, random samples of the water are analysed by the "AGES", A-1226 Vienna, to check, if the water fulfils the requirements for drinking water for humans.
- Identification: Labelling with felt-tipped pen on the tail and on the cage.


ENVIRONMENTAL CONDITIONS
- Room number: EH1-23.
- Room temperature: Ranges from 19.93 to 21.90 °C (continuous control and recording).
- Relative humidity: Ranges from 40.91 to 73.72 % (continuous control and recording).
- Air exchange: 12 per hour.
- Light: Artificial light from 6 a.m. to 6 p.m.
- Cages: Single caging in Makrolon cages type III (37.5 cm x 21.5 cm bottom area, 18 cm height). Wire mesh lids. Sanitation of cages once a week.
- Bedding material: Aspen wood chips, Fa. ABEDD Dominik Mayr KEG, A-8580 Köflach, autoclaved. Random samples of the bedding material are analysed for contaminants by the supplier. Changes 1 / week.
- Environmental enrichment: Nibbling wood bricks (10 cm x 2 cm x 2 cm) and nesting material, both from the same material and source as the bedding material, were offered to the animals once a week.
- Acclimatisation: At least 7 days.

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 6.5 cm x 8 cm (52 cm²)
- % coverage: at least 10 % of the estimated body surface
- Type of wrap if used: semi-occlusive dressing (Fixomull Stretch, Fa. Beiersdorf)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test substance was wiped off using wet cellulose tissue, if necessary.
- Time after start of exposure: 24 hours

A single dermal administration was performed by spreading the test substance on an area of at least 10 % of the estimated body surface:
The body surface was calculated using the formula: body surface (cm²) = 10 x body weight (g)2/3
The test site was located on the dorsal thoracic region. An area of 6.5 cm x 8 cm (52 cm²) was marked on a relaxed animal.
The hair of the dorsal trunk was clipped with an electrical hair clipper (Aesculap GH, 0.1 mm cutter head) one day before application of the test substance. The amounts of the test substance were calculated and weighed for each individual using the body weights determined on the day of the administration.
A cellulose patch (Pehazell, Hartmann AG) with the calculated amount of the test substance on the surface and soaked with deionised water to get optimal contact with the skin, was applied to the test site and held in place by fixing marginally with non irritating tape (Blenderm Wundpflaster, 3M).
The test site was covered by a semi-occlusive dressing (Fixomull Stretch, Fa. Beiersdorf).
The duration of exposure was 24 hours.
At the end of the exposure period the dressing, the tape and the patch were removed.
Residual test substance was wiped off using wet cellulose tissue, if necessary.

Duration of exposure:

24 hours

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

No skin examination of the administration site was possible during the exposure period, while it was covered by the patch and wrappings.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations were performed 0 - 0.5, > 0.5 - 1, > 1 - 2, > 2 - 4 and > 4 - 6 hours after administration of the test substance (p.a.) and then at least once a day for a total of 14 days.
- Necropsy of survivors performed: yes
- Clinical signs including body weight : Observations included but were not limited to changes in skin, fur, eyes, the occurrence of secretions and excretions, autonomic activity, changes in gait, posture and the presence of convulsions.
Body weights were determined
• before administration.
• 7 days p.a.
• 14 days p.a.
Body weight gain was calculated for each week of the study, i.e. between
• 0 and 7 days p.a.
• 7 and 14 days p.a.

All animals were sacrificed by inhalation of 80 % CO2 + 20 % O2 14 days p.a. and subjected to a necropsy including a gross pathological examination

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

All animals survived until the scheduled termination of the study.

Clinical signs:

other: General findings: All animals but one male did not show any clinical signs during the entire observation period. Chromodacryorrhoea was noted in one male from 4 h until 6 h p.a. This might be due to the discomfort, caused by the dressing and was not cons

Gross pathology:

No abnormal findings were made in the animals at terminal necropsy.

Table: Body weights and body weight gain.

Individual data, mean and standard deviation SD.

 

Dose	Animal	Body weight (g)				Body weight gain (g)
Sex	No.	before administr.	7 days p.a.	14 days p.a.	death	0-7 days p.a.	7-14 days p.a.
	11	272	313	354	-	41	41
2000 mg/kg	12	287	339	393	-	52	54
male	13	283	310	345	-	27	35
	14	270	312	355	-	42	43
	15	272	304	343	-	32	39
	mean	276.8	315.6	358.0	-	38.8	42.4
	SD	7.7	13.5	20.3	-	9.7	7.1
	16	239	249	267	-	10	18
2000 mg/kg	17	230	242	255	-	12	13
female	18	229	237	247	-	8	10
	19	227	257	263	-	30	6
	20	237	247	260	-	10	13
	mean	232.4	246.4	258.4	-	14.0	12.0
	SD	5.3	7.5	7.7	-	9.1	4.4

Table: Observations in life.

Findings	Dose (mg / kg), sex	No. of the affected animals	Observation time (p.a.)    first      last
chromodacryorrhoea	2000, m	11	4 h - 6 h
test substance related stain of skin	2000, m	11	1 d - 14 d
		12	1 d - 14 d
		13	1 d - 12 d
		14	1 d - 12 d
		15	1 d - 14 d
	2000, f	16	1 d - 13 d
		17	1 d - 14 d
		18	1 d - 12 d
		19	1 d - 12 d
		20	1 d - 14 d

Table: Necropsy findings.

SYSTEM Organ, finding	Dose (mg / kg) sex	No. of affected animals
no abnormal findings	2000, m	11, 12, 13, 14, 15
	2000, f	16, 17, 18, 19, 20

Results

dose (mg/kg)	sex	No. of animals			prominent findings
		exposed	affected	deceased	in life		post mortem
					systemic	local
2000	male	5	1	0	none	chromodacryorrhoea	none
2000	female	5	0	0	none	none	none

Staining of the skin which is attributed to the staining property of the test substance was observed in all animals.

Interpretation of results:

GHS criteria not met

Remarks:

according to EU GHS

Conclusions:

No local or systemic test substance related effects were noted from clinical observations or post-mortem examination at a dose of 2000 mg test substance per kg body weight. The LD50 dermal of the test substance is higher than 2000 mg/kg body weight in rats.

Executive summary:

The aim of the study was to investigate acute toxic effects of the test substance after a single dermal administration to rats in conformance with the OECD Guideline 402, 1987 and the Council Regulation (EC) No 440/2008, Method B.3. and in compliance with GLP criteria.

The test substance was administered once topically on an area of approximately 6.5 cm x 8 cm on the dorsal thoracic region of 5 male and 5 female Sprague Dawley rats. The dose was 2000 mg per kg body weight. A cellulose patch with the calculated amount of the test substance on the surface and soaked with deionised water to get optimal contact with the skin, was applied to the test site and held in place by fixing marginally with non irritating tape. The test site was covered by a semi-occlusive dressing. The duration of the exposure was 24 hours. Body weights were investigated before the administration, 7 and 14 days after the administration (p.a.). Clinical observations were performed at least once per day. All animals were sacrificed and necropsied 14 days p.a.  

No local or systemic toxic effects related to administration of the test substance were noted from clinical observations or post-mortem-examination at a dose of 2000 mg of the test substance per kg body weight.

No mortality occurred. All animals but one male did not show any clinical signs during the entire observation period.

Chromodacryorrhoea was noted in one male from 4 h until 6 h p.a. This might be due to the discomfort, caused by the dressing and was not considered to be toxicologically relevant. A yellow staining of the skin was observed in all animals from 1 d until a maximum of 14 d p.a. This stain is attributed to a staining property of the test substance and not considered to be a toxic effect. No other alterations to the exposed skin by the test substance were found.  All animals gained weight in both weeks p.a., all animals recovered fully. The LD50 dermal was concluded to be > 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

guideline study

Additional information

Acute oral toxicity

The aim of the study was to investigate acute toxic effects of the test substance after a single peroral administration to rats in conformance with the OECD Guideline 423, 17 December 2001 and the Council Regulation (EC) No 440/2008, Method B.1 tris in compliance with GLP criteria.

The test substance was administered once orally via gavage as a solution in deionised water to female Crl:CD(SD) rats. The dosing was performed sequentially to groups of 3 animals per step using a starting dose 2000 mg per kg body weight. The dose volume was 10 mL per kg body weight for all groups. Body weights were investigated before administration, 7 and 14 days after the administration (p.a.). Clinical observations were performed at least once per day and animals were sacrificed and necropsied 14 days p.a.

Results

Dose (mg/kg)	Step No.	No. of animals			Prominent findings
		exposed	affected	deceased	in life	post mortem
2000	1	3	3	0	signs of reduced well-being	none
2000	2	3	3	0	signs of reduced well-being	none

All animals showed signs of reduced well-being from 1 h until 6 h p. a. This term encompasses unspecific alterations, like sedation, apathy, piloerection, hunched posture or closed eyes, in single or multiple occurrence. No animal died and they fully recovered . All animals gained weight in both weeks p.a. No severe toxic effects present were recorded in life or post-mortem.

Acute inhalation toxicity

The study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of inhalable size. The likely route of human exposure is the dermal or oral route. Based on the high viscosity of the substance no exposure to aerosols, particles or droplets of ihalable size is expected during handling. In addition the LD50oral rat is >5000 mg/kg body weight and the LD50dermal rat is >2000 mg/kg body weight. Thus an additional inhalation study is not justified.

Acute dermal toxicity

The aim of the study was to investigate acute toxic effects of the test substance after a single dermal administration to rats in conformance with the OECD Guideline 402, 1987 and theCouncil Regulation (EC) No 440/2008, Method B.3. and in compliance with GLP criteria.

The test substance was administered once topically on an area of approximately 6.5 cm x 8 cm on the dorsal thoracicregion of 5 male and 5 female Sprague Dawley rats.The dose was 2000 mg per kg body weight.A cellulose patch with the calculated amount of the test substance on the surface and soaked with deionised water to get optimal contact with the skin, was applied to the test site and held in place by fixing marginally with non irritating tape.The test site was covered by a semi-occlusive dressing.The duration of the exposure was 24 hours. Body weights were investigated before the administration, 7 and 14 days after the administration (p.a.). Clinical observations were performed at least once per day. All animals were sacrificed and necropsied 14 days p.a.  

No local or systemic toxic effects related to administration of the test substance were noted from clinical observations or post-mortem-examination at a dose of 2000 mg of the test substance per kg body weight.

No mortality occurred.All animals but one male did not show any clinical signs during the entire observation period.

Chromodacryorrhoea was noted in one male from 4 h until 6 h p.a. This might be due to the discomfort, caused by the dressing and was not considered to be toxicologically relevant. A yellow staining of the skin was observed in all animals from 1 d until a maximum of 14 d p.a. This stain is attributed to a staining property of the test substance and not considered to be a toxic effect. No other alterations to the exposed skin by the test substance were found.  All animals gained weight in both weeks p.a., all animals recovered fully. The LD50 dermal was concluded to be > 2000 mg/kg bw.

Justification for classification or non-classification

No classification is derived for acute toxicity after oral or dermal administration, as the LD50 was >5000 (oral toxicity) and >2000 (dermal toxicity) mg/kg body weight according to Regulation (EC) No 1272/2008.