Reaction mass of (2-methoxymethylethoxy)propanol and [2-(2-methoxymethylethoxy)methylethoxy]propanol and sodium methanolate

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:

supporting study

Study period:

1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Test procedures were in accordance with accepted standard methods, well documented. Potential findings of developmental effects are limited by a lack of robust findings, low numbers of animals under test, and normal variation seen for the endpoints. The data were obtained from a secondary source (OECD, 2006)

Data source

Reference

Reference 1

Reference Type:

other: NTP-CERHR Review

Title:

NTP-CERHR Monograph on the potential human reproductive and developmental effects of methanol

Author:

NTP

Year:

2003

Bibliographic source:

NIH Publication No. 03-4478, September, 2003.

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1999

Materials and methods

Principles of method if other than guideline:

Test method in general accordance with standard methods.

GLP compliance:

not specified

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

Methanol, reagent special grade from Junsei Chemicals Co.
<1 ppm vinyl chloride; <3 ppm formaldehyde

Test animals

Species:

monkey

Strain:

Macaca fascicularis

Details on test animals or test system and environmental conditions:

Female animals exposed pre-breeding, breeding and during pregnancy. Portions of this study measured methanol pharmacokinetics, maternal toxicity, reproductive toxicity and developmental toxicity.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

Adult female monkeys were exposed to methanol vapor for 2.5 hours daily before breeding, during breeding and during pregnancy. Postnatal development evaluations were performed on 8 to 9 infants per group, in total 34, of which 26 were in-utero treated.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

No data

Duration of treatment / exposure:

Prebreeding: about 120 days
Birth: first 9 months of life of offspring

Frequency of treatment:

Daily, 2.5 hours

Duration of test:

As specified under duration of treatments

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 200, 600 or 1800 ppm (0, 0.262, 0.786 or 2.358 mg/L)
Basis:
nominal conc.

No. of animals per sex per dose:

11-12 adult female monkeys/group

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Clinical observations

Blood methanol and formate concentrations

Fetal examinations:

Not performed

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

1 800 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
See discussion below

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

1 800 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

2

Dose descriptor:

NOAEL

Effect level:

1 800 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Offsrping Behavioral Assessments

The results or behavioral assessments of offspring did not indicate methanol-induced effects on most parameters of behavioral development. No consistent effects due to  methanol exposure were observed on early reflex responses, gross motor development, spatial and concept learning and memory, and social behavior.

 

Methanol exposure was associated with ratings of "low arousal" on the Neonatal Behavioral Scale. The effects were observed when all of the methanol-exposed infants were compared with controls. Further comparisons, however did not indicate a dose-dependence of the effect.

 

Methanol exposure was also associated with a delay in early sensorimotor development of male infants only (Visually

 Directed Reaching Test). The effect was observed after controlling for the shortened gestation length observed for the 3 methanol-exposed groups. The delay was dose-dependent and ranged from 9 days for the 200 ppm exposure group to over 2 weeks for the 600 ppm- and 1800 ppm-exposure groups. This observation is based on results from group sizes of 8 to 9 infant animals, with 2 to 5 males and 4 to 7 females per group (II, p. 86). The statistical significances (linear contrast test based on ANOVA) of p = or <0.04: This test indicated a significant difference between control infants compared with all methanol-exposed offsprings combined, as well as with the 600- and 800-ppm groups for males (p<0.04). The comparison between the control group and  the 200-ppm was nerly significant (p=0.09).

 

The results of the Fagan-Test of Infant Intelligence indicated a possible effect of methanol exposure on visual recognition memory when complex stimuli (social problems) were used in testing. Although there were no mean group differences in the novelty scores across the 4 exposure groups, only the control group exhibited a significant novelty preferences for social stimuli.

Blood Levels, Methanol

There were no significant differences in concentrations of blood methanol during the 4 exposure phases of the study. Baseline methanol was approx. 2 microg/mL. At the 1800 ppm exposure concentration, methanol blood levels ranged up to 35 -40 microg/mL. After a 5 -hour elimination phase, blood methanol levels at the highest exposure concentration were near baseline.

Blood Levels, Formate

Irrespective of exposure concentration, there was no evidence of significant increase in formate above the background range of 0.15 to 0.30 mM.

Wasting Syndrome

Prenatal methanol exposure was associated with a wasting syndrome in 2/7 female offspring from the same cohort of animals at the highest exposure concentration. These animals became weak and were euthanized at 20 or 36 months. Necropsies showed sever malnutrition and gastroenteritis. This symptom was not observed in any offspring of the other cohort.

Applicant's summary and conclusion

Conclusions:

Overall, a robust effect of prenatal methanol exposure on neurobehavioral development in nonhuman primates during the first 9 months of life was not provided by this study. The NOAEL for both maternal and offspring effects was 1800 ppm.