Carbon monoxide

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: Non GLP

Data source

Reference

Reference Type:

publication

Title:

Threshold for carbon monoxide induced fetotoxicity

Author:

Singh, J and Scott, L.H

Year:

1984

Bibliographic source:

Teratology, 30., pp 253-257

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Pregnant female CD-1 mice were exposed to CO in air at 0, 65, 125, 250 or 500 ppm from gestation day 7 to 18 continuously.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Carbon monoxide

EC Number:

211-128-3

EC Name:

Carbon monoxide

Cas Number:

630-08-0

Molecular formula:

CO

IUPAC Name:

carbon monooxide

Details on test material:

- Name of test material (as cited in study report): Carbon monoxide
- Substance type: gas
- Physical state: colourless gas
- Analytical purity: not reported
- Impurities (identity and concentrations): not reported
- Composition of test material, percentage of components: not reported
- Isomers composition: not reported
- Lot/batch No.: not reported
- Expiration date of the lot/batch: not reported
- Stability under test conditions: not reported
- Storage condition of test material: not reported

Test animals

Species:

mouse

Strain:

CD-1

Administration / exposure

Route of administration:

inhalation: gas

Type of inhalation exposure (if applicable):

whole body

Vehicle:

clean air

Analytical verification of doses or concentrations:

no

Details on mating procedure:

Females were mated with males of the same strain prior to exopsure to the test substance.

Duration of treatment / exposure:

Gestation days 7 to 18

Frequency of treatment:

Continuous

Duration of test:

12 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 65, 125, 250 and 500 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

Not stated, however 17 litters/treatment group were obtained

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:

NOAEC

Effect level:

ca. 500 ppm (nominal)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Effect levels (fetuses)

Dose descriptor:

NOAEC

Effect level:

ca. 65 ppm (nominal)

Basis for effect level:

other: embryotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

No visible signs of maternal toxicity or rate of pregnancy were reported.

All animals survived till scheduled necropsy.

Mean percentage mortality/litter increased significantly (p< 0.01) in animals dosed at 500 ppm compared to the control. A dose dependent decrease in foetal bodyweight was observed, with animals dosed at 125, 250 and 500ppm all exhibiting statistically significant lower foetal bodyweights compared to the control group (see below):

CO (ppm)	No. Of litters	No. Of implantations	%Foetal mortality	No. of dead or resorbed foetus/litter	Foetal body wt (g)
0	17	197	4.52	0.53	0.9
65	17	210	5.89	0.76	0.86
125	17	183	12.50	1.23	0.83*
250	17	193	15.50	2.05	0.74**
500	17	182	55.30***	6.35***	0.68**
*     significantly different from control at p<0.05 **      significantly different from control at p<0.01 ***     significantly different from control and rest of the CO treatments at p<0.01

A small number of skeletal anomalies (lack of ossification) were observed in foetuses from all groups however these anomalies were not dose dependent.

Applicant's summary and conclusion

Conclusions:

The data presented in this paper would suggest that maternal CO exposure as low as 125ppm can affect foetal growth and that higher levels impair foetal survival. High levels of CO (up to 500 ppm) had no effect on pregnancy rates, compared to the control group.

The embryotoxic NOAEL was considered to be 65ppm.
The embryotoxic LOAEL was considered to be 125ppm (based on reduction in foetal bodyweight)
As no maternal toxic effects were observed, a LOAEL was not established, therefore the maternal NOAEL was considered to be 500ppm (highest dose tested).

Executive summary:

Following confirmation of a copulation plug, 5 groups of pregnant female mice (n=1 litters) were continuously exzposed to carbon monoxide at doses of 0, 65, 125, 250 and 500 ppm during gestation days 7 to 18. On day 18 aniamls were killed and uterine horns were examined for gross malformations.One third of the foetuses from each litter were examined for skeletal malformations and unossifications of ribs, sternebrae, spine and limbs.

All animals survived till the scheduled necropsy.Mean percentage mortality/litter increased significantly (p<0.01) in animals dosed at 500ppm compared to the control. A dose dependent decrease in foetal bodyweight was observed, with animals dosed at 125, 250 and 500ppm all exhibiting statistically significant lower foetal bodyweights compared to the control group.

A small number of skeletal anomalies (lack of ossification) were observed in foetuses from all groups however these anomalies were not dose dependent.

The data presented in this paper would suggest that maternal CO exposure as low as 125ppm can affect foetal growth and that higher levels impair foetal survival. High levels of CO (up to 500 ppm) had no effect on pregnancy rates, compared to the control group.

The embryotoxic NOAEC was considered to be 65ppm.

The embryotoxic LOAEC was considered to be 125ppm (based on reduction in foetal bodyweight)

As no maternal toxic effects were observed, a LOAEC was not established, therefore the maternal NOAEC was considered to be 500ppm (highest dose tested).