2-methoxy-1-methylethyl acetate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-study.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

dosing from GD 6-15 only - compared to current guideline with dosing from GD6-20

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-methoxy-1-methylethyl acetate

EC Number:

203-603-9

EC Name:

2-methoxy-1-methylethyl acetate

Cas Number:

108-65-6

Molecular formula:

C6H12O3

IUPAC Name:

2-methoxy-1-methylethyl acetate

Details on test material:

- Name of test material (as cited in study report): PGMA
- Composition of test material, percentage of components: 97.3% of 2-methoxy-1-methylethyl acetate and 2.0 % of 1- methoxy-2- ) methylethyl acetate

Test animals

Species:

rat

Strain:

Sprague-Dawley

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

From Days 6 through 15 for 6 hours per day, pregnant rats were exposed either to PM Acetate vapor or room air. Vapors were generated by piping hot air through PM Acetate coated glass beads thus evaporating the liquid (reference 9). Chamber concentrations were measured three times a day at Hours 1, 3 and 5 by pumping chamber air to a MIRAN 80 Infrared Analyzer.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

days 6-15 of gestation

Frequency of treatment:

6 hours/day

Duration of test:

21 days

No. of animals per sex per dose:

Main study: 23 pregnant rats in dose groups 0, 500, 2000 ppm; 20 pregnant rats in dose group 4000 ppm
(due to variable fertility)

Control animals:

yes, concurrent vehicle

Details on study design:

Pregnant SD female rats were exposed to PGMA (purity: 97.3% of 2-methoxy-1-methylethyl acetate and 2.0 % of 1- methoxy-2- ) methylethyl acetate) vapour from Days 6 through 15 of gestation, once daily for 6 hours/day at nominal dose of 0, 500, 2,000, 4,000 ppm (0, 2700, 10800, 21600 mg/m3). The animals were sacrificed on Day 20 of gestation to evaluate the potential maternal, embryonic and teratogenic parameters of PGMA

Examinations

Maternal examinations:

Yes

Ovaries and uterine content:

Yes

Fetal examinations:

Yes

Statistics:

Yes

Indices:

Yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Most of the effects observed in dams were transient in nature. Reductions in muscle tone (2000 and 4000 ppm), food consumption (500, 2000 and 4000 ppm) and body weight (2000 and 4000) were seen during the exposure period. At 2000 and 4000 ppm exposure groups, dyspnea, ruffled pelt and red discharges from the eyes or mouth were observed. No toxic signs were observed in the 500 ppm exposure group. The effect on nasal cavity was not examined in this experiment.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

500 ppm

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

LOAEL

Effect level:

2 000 ppm

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No developmental toxicity was observed at any of the doses tested

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 4 000 ppm

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Pilot Study.

1.Ataxia was observed intermittently in several rats only in the 3000 ppm exposure group during exposure, but subsided soon after the rats were returned to their boxes.

2. Food consumption by dams as a percentage of body weight was lower in the 3000 ppm exposure group when compared to dams in the control group. This reduction coincided with the exposure period (Days 6 through 15) with the exception of the second and third exposure (Days 7 and 8). Food consumption returned to normal upon cessation of exposure. In the 1500 ppm exposure group, food consumption was lower only after the first exposure and in the 400 ppm exposure group it was never lower (data for the pilot study not shown herein).

3. Body weights, liver-to-body weight ratios and liver to brain weight ratios were not significantly different in any exposure group. There were no dose-related gross necropsy findings in the dams or fetuses.

 

Main Developmental Toxicity Study.

1.Group parameters. Group indexes, counts and other summary data for the study are presented without analysis in Table 1.

 

TABLE 1.GROUP PARAMETERS

PM Acetate Rat Inhalation Developmental Study

	Control	500 ppm	2000 ppm	4000 ppm
Females mated	25	25	25	25
Fatalities	0	0	0	0
Females at sacrifice	25	25	25	25
Females pregnant	23	23	23	20
Fertility index (%)	92	92	92	80
Litters	23	23	23	20
Gestation Index (%)	100	100	100	100
Implantations (total)	333	330	320	278
Implantations per dam	14.5	14.3	13.9	13.9
Fetuses (total)	319	304	307	260
Fetuses per dam	13.9	13.2	13.3	13.0
Index of alive fetuses (%)	100	100	100	100
Dead Fetuses (total)	0	0	0	0
Dead Fetuses per dam	0	0	0	0
Resorptions (total)	14	26	13	18
Early resorptions	14	26	8	18
Late resorptions	0	0	5	0
Resorptions per dam	0.6	1.1	0.6	0.9
Resorption index (%)	4.20	7.88	4.06	6.47
Malformations (total)	0	1	1	0
Litters with Malformations	0	1	1	0
Malformations per dam	0	0.04	0.04	0
Index of malformations (%)	0	0.33	0.33	0
Variations (total)	17	19	16	11
Litters with Variations	9	13	7	6
Variations per dam	0.74	0.83	0.70	0.55
Index of variations (%)	5.33	6.25	5.21	4.23
Runts	0	0	2	3
Sex Ratio (M/F)	1.10	0.90	0.99	1.08

 

2. Maternal parameters.

a. Toxic signs. Nearly half of the 20 dams in the 4000 ppm exposure group exhibited dyspnea at various times throughout the exposure period (Days 6 through 15). Breathing returned to normal soon after the dams were returned to their boxes. Half had red to reddish brown discharges from the nose and/or eyes on Days 8 and 10 through 15. Four dams were observed to have yellow staining in the fur of the urogenital area ranging from slight to marked on Days 6, 8, 13 and 14. Reduced muscle tone was observed during handling in 15 dams on two separate occasions. Movement returned to normal within 20 minutes of being returned to their boxes. In the 2000 ppm exposure group, one dam exhibited dyspnea, one had a ruffled pelt and two had red discharges from the eye or mouth. No toxic signs were observed in the 500 ppm exposure group.

b. Food consumption. In the 4000 ppm exposure group, a reduction of food consumption as a percentage of maternal body weight coincided with exposure to PM Acetate. A similar pattern was seen in the 2000 ppm exposure group where food consumption was lower on Days 7, Days11 through 13 and Day 15. In the 500 ppm exposure group, food consumption was lower on Days 7 and11

c. Maternal body weights and body weight gains. Maternal body weights were lower in the 4000 and 2000 ppm exposure group after the last day of exposure only. Maternal body weights in the 500 ppm exposure group were always the same as controls.However, when weight gains were analyzed, dams in the 4000 ppm exposure group did not gain as much as controls during the exposure period and gained less overall. Dams in the 2000 ppm exposure group gained less weight during the first two thirds of the exposure period and less overall also Dams in the 500 ppm exposure group gained weight at the same rate as dams in the control group.

d.Maternal organ weight ratios. There were no differences in relative liver or uterus weights between dams in the control group and dams in any exposure group whether ratios were calculated from body weights or brain weights.

3.Litter and Fetal Parameters.

a. Corpora lutea, implantation, litter size, resorption and fetal death. The number of corpora lutea, implantation sites and live fetuses per litter was the same in the exposed groups as controls. Both the percent of conceptuses resorbed per litter and the percent of litters which contained a resorption were the same in the exposed groups as the controls. There were no dead fetuses in any litter.

b. Fetal body weights and runts. There were no dose related differences in fetal body weights. The average fetal body weights in the 4000 and 2000 ppm exposure groups was approximately 5 percent lower than the low and controls. This difference was statistically significant in the 2000 ppm exposure group, however, the 4000 ppm exposure group was marginally nonsignificant. There was no difference in the percent of litters which contained runts.

c. Fetal sex ratio. There was no difference in the male to female sex ratio.

d. Malformations and variations. There were no differences in the percent of fetuses per litter that were malformed, had variations or were normal. In addition, there were no differences in the percent of litters which contained a malformation, a variation or contained all normal fetuses.

Applicant's summary and conclusion

Conclusions:

A NOAEC was established at 500 ppm (2700 mg/m3 measured) for dams and 4,000 ppm (22464 mg/m3, measured) for foetuses.

Executive summary:

In a GLP study, pregnant SD female rats were exposed to PGMA (purity: 97.3% of 2-methoxy-1-methylethyl acetate and 2.0 % of 1- methoxy-2- ) methylethyl acetate) vapour from Days 6 through 15 of gestation, once daily for 6 hours/day at nominal dose of 0, 500, 2,000, 4,000 ppm (0, 2700, 10800, 21600 mg/m3). The animals were sacrificed on Day 20 of gestation to evaluate the potential maternal, embryonic and teratogenic parameters of PGMA. Most of the effects observed in dams were transient in nature. Reductions in muscle tone (2000 and 4000 ppm), food consumption (500, 2000 and 4000 ppm) and body weight (2000 and 4000) were seen during the exposure period. At 2000 and 4000 ppm exposure groups, dyspnea, ruffled pelt and red discharges from the eyes or mouth were observed. No toxic signs were observed in the 500 ppm exposure group. The effect on nasal cavity was not examined in this experiment. No developmental toxicity was observed. A NOAEC was established at 500 ppm (2700 mg/m3, measured) for dams and 4000 ppm (22464 mg/m3, measured) for foetuses