Formaldehyde

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:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Acceptable with some restrictions: No data about purity of the test substance or stability in food; only low dose tested without maternal toxicity; some evaporation of formaldehyde prior to consumption presumed (resulting in lower dose levels). Study limited to a restricted number of parameters (e.g. data on visceral or skeletal alterations only in stillborn pups or pups which died later in post natal observation period, no data on maternal weight gain). No statistical analysis.

Data source

Reference

Reference Type:

publication

Title:

Reproduction study with formaldehyde and hexamethylenetetramine in Beagle dogs

Author:

Hurni H & Ohder H

Year:

1973

Bibliographic source:

Fd Cosmet Toxicol 11: 459-462

Materials and methods

Principles of method if other than guideline:

Teratogenic effects in dogs after oral exposure via the food.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Formaldehyde

EC Number:

200-001-8

EC Name:

Formaldehyde

Cas Number:

50-00-0

Molecular formula:

CH2O

IUPAC Name:

formaldehyde

Details on test material:

- Name of test material (as cited in study report): formaldehyde

Specific details on test material used for the study:

- Specification
40% formalin (presumably stabilized with 10% methanol)

Test animals

Species:

other: dog

Strain:

other: Beagle

Details on test animals or test system and environmental conditions:

- Source: Closed breeding colony of the same laboratory
- Sex: Female
- Age/weight at study initiation: no data / ca. 12 kg
- Dogs received certified diet (dog pellets, Nafag AG, Gossau, Switzerland).
- 4-5 pregnant dogs in one indoor cubicle plus outdoor run; animals single in whelping rooms 1 week before term.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Solution of the required daily dose in 2 ml were prepared weekly and sprayed on the pellets prior to feeding. Pellets were consumed within 5-10 min (authors statement: no volatilization; comment: some evaporation expected).

Details on exposure:

Concentration in food: 0, 125 and 375 ppm (0, 0.012, 0.037%)
food consumption per day: 300 g per animal per day corresponding to 0, 3.1, or 9.4 mg/kg bw/day (authors calculation).
Controls received the plain diet.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

No details

Duration of treatment / exposure:

Day 4 after mating up to day 56

Frequency of treatment:

once daily

Duration of test:

Normal birth. Pups observed up to 9 months after birth

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

125 ppm

Remarks:

- 0.012%
- 3.1 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

375 ppm

Remarks:

- 0.037%
- 9.4 mg/kg bw/day

No. of animals per sex per dose:

9-10 pregnant bitches (10-11 mated bitches)

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

- Body weight Yes, maternal weight determined at weekly intervals.
- Food consumption See above
- Clinical signs No data

Ovaries and uterine content:

No data

Fetal examinations:

External malformations examined immediately after birth and after 8 weeks. Autopsy of stillborn pups and those lost before weaning. Further parameters: total pups at birth, total live pups at birth, total pups at weaning, mean live (or total) pups per litter at birth and at weaning, mean litter size, sex ratio, mean pup weight (measured daily after birth for 8 days).
Skeletal and visceral malformations examined only in stillborn or pups who died postnatal.

Statistics:

no

Indices:

no data

Historical control data:

no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

No effects.

No data about clinical symptoms and maternal weight gain. No effects on number of pregnant bitches, number of litters and mean length of gestation (range or SD not given). No local maternal effects in the gastro-intestinal tract expected (max. concentration 0.037% in the diet)

Effect levels (maternal animals)

Dose descriptor:

LOAEL

Effect level:

> 9.4 mg/kg bw/day (nominal)

Basis for effect level:

other: study not sufficient for identifying a NOAEL, no local effects expected (max. concentration in the diet: 0.037%)

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:

No effects.

No effects on parameters listed above. Mean values given but no data on SD, SE or range. No skeletal or visceral malformation in stillborn pups or pups which died later (no further details).

Effect levels (fetuses)

Dose descriptor:

LOAEL

Effect level:

> 9.4 mg/kg bw/day (nominal)

Basis for effect level:

other: study not sufficient for identifying a NOAEL

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

No effects on behaviour, appearance, motility and muscular co-ordination in dogs observed for a more prolonged period.

Applicant's summary and conclusion

Conclusions:

No developmental effects in dogs exposed via the diet to doses up to 9.4 mg/kg bw/day but limited number of parameters examined.

Executive summary:

Study meets generally accepted scientific standards but limited number of parameters examined. Further deficiencies: No data about purity of the test substance; only low dose tested without maternal toxicity; some evaporation of formaldehyde prior to consumption presumed (resulting in lower dose levels). Study limited to a restricted number of parameters (e.g. data on visceral or skeletal alterations only in stillborn pups or pups which died later in post natal observation period, no data on maternal weight gain). No statistical analysis.

Pregnant Beagle dogs (9-10 pregnant bitches per dose) were exposed from day 4 after mating up to day 56 to a diet containing formaldehyde at dose levels of 0, 3.1, or 9.4 mg/kg bw/day. The dose levels (max. 9.4 mg/kg bw) and concentrations (max. 0.037% in the diet) were relative low (no local effects expected). No toxic effects were reported in the bitches (but no data on body weight gain). External malformations were examined immediately after birth and after 8 weeks. Autopsy was performed on stillborn pups and those lost before weaning. Further parameters: total pups at birth, total live pups at birth, total pups at weaning, mean live (or total) pups per litter at birth and at weaning, mean litter size, sex ratio, mean pup weight (measured daily after birth for 8 days). Concerning the investigated parameters no developmental toxicity was detected.

Conclusion: no developmental effects in dogs exposed via the diet to doses up to 9.4 mg/kg bw/day but limited number of parameters examined.