Iron digluconate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

Date of study initiation: August 5, 2000

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

Study is reported by US-FDA in the drug approval process for the product Ferinject (NDA 22-054 Ferinject) as iron replacement product indicated for the treatment of iron deficiency anemia, the original study report is not available but study and test item summaries can be accessed via: Drug Approval Package NJECTAFER (ferric carboxymaltose) Injection Company: Luitpold Pharmaceuticals, Inc. Application No.: 203565 Approval Date: 07/25/2013 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203565Orig1s000TOC.cfm Pharmacology Review(s), Chemistry Review(s) and Other Review(s)

Data source

Reference

Reference 1

Reference Type:

secondary source

Title:

Unnamed

Year:

2013

Report date:

2013

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

2000

Report date:

2000

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

Principles of method if other than guideline:

To study the potential teratogenic effects of VIT-45 in pregnant rabbits, VIT-45 was given by intravenous infusion to rabbits (22/group) at 0, 4.5, 9, 13.5, and 18 mg/kg/day from gestation days 6 to 19.

Study is reported by US-FDA in the drug approval process for the product Ferinject (NDA 22-054 Ferinject) as iron replacement product indicated for the treatment of iron deficiency anemia, the original study report is not available but study and test item summaries can be accessed via: Drug Approval Package NJECTAFER (ferric carboxymaltose) Injection Company: Luitpold Pharmaceuticals, Inc. Application No.: 203565 Approval Date: 07/25/2013 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203565Orig1s000TOC.cfm
Pharmacology Review(s), Chemistry Review(s) and Other Review(s)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

9007-72-1

Cas Number:

9007-72-1

IUPAC Name:

9007-72-1

Constituent 2

Reference substance name:

Ferric Carboxymaltose

IUPAC Name:

Ferric Carboxymaltose

Test material form:

other: Aqueous solution of dark brown colour (intended for intravenous use)

Details on test material:

- Molecular formula (as other than submission substance): [FeOx(OH)y(H2O)z]n [{C6H10O5)m(C6H12O7)}l]k where n=~10³, m=~8, l=~11 and k=~4
- Molecular weight (as other than submission substance): ca. 150'000 g/mol

- Physical state: The pure test item is a brown amorphous powder ( Chemistry Review(s), Reference ID: 3142758, page 9 of 74, i.e. p 26 of 45 of the PDF document)
- Lot/batch No.: 894209B

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: 19-27 weeks
- Weight at study initiation: 3.45 - 5.55 kg
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data

Study initiation date: 2000-08-05

Administration / exposure

Route of administration:

intravenous

Vehicle:

other: watery solution of sodium chloride 0.9 %

Details on exposure:

no data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Details on mating procedure:

no data

Duration of treatment / exposure:

treatment from gestation day 6 to 19

Frequency of treatment:

once daily i.v.

No. of animals per sex per dose:

22 female rabbits/group, for dose group 18 only 10 animals/group

Control animals:

yes, concurrent vehicle

Details on study design:

no data

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: no data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION ): Yes , daily

WATER CONSUMPTION: No data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day: no data
- Organs examined: yes, corpora lutea, gravid uterus

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes
- Head examinations: Yes: all per litter

Statistics:

no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Two dams per dose group died or were sacrificed. One dam in dose group 4.5, 9 and 18 mg/kg and two dams of group 13.5 mg/kg aborted. Prior to death/sacrifice dams in group 13.5 and 18 mg/kg had weight loss and reduced food intake. Most of these dose groups dams had liver tinged orange with accenturated lobular pattern. Brown/dark pinna was noted in the rabbits at 9 and 13.5 mg/kg and orange/brown eyelids in rabbits at 18 mg/kg. At necropsy orange/brown discoloration in various organs were noted it dams of group 9, 13.5 and 18 mg/kg/day. Preimplantation loss was marked in high dose group (33%) compared to control (18%).

Effect levels (maternal animals)

Dose descriptor:

LOAEL

Effect level:

4.5 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: at maternal toxic dose

Details on embryotoxic / teratogenic effects:
Three fetuses at high dose and two fetuses in 13.5 mg/kg group had marked domed craniums. Both 13.5 mg fetuses had additionally internal hydrocephaly or suspected hydrocephaly (major malformations). One fetus in 9 mg group had moderately domed cranium (minor malformation). The domed cranium was in incidence and severity dose related.

Effect levels (fetuses)

Key result

Dose descriptor:

NOEL

Effect level:

4.5 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: Basis for effect level / Remarks: head malformation

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1: Litter value – group value

Live young

Resorption

Implantation Loss %

Group

No. pregnant dams

Corpora lutea

Implant-ations

Males

Females

Total

Early

Late

Total

Pre-

Post-

1(control)

22

Means/ SD

12.5/3.4

10.1/2.9

4.1/1.7

4.1/2.29

8.2/2.3

0.9/0.9

1.0/1.0

1.9/1.3

18.1

17.4

2(4.5 mg/kg)

16

Means/ SD

13.1/1.9

11.5/2.8

4.9/1.7

4.7/1.8

9.6/2.5

0.5/0.7

1.4/1.2

1.9/1.3

13.1

15.0

3(9 mg/kg)

19

Means/ SD

11.6/2.0

9.6/3.1

3.9/2.0

4.4/2.1

8.3/3.5

0.6/0.8

0.7/0.9

1.3/1.1

16.3

14.0

5(13.5mg/kg)

16

Means/ SD

12.1/2.0

10.6/2.7

4.1/2.2

5.1/2.4

9.2/2.7

0.7/0.8

0.8/1.1

1.4/1.5

12.2

13.7

4(18 mg/kg)

7

Means/ SD

12.1/1.9

8.4/3.4

3.1/2.8

3.7/2.2

6.9/3.1

0.1/0.4

1.4/1.2

1.6/1.3

32.7

17.0

Table 2: Fetal examination – major abnormalities – group incidences

Gross Observation
	Fetus				Litters
Group	1	2	3	5	1	2	3	5
Dose (mg Fe/kg/day)	0	4.5	9	13.5	0	4.5	9	13.5
Number examined	181#	154	158	147	22	16	19	16
Number affected	2	1	2	3	2	1	2	3
Malformations
Marked internal hydrocephaly/suspected, marked domed cranium	-	-	-	2	-	-	-	2
Partially fused bilateral frontal, small left orbital socket	1	-	-	-	1	-	-	-
Fused bilateral parietal to interparietal, partially fused bilateral frontal, dilated pulmonary trunk, narrow ascending aorta, retroesophageal aortic arch, large/small atria, misshapen ventricle	-	1	-	-	-	1	-	-
Palatine irregularity, protruding tongue, incompletely ossified cranial bones and vertebral elements, irregularly ossified, kinked and medially thickened ribs, irregularly ossified long bones	-	-	-	1	-	-	-	1
Dilated ascending aorta and aortic arch, transposition of ascending aorta and dorsally displaced pulmonary trunk, displaced ductus arteriosus, ventricular septal defect	-	-	1	-	-	-	1	-
Lumbar scoliosis	-	-	1	-	-	-	1	-
Lumbosacral vertebral irregularities	1	-	-	-	1	-	-	-

  # Includes 1 early birth

Table 3: Fetal examinations – placental abnormalities – group incidences

Gross Observation
	Fetus				Litters
Group	1	2	3	5	1	2	3	5
Dose (mg Fe/kg/day)	0	4.5	9	13.5	0	4.5	9	13.5
Number examined	181#	154	158	147	22	16	19	16
Malformations
Amniotic sac, milky fluid in	1	-	-	-	1	-	-	-
Amniotic sac, tinged orange	-	-	-	55	-	-	-	6
Placenta, milky fluid around	1	1	-	-	1	1	-	-
Placenta, maternal potion tinged orange	-	-	-	95	-	-	-	10
Placenta, pale and swollen	-	-	-	9	-	-	-	1
Number of fetuses affected	1	1	-	122	1	1	-	13

  # Includes 1 early birth

Applicant's summary and conclusion

Conclusions:

The test substance does only show fetal effects at maternal toxic dose. Therefore, it is not considered as teratogenic.

Executive summary:

Pregnant rabbits were treated intravenously with ferric carboxymaltose (CAS 9007-72-1) at the doses of 4.5, 9, 13.5 and 18 mg Fe/kg /day from day 6 to 19 of pregnancy. After sacrifice or premature death section was performed on dams and fetuses.

Two dams per dose group died or were sacrificed. Prior to death/sacrifice dams in group 13.5 and 18 mg/kg suffered from weight loss and reduced food intake and showed a liver tinged orange with accentuated lobular pattern. Orange/brown discoloration in variuos organs were noted it dose group 9 mg/kg upwards. Several dams starting at dose group 4.5 mg/kg onwards aborted. Preimplantation loss was marked in high dose group (33 %) compared to control (18 %).

Three fetuses at high dose and two fetuses in 13.5 mg/kg developed marked domed craniums. Both 13.5 mg fetuses had additionally internal hydrocephaly or suspected hydrocephaly (major malformations). One fetus in 9 mg group had moderately domed cranium (minor malformation). The domed cranium was in incidence and severity dose related. All fetal effects appeared at maternal toxic dose. Therefore, ferric carboxymaltose is assumed to be not teratogenic under the conditions of this test.