Erythromycin

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 22, 1985 to Febrauary 13, 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Segment II study conducted to GLP- adequate and acceptable for development endpoint.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

The purpose of this study was to re-evaluate the embryolethal and teratogenic potentials of ABBOTT-56268 following daily oral administration to pregnant rats during the period of major organogenesis.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Erythromycin

EC Number:

204-040-1

EC Name:

Erythromycin

Cas Number:

114-07-8

Molecular formula:

C37H67NO13

IUPAC Name:

6-{[4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-4-[(5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy]-3,5,7,9,11,13-hexamethyloxacyclotetradecane-2,10-dione (non-preferred name)

Test animals

Species:

rat

Strain:

other: Crl:Cn@(SD)BR rats

Details on test animals or test system and environmental conditions:

Crl:Co® (SD)BR rats were used because this is the strain in which a small number of cardiovascular abnormalities were noted among fetuses whose dams were exposed to 150 mg/kg/day of ABBOTT-5
6268.

TEST ANIMALS
- Source:Charles River Laboratories. sperm-positive female Crl:co®(SD)BR rats,2 bred by the suppl ier and shipped so as to arrive prior to gestation day 6
-
- Fasting period before study:
- Housing:housed in individual stainless steel hanging cages
- Diet (e.g. ad libitum):Certified Rodent Chow® #50023
- Water (e.g. ad libitum): yes tap water
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): in a temperature- regulated (72 ± 5°F) room.Temperature and humidity were continuously monitored.
- Photoperiod (hrs dark / hrs light): The room was on a 14-hour daily light cycle. IN-LIFE DATES: August 22, 1985 through September 7, 1985

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.2% hydroxypropylmethylcellulose

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Rats in groups T1, T2 and T3 received ABBOTT-56268 suspended in 0.2% hydroxypropylmethylcellulose . Animals in the T0 group received the suspending medium only.Personnel in D-468 prepared the T1, T2, T3 formulations once each week.

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0.2%
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of dosing formulations for groups T0-T4 were sent to D-417 (PPD Analytic Research) for analysis of ABBOTT- 56268 concentrations.
Assay results for the submitted ABBOTT-56268 formulations were within 2-3% of theoretical in all cases.

Duration of treatment / exposure:

day 6 of gestation to day 20 of gestation.

Frequency of treatment:

Administered once each day by gavage

Duration of test:

treatment dates. August 22, 1985 through September 7, 1985.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

15 mg/kg bw/day (nominal)

Remarks:

Basis:
analytical conc.

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

Basis: analytical conc.

Doses / concentrations 3

Dose / conc.:

150 mg/kg bw/day (nominal)

Remarks:

Basis: analytical conc

No. of animals per sex per dose:

20 females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

All animals were observed at least twice daily (approximately 1-2 and 24 hours post-treatment) durin g the treatment period for signs of altered behavior or physical condition. Once treatment was susp



ended single daily observations were instituted. Body weights were recorded on gestational days 6, 9,
12 and 15 and once again just prior to laparotomy on
gestational day 20. Food consumption was measured for gestational days 6- 9, 9-12 and 12-15. Any animal that died was examined by a pathologist

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily (approximately 1-2 and 24 hours po st-treatment) during the treatment period for signs of altered behavior or physical condition. Once treatment was suspended single daily observations were instituted

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule: All animals were observed at least twice daily (approximately 1-2 and 24 hours p ost-treatment) during the treatment period for signs of altered behavior or physical condition. Once treatment was suspended single daily observations were instituted

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded on gestational days 6, 9, 12 and 15 and once again just prior to laparotomy on
gestational day 20.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes. Food consumption was measured for gestational days 6- 9, 9-12 and 12-15.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: All fetuses were then delivered by abdominal section, sexed, weighed and examined for grossly visible external abnormalities. Number and uterine positions of live and dead fetuses, resorptions, degenerating fetuses and any abnormalities were recorded

OTHER: All fetuses were then processed for further evaluation.All specimens were placed in Bouin
's Solution and were allowed to stand for one to several weeks to permit decalcification, then were examined for visceral defects.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:

Number and uterine positions of live and dead fetuses, resorptions, degenerating fetuses and any abnormalities were recorded.

Fetal examinations:

- External examinations: Yes: [all per litter }
- Soft tissue examinations: Yes: [all per litter)



- Skeletal examinations: Yes: [all per litter
- Head examinations: No data

Statistics:

Data pertaining to maternal body weight and food consumption, fetal weights, sex ratios, resorbed embryos and degenerate fetuses, litter size and fetal abnormalities were summarized.Appropriate statistical evaluation (as determined by Nonclinical Statistics) was performed as needed. All statistica
l tests were performed at the 0.05 level of significance.

Historical control data:

Due to the extreme rarity of such abnormalities among concurrent or historical controls, even this l ow level of cardiovascular abnormalities must be judged to be drug-related. The absence of serious abnormalities in a study performed at comparable doses in another strain of rat (Slc:Wistar) points to the possibility that these adverse developmental findings may be strain specific.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Maternal deaths and treatement related observations:One control animal died as a result of an int ubation accident; all other animals survived.
Overt clinical signs were not evident.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight gain and food consumption were adversely affected at the 150 mg/kg/day dose of ABB OTT-56268.
Lesser effects on both parameters at the 50 mg/kg/day dose of ABBOTT-56268 and no effect at 15 mg/kg/day dose.

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: body weight
Maternal deaths and treatement related observations:One control animal died as a result of an int ubation accident; all other animals survived.
Overt clinical signs were not evident.

Body weight gain and food consumption were adversely affected at the 150 mg/kg/day dose of ABB OTT-56268.
Lesser effects on both parameters at the 50 mg/kg/day dose of ABBOTT-56268 and no effect at 15 mg/kg/day dose.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

>= 50 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): No statistically significant differences, but mean weight of T3 (150 mg/kg/day, ABBOTT-
56268)fetuses was slightly reduced compared with controls.

External malformations:

not specified

Description (incidence and severity):

The only serious grossly visible abnormalitywas a markedly reduced lower jaw
10 a T2 (50 mg/kg, ABBOTT-56268) fetus. Superficial hematomas were noted among 3 T0, 2 T1 and
1 T3 fetuses.

Visceral malformations:

not specified

Description (incidence and severity):

.A statistically significant increasing trend in incidence of undescended testes among ABBOTT-56268-treated groups was noted.In terms of incidence this was O T0, 0 T1, 1 T2 and 2 T3 fetuses.No biological significance is attributed to these small differences.

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: A low level of major cardiovascular abnormalities was found rat fetuses following oral administration at 150 mg/kg/day.This dosage was maternally toxic as well. No significant developmental effects were noted at a dosage of 50 mg/kg/day.

Details on embryotoxic / teratogenic effects: Embryolethality: no effect
Feta weights: No statistically significant differences, but mean weight of T3 (150 mg/kg/day, ABBOTT-
56268)fetuses was slightly reduced compared with controls.
Fetal Development: Incidence of major malformations was quite low; however, the few cardiovascular abnormalities noted (3 abnormal fetuses in 2 litters), were confined to the T3 (150 mg/kg/day) group.

Gross Abnormalities.The only serious grossly visible abnormalitywas a markedly reduced lower jaw
10 a T2 (50 mg/kg, ABBOTT-56268) fetus. Superficial hematomas were noted among 3 T0, 2 T1 and
1 T3 fetuses.

Visceral Findings.A statistically significant increasing trend in incidence of undescended testes among ABBOTT-56268-treated groups was noted.In terms of incidence this was O T0, 0 T1, 1 T2 and 2 T3 fetuses.No biological significance is attributed to these small differences.

Effect levels (fetuses)

Remarks on result:

not determinable

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The incidence of major cardiovascular malformations was very low in this study.However, the 3 affected fetuses (from 2 litters) were in the T3 (150 mg/kg, ABBOTT-56268) group. This dosage wa s maternally toxic as well. Due to the extreme rarity of such abnormalities among concurrent or his
torical controls, even this low level of cardiovascular abnormalities must be judged to be drug-related. The absence of serious abnormalities
in a study performed at comparable doses in another strain of rat (Slc:Wistar) points to the possibility that these adverse developmental findings may be strain specific.

No significant developmental effects were noted at a dosage of 50 mg/kg/day.