AERO 5100 PROMOTER

Endpoint summary

Description of key information

Oral (OECD 420 and 401), rat: LD50 > 500 - < 2000 mg/kg bw

Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw (limit test)

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 Apr - 19 May 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

adopted 17 July 1992

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

other: Hsd:Sprague-Dawley(CD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Ltd, Bicester, UK
- Age at study initiation: approx. 5 - 7 weeks
- Weight at study initiation: 115 - 140 g
- Fasting period before study: overnight prior to and for approx. 4 h after dosing
- Housing: in groups of up to 5 animals of the same sex in metal cages (RS Biotech Sub-Dividable Rodent Cages - polished stainless steel, 20 cm high x 39 cm wide x 39 cm long)
- Diet: RM1(E) SQC expanded pellet (Special Diet Services), ad libitum
- Water: drinking water, ad libitum
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 - 24
- Humidity (%): 34 - 60
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 0.505 mL/kg bw

Doses:

Range-finding study: 500 and 2000 mg/kg bw
Main study: 500 mg/kg bw

No. of animals per sex per dose:

Range-finding study: 1 female
Main study: 5 males and 5 females

Control animals:

no

Details on study design:

Range-finding study:
- Duration of observation period following administration: 7 days
- Frequency of observations: Animals were observed at least twice daily for mortality. Individual body weights were recorded on Day 1 (prior to dosing) and 8 or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Main study:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed at least twice daily for mortality. Individual body weights were recorded on Day 1 (prior to dosing), 2, 3, 4, 8 and 15 or at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Preliminary study:

The results from the preliminary study demonstrated the non-lethal dose to be below 2000 mg/kg bw and in accordance with the test guideline criteria and on the basis of findings at 500 mg/kg bw. No further preliminary study animals were used as findings at 500 mg/kg bw indicated this dosage to be suitable for use in the main study.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 500 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Range-finding study: No mortality was observed at 500 mg/kg bw. The animal at 2000 mg/kg bw was sacrificed approx. 24 h after dosing for ethical reasons.

Main study: No mortality occurred during the study period of the main study.

Clinical signs:

other: Range-finding study: Piloerection, hunched posture, waddling/unsteady gait, lethargy, abnormal respiration (characterised by increased, decreased and gasping/noisy respiration), partially closed eyelids, pallid extremities, walking on toes, increased sali

Gross pathology:

Range-finding study: No abnormalities were noted at 500 mg/kg bw. Macroscopic examination of the sacrificed animal revealed congestive changes (characterised by dark tissue/prominent blood vesseld) in the subcutaneous tissue, brain, heart, liver, spleen, kidneys and along the alimentary tract. Additionally, enlarged/swollen tissues and fluid contents were observed along the alimentary tract.

Main study: No abnormalities were observed at macroscopic examination.

Interpretation of results:

other: CLP/EU GHS criteria are met, Category 4 classification is required according to Regulations (EC) No 1272/2008

Conclusions:

In this acute oral toxicity study in male and female rats a LD50 value > 500 - < 2000 mL/kg bw was found.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

500 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

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:

29 Apr - 13 May 1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted 24 February 1987

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:

other: Hsd:Sprague-Dawley(CD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Ltd, Bicester, UK
- Age at study initiation: approx. 8 - 11 weeks
- Weight at study initiation: 212 - 312 g
- Housing: individually in metal cages (RS Biotech Sub-Dividable Rodent Cages - polished stainless steel, 20 cm high x 39 cm wide x 39 cm long)
- Diet: RM1(E) SQC expanded pellet (Special Diet Services), ad libitum
- Water: drinking water, ad libitum
- Acclimation period: at least 20 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 - 24
- Humidity (%): 34 - 58
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 50 mm x 50 mm clipped skin of the dorso-lumbar region
- % coverage: approx. 10%
- Type of wrap if used: The treated skin was covered with porous gauze held in place with non irritating dressing and further covered by a waterproof dressing encircled firmly around the trunk.

REMOVAL OF TEST SUBSTANCE
- Washing: Residual test substance was removed with warm water (30 to 40 °C).
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount applied: 2.021 mL/kg bw

Duration of exposure:

24 h

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed soon after dosing at frequent intervals for the remainder of Day 1. On subsequent days animals were observed once in the morning and again at the end of the experimental day (with exception of Day 15 - morning only). Individual body weights were determined on Days 1 (prior to dosing), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: The nature and severity of the clinical signs and time were recorded at each observation.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the study period.

Clinical signs:

other: Clinical signs of reaction to treatment were confined to one animal and characterised by lethargy, partially closed eyelids and pallid extremities (notable between 4 and 6 h after dosing only). There were no signs of reaction to treatment in any of the ni

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

Well-defined dermal irritation was observed on four males and four females resolving completely by Day 8. The signs were accompanied in the occasional animal by localised reactions characterised by desquamation of the stratum corneum, necrosis and a patchy (dry area of skin) response at the edge of the treatment site in one further female. There were no other signs of reaction to treatment and recovery was complete in all instances by Day 9.

Table 1. Dermal reactions observed following 24 h exposure with undiluted test substance.

Dose (mg/kg bw)	Sex	Animal no.	E = Erythema O = Oedema	Days after dosing
				2	3	4	5	6	7	8	9 to 15
2000	Male	1	E	1	1	0	0	0	0	0	0
			O	1	0	0	0	0	0	0	0
		2	E	0	0^A	0^A	0	0	0	0	0
			O	0	0	0	0	0	0	0	0
		3	E	1	1	0	0	0	0	0	0
			O	0	0	0	0	0	0	0	0
		4	E	2	1	0	0	0	0	0	0
			O	1	1	0	0	0	0	0	0
		5	E	2	1	1	0	0	0	0	0
			O	1	1	0	0	0	0	0	0
	Female	1	E	2	2^B	2^A,B	2^A	2^A	1^A	0^A	0
			O	2	3	3	2	1	0	0	0
		2	E	2	2^A	2^A	2^A	2^A	1^A	0^A	0
			O	1	1	1	1	1	0	0	0
		3	E	2	1^A	1^A	1^A	1^A	0^A	0	0
			O	1	1	1	1	1	0	0	0
		4	E	0	0	0	0	0	0	0	0
			O	0	0	0	0	0	0	0	0
		5	E	2^C	1^C	1^C	0	0	0	0	0
			O	1	1	0	0	0	0	0	0

A: desquamation of the stratum corneum (characterized by dryness and sloughing and/or scaling)

B: necrosis (localized)

C: patchy response (dry area of skin) at edge of dose site

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008

Conclusions:

In this acute dermal toxicity study a LD50 value > 2000 mg/kg bw in male and female rats was found.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

The acute oral toxicity of the test substance was assessed in a study in rats according to OECD Guideline 420 and in compliance with GLP (McRae, 1998). In a preliminary study one animal each was treated with 500 or 2000 mg/kg bw. Animals were observed for mortality and general clinical conditions twice daily for 14 days. Body weights were recorded on Day 1 (prior to administration), 2, 3, 4, 8 and 15. Necropsy was performed at the end of the observation period at terminal sacrifice. In the preliminary study, piloerection, hunched posture, waddling/unsteady gait, lethargy, abnormal respiration (characterised by increased, decreased and gasping/noisy respiration), partially closed eyelids, pallid extremities, walking on toes, increased salivation, increased lacrimation, ungroomed appearance and dull colouring to eyes was evident in both animals. These signs were accompanied with protruding eyes at 500 mg/kg bw and with soft to liquid faeces, increased lacrimation, thin appearance, prostration and blue/cold extremities at 2000 mg/kg bw. The signs disappeared at 500 mg/kg bw by Day 8. Based on the results of the preliminary study a total dose of 500 mg/kg bw was administered to 5 male and 5 female rats in the main study. None of the animals died. Piloerection, increased salivation and ungroomed appearance were observed in all animals within 7 min of dosing. These signs persisted and were accompanied at later intervals on Day 1 or thereafter during the study with hunched posture, waddling/unsteady gait, lethargy, partially closed eyelids, pallid extremities, walking on toes, dull colouring to eyes in all rats and accompanied in a number of animals by abnormal respiration, increased lacrimation, increased sensitivity to touch, thin appearance, protruding eyes, discoloured bright/yellow urine, body tremors, prostration, blue/cold extremities and swollen abdomen. Recovery of surviving rats as judged by external appearance and behaviour was complete by Day 6.The body weight gain was not affected by the administration of the test substance. No abnormalities were observed at necropsy. Based on the results of this study, the oral LD50 value was determined to be > 500 - < 2000 mg/kg bw in rats.

In a supporting study, the acute oral toxicity of the test substance was assessed in rats equivalent to OECD Guideline 401 and in compliance with GLP (Kingery, 1982). In a preliminary study doses of 50, 100, 1000, 2000, 3000 and 4000 mg/kg bw were administered to 2 males and 2 females, respectively. One male and two females of 1000 mg/kg bw group and all animals of 2000, 3000 and 4000 mg/kg bw groups died. Based on the results of the preliminary study, dose levels of 450, 700, 900 and 5000 mg/kg bw were selected for the main study and were administered to 5 male and 5 female animals. Animals were observed for mortality and general clinical conditions frequently on the day of administration and twice daily thereafter for 13 days. Body weights were recorded on the day prior to dosing (Day -1) and on Days 0, 1, 2, 3, 6, 10 and 13. Necropsy was performed at the end of the observation period at terminal sacrifice. In the main study, Mortality occurred 5 h after dosing at 5000 mg/kg bw (1/10), on Days 1 to 2 at 700 mg/kg bw (1/10), at 900 mg/kg bw (9/10) and at 5000 mg/kg bw (9/10). All survivors appeared normal by Day 6 with exception of one animal at 700 mg/kg bw, which died on Day 9. Signs of systemic toxicity were observed 30 min after dosing at all dose levels. Reactions ranged from lethargy, ataxia, inactivity, salivation, lacrimation to bodies cool to touch and slowed respiration. The severity of reactions appeared similar at all dose levels on the day of dosing but the incidence and length of time effected as well as mortality appeared directly related to amount of test substance ingested. Mean body changes appeared to be decreased for animals found dead. Positive gross pathologic findings (intestines mucoid with or without focal hemorrhage, focal hemorrhage or congestion on stomach and/or focal hemorrhage of lung) occurred at 700, 900 and 5000 mg/kg bw. Based on the results of this study, the oral LD50 value was calculated to be 773 mg/kg bw in rats.

 

Dermal

The acute dermal toxicity of the test substance was assessed in a limit test performed in 5 male and 5 female Wistar rats according to OECD Guideline 402 and in compliance with GLP (McRae, 1998). The test substance was applied at a single dose of 2000 mg/kg bw to the clipped skin of the animals and was then held in contact with an occlusive dressing for 24 hours. Animals were observed for mortality, overt signs of toxicity and evidence of primary irritation twice a day for a 14-day period. Body weights were recorded prior to administration (Day 1) and on Days 8 and 15. Macroscopic examination was performed at the end of the observation period at terminal sacrifice. None of the animals died and clinical signs of reaction to treatment were confined to one animal and was characterised by lethargy, partially closed eyelids and pallid extremities (notable between 4 and 6 h after dosing only). No body weight gain was observed in one male and a slightly low weight gain was observed in two females on Day 8 only. All remaining animals showed an expected gain in body weight during the study. No abnormalities were observed at necropsy. Based on the results of this study, the LD50 value for acute dermal toxicity was determined to be > 2000 mg/kg bw in rats.

In a supporting study, the acute dermal toxicity of the test substance was assessed in a limit test performed in 5 male and 5 female New Zealand White rabbits according to OECD Guideline 402 and in compliance with GLP (Kingery, 1981). The test substance was applied at a single dose of 2040 mg/kg bw to the abraded skin of the animals and was then held in contact with an occlusive dressing for 24 hours. Animals were observed for mortality and signs of toxicity frequently on the day of dosing and twice a day for a 14-day period. Body weights were recorded one day prior to administration (Day -1) and on Days 0, 6 and 13. Macroscopic examination was performed at the end of the observation period at terminal sacrifice. None of the animals died and no signs of systemic toxicity were observed. The body weight gain was not affected by the administration of the test substance. No abnormalities were observed at necropsy. Based on the results of this study, the LD50 value for acute dermal toxicity was determined to be > 2040 mg/kg bw in rabbits.

Justification for classification or non-classification

The available data on acute oral toxicity of the test substance meet the criteria for classification as Acute Tox. 4 (H302) according to Regulation (EC) 1272/2008.

The available data on dermal toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.