Erythromycin, 9-oxime, monohydrochloride

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From January 24, 2006 to February 21, 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study was performed according to OECD Guideline 402 and EU method B.3, with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

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

Test material

Test material information

Constituent 1

Reference substance name:

(3R,4S,5S,6R,7R,9R,10E,11S,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-10-(hydroxyimino)-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyloxacyclotetradecan-2-one hydrochloride

Cas Number:

26116-57-4

Molecular formula:

C37H69ClN2O13

IUPAC Name:

(3R,4S,5S,6R,7R,9R,10E,11S,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(Dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-10-(hydroxyimino)-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyloxacyclotetradecan-2-one hydrochloride

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): Erythromycin A-9 Oxime (E) Hydrochloride.
- Physical state: white powder.
- Lot/batch No.: B5310059
- Storage condition of test material: at ambient temperature, in the dark.
- Other:
pH: 6.16 (1% solution in deionised water, w/v, determined with a pH-Meter WTW pH340)

Test animals

Species:

rat

Strain:

other: CRL: CD (SD) BR SPF

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland GmbH, D-94633 Sulzfeld.
- Age at study initiation: approximately 8 weeks (males) and 12 weeks (females) at the time of administration.
- Weight at study initiation:
Animal No. 121: 275 g
Animal No. 122: 258 g
Animal No. 123: 265 g
Animal No. 124: 246 g
Animal No. 125. 258 g
Animal No. 126: 248 g
Animal No. 127: 239 g
Animal No. 128: 226 g
Animal No. 129: 230 g
Animal No. 130: 230 g

- Housing: Single caging in Makrolon cages type III (39 cm x 23 cm x 18 cm). Wire mesh lids. Sanitation of cages once a week.
- Diet (e.g. ad libitum): Altromin 1324 forte (Producer: Altromin GmbH, D-32791 Lage) gamma irradiated with 25 kGy 60Co, ad libitum.
- Water (e.g. ad libitum): Tap water, offered in Makrolon bottles with stainless steel canules, ad libitum.
- Acclimation period: at least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Average of 21.9 ºC (continous control and recording)
- Humidity (%): Average of 48.0 % (continous control and recording)
- Photoperiod (hrs dark / hrs light): Artificial light from 6 a.m. to 6 p.m.
- Air change: 12 per hour.

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 6.5 cm x 8 cm
- % coverage: 10 % of the estimated body surface.
- Type of wrap if used: non irritating tape (Blenderm Wundpflaster, 3M)

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.

Duration of exposure:

24 hours.

Doses:

Range-finding study: 400, 894 or 2000 mg/kg bw.
Main study: limit-test with one dose of 2000 mg/kg bw.

No. of animals per sex per dose:

Five

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing:
Body weights: before administration, 7 and 14 days after administration.
Clinical observations: at least once per day (Observations: 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 at least 2 weeks; 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)
- Necropsy of survivors performed: yes

Results and discussion

Preliminary study:

In a range-finding study 3 groups of one male and one female each were dosed with 400, 894 or 2000 mg/kg bw. All animals survived for 7 days p.a. Therefore a limit-test with one dose of 2000 mg/kg bw was performed.

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: No local or systemic effects related to administration of the test substance were noted from clinical observations. General findings: all animals were normal during the entire observation period. Observation of skin condition: exposed skin was not found t

Other findings:

- Other observations:
Staining of skin which is attributed to the staining properties of the test substance was observed in all animals.
Necropsy findings: all animals were normal at terminal necropsy.
Sex differences: No noteworthy sex difference in the response to the test substance was derived from clinical observations or post-mortem findings.

Any other information on results incl. tables

Table 1. Synopsis of the results.

Dose (mg/kg)	Sex	No. of animals			Prominent findings
		exposed	affected	deceased	in life		post mortem
					systemic	local
2000	male	5	0	0	none	none	none
2000	female	5	0	0	none	none	none

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

No local or systemic test substance effects were noted at clinical observations or post-mortem examination at a dose of 2000 mg test substance per kg body weight. The dermal LD50 value of the test substance in rats was established to exceed 2000 mg/kg body weight.

Executive summary:

Assessment of acute dermal toxicity of the test substance was determined according to the OECD 402 Guideline and B.3 EU Method, with GLP. The test substance was administered once dermally on an area of approximately 6.5 cm x 8 cm on the dorsal thoracal region of 5 male and 5 female Sprague Dawley rats. The dose was 2000 mg/kg bw. 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. Patch and tape were covered semi-occlusively by a dressing. The duration of the exposure was 24 hours. The dermal LD50 value of the test substance in rats was established to exceed 2000 mg/kg bw.