Valeric acid

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Unsuitable test sytem. Range-finding study.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Reference 2

Reference Type:

other company data

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Principles of method if other than guideline:

Investigation of the tolerance/adverse effects (maternal toxicity and fertility) of test substance in pregnant rats by application of graduate doses of test substance from day 6 through day 15 of gestation.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Valeric acid

EC Number:

203-677-2

EC Name:

Valeric acid

Cas Number:

109-52-4

Molecular formula:

C5H10O2

IUPAC Name:

pentanoic acid

Details on test material:

- Name of test material (as cited in study report): C-180
- Physical state: clear colorless liquid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Lot/batch No.: no data
- Stability under test conditions: no data
- Storage condition of test material: at room temperature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc., Kingston, NY, USA
- Age at study initiation: 12 weeks
- Weight at study initiation: 177 - 285 g
- Fasting period before study: no data
- Housing: induvidually in stainless steel wire-mesh cages
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow, ad libitum
- Water (e.g. ad libitum): tap water (via water bottles), ad libitum
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24
- Humidity (%): 25 - 56
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: From: September 16, 1981 To: November 7, 1981

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: dissolution of test substance in vehicle and subsequently stirring for 5 minutes

VEHICLE
- Justification for use and choice of vehicle (if other than water): suitable solvent
- Concentration in vehicle: 100 mg/mL
- Amount of vehicle (if gavage): 1.0 mL/kg bw for low dose group, 5.0 mL/kg bw for mid-dose group, 10.0 mL/kg bw for high dose group
- Lot/batch no. (if required): no data
- Purity: no data

Details on mating procedure
- M/F ratio per cage: 1/2
- Length of cohabitation: maximal 16 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 9 days of unsuccessful pairing, females were rotated to males that had successfully mated
- Further matings after two unsuccessful attempts: no data
- After successful mating each pregnant female was caged (how): induvidually in stainless steel wire-mesh cages

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- M/F ratio per cage: 1/2
- Length of cohabitation: maximal 16 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 9 days of unsuccessful pairing, females were rotated to males that had successfully mated
- Further matings after two unsuccessful attempts: no data
- After successful mating each pregnant female was caged (how): induvidually in stainless steel wire-mesh cages

Duration of treatment / exposure:

from day 6 to day 15 of gestation (only dams)

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 500, 1000 mg/kg bw and day
Basis:
actual ingested

No. of animals per sex per dose:

6

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: not required for a range finding study
- Rationale for animal assignment (if not random): random assignment
- Other: only female animals were used, exposure period from day 6 to day 15 of gestation. Animals were killed after 15 days of gestation (Day 16).

Examinations

Maternal examinations:

SACRIFICE
- Male animals: no data; male animals were not examined.
- Maternal animals: dams were sacrificed by carbon dioxide asphyxiation on day 16 of gestation.

GROSS NECROPSY
- Gross necropsy was performed . The uterus of each female was examined to confirm pregnancy. The number of corpora lutea per ovary, the number and placement of uterine implantations, resorptions and live and dead fetuses were recorded.

HISTOPATHOLOGY / ORGAN WEIGHTS
- not examined

Ovaries and uterine content:

GROSS NECROPSY
- Gross necropsy was performed . The uterus of each female was examined to confirm pregnancy. The number of corpora lutea per ovary, the number and placement of uterine implantations, resorptions and live and dead fetuses were recorded.

Fetal examinations:

GROSS NECROPSY
- Gross necropsy was performed . The uterus of each female was examined to confirm pregnancy. The number of corpora lutea per ovary, the number and placement of uterine implantations, resorptions and live and dead fetuses were recorded.

HISTOPATHOLOGY / ORGAN WEIGHTS
- not examined

Statistics:

Bartlett's test for homogeneity of variance (Bartlett, 1937) to compare data of control group to data of treated groups followed by by a one-way classification analysis of variance (ANOVA) (Snedecor and Cochran, 1957).
Comparision of group mean values by the multiple pairwise comparison procedure of Scheffe (1953) if ANOVA of homogeneous data were significant and by Games and Howell's multiple pairwise comparison procedure (1976) if ANOVA of heterogeneous data were significant.
Ovarian and uterine data were analyzed on a per litter basis using nonparametric comparision of group means (Kruskal and Wallis 1952, Miller 1966)

Historical control data:

no

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Only pregnant females were examined

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Two animals of the low dose group died during treatment (at day 10 and day 12). Gross pathology findings indicate tracheal intubation as cause of death (see reference 2). There was no mortality at 500 or 1000 mg/kg bw and day.

Clinical signs were seen in one or two animals of all dose groups. A clear dose related effect is not evident.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No statistically significant effects on body weight were noted. The rats dosed at 100 mg/kg bw showed a slight decrease in body weight from day 9 to day 12. For the 1000 mg/kg bw dose group, the mean body weight decreased from day 6 to day 9. There was no dose related effect.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Gross pathology findings were observed in 2 animals of the 100 mg/kg bw dose group (affected organs: lung, kidney, stomach), in 1 animal of the 500 mg/kg bw dose group (affected organ: lung) and in 2 animals of the 1000 mg/kg bw dose group (affected organ: kidney). The observed effects were not dose related.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Not examined

OTHER FINDINGS (PARENTAL ANIMALS) - OVARIAN AND UTERINE DATA
There were no significant effects on ovarian or uterine parameters. Mean ovarian and uterine data were comparable between the control and the treated groups except the mean percent resorption in the group dosed with 1000 mg/kg bw. The deviation was caused by one animal which had 100% resorption at its implantation sites.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

LOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:not examined

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Based on a transient body weight effect and gross pathology at 1000 mg/kg bw and no significant effect at 500 mg/kg bw, a dose of 750 mg/kg bw was selected as teratology screen dose (reference 2).

Applicant's summary and conclusion

Conclusions:

The investigation of the maternal toxicity of n-valeric acid in pregnant rats did not show significant differences between control and treated groups.
Based on a transient body weight effect and gross pathology at 1000 mg/kg bw and no significant effect at 500 mg/kg bw, a dose of 750 mg/kg bw was selected as teratology screen dose.

Executive summary:

A maternal tolerance study was performed with n-valeric acid in order to determine dose levels for a subsequent teratology screening study. N-valeric acid was administered to pregnant female Sprague-Dawley rats, 6 animals per dose, by gavage at dose levels of 0, 100, 500, and 1000 mg/kg bw. Animals were treated daily from day 6 to day 15 of gestation. At day 16 of gestation, animals were sacrificed and mortality, clinical signs, body weight, food consumption, water consumption, gross pathology, and ovarian and uterine parameters were evaluated.   The observed data did not demonstrate significant differences between control and treated groups. A dose related effect was not observed.   A NOAEL was not determined.   Based on a transient body weight effect and gross pathology at 1000 mg/kg bw and no significant effects at 500 mg/kg bw, a dose of 750 mg/kg bw was selected as teratology screening dose. The study procedure did not follow a valid test guideline but may be regraded as a range finding study.