Malic acid

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Experimental data published in peer reviewed journal

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2001

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

no

Remarks:

Study pre-dates implementation of GLP regulations

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Malic acid

EC Number:

230-022-8

EC Name:

Malic acid

Cas Number:

6915-15-7

Molecular formula:

C4H6O5

IUPAC Name:

2-hydroxybutanedioic acid

Details on test material:

No data

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

No data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: No data

VEHICLE
- Concentration in vehicle: Up to 175 mg/mL
- Amount of vehicle (if gavage): Up to 2 mL/kg

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: No data
- Length of cohabitation: No data
- Proof of pregnancy: vaginal plug, referred to as day 0 of pregnancy

Duration of treatment / exposure:

Days 6-15 of gestation

Frequency of treatment:

Daily

Duration of test:

20 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

3.5 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

16.2 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

75.4 mg/kg bw/day (nominal)

Doses / concentrations 5

Dose / conc.:

350 mg/kg bw/day (nominal)

No. of animals per sex per dose:

25-29 / group
Number gravid/number mated: 0.0 mg/kg (controls) = 23/25; 3.5 mg/kg (low dose) = 20/25; 16.2 mg/kg = 21/29; 75.4 mg/kg = 22/25; 350 mg/kg (high dose) = 26/28

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations included: Appearance, behaviour and food consumption.

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 11, 15 and 20 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Uterus and urogenital tract

Ovaries and uterine content:

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

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes, 1/3 of litter
- Skeletal examinations: Yes, 2/3 of litter
- Head examinations: No data

Statistics:

No data

Indices:

No data

Historical control data:

No data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: lack of observed maternal toxicity

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

350 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Lack of treatment-related effects

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

Summary of findings of the embryo-foetal toxicity study in rats.

Daily Dose (mg/kg)	0 (Control)	3.5	16.2	75.4	350.0
Dams/Does:
No. Used/No. Pregnant	25/23	25/20	29/21	25/22	28/26
No. Died or Sacrificed Moribund	0	0	0	0	2
No. Aborted or with Total Resorption of Litter	0	0	0	0	0
Clinical Observations	-	-	-	-	-
Necropsy Observations	-	-	-	-	-
Body Weight (g^a)	346	348	339	325	321
Total No. dams with resorptions	2	0	3	5	2
Mean % resorptions	8.70	0.00	14.3	13.6	8.33
Mean No. Implantations	11.4	12.0	11.3	10.4	10.3
Litters:
No. Litters Evaluated	23	20	21	22	24
Mean No. Live Foetuses	11.3	12.0	11.2	10.1	10.3
No. of Litters with dead Foetuses	2	2	2	2	1
Mean Foetal Body Weight (g)	3.80	3.93	3.79	3.79	3.78
Foetal Sex Ratio (♂/♀)	0.77	0.99	0.88	1.18	0.89
Foetal Anomalies:
Gross External	0	0	0	0	0
Visceral Anomalies	0	0	0	0	0
Skeletal Variations	232	151	105	171	138
Key: - = No noteworthy findings       a = At termination

Applicant's summary and conclusion

Conclusions:

Administration of malic acid to pregnant rats for 10 consecutive days during the critical period of organogenesis had no clear effect on maternal or foetal survival. The number and nature of abnormalities of the soft or skeletal tissues were no different from those seen in control animals.

Executive summary:

Developmental toxicity has been investigated using methods similar or equivalent to those described in OECD TG 414. Administration of malic acid to pregnant rats for 10 consecutive days during the critical period of organogenesis had no clear effect on maternal or foetal survival. The number and nature of abnormalities of the soft or skeletal tissues were no different from those seen in control animals. The NOAEL from the study was 350 mg/kg body weight/day.