[2-(2-methoxymethylethoxy)methylethoxy]propanol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1983-1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The data quality from this study is considered acceptable. The report included documentation for methods and results. This study reaches Klimisch level 1. GLP-study equivalent to OECD guideline 414. Quality Check: This study was identified as key for this toxicity endpoint because of the methods followed (which were comprehensively documented in the report). The report contained signed GLP and Quality Assurance statements. The report adequately described the various study parameters, satisfying OECD Protocol 414: "Teratogenicity" (12 May 1981), including the numbers and type of test animals used and their husbandry conditions. Test material characterization was adequate. The amount of test material to which test subjects were exposed complied with guidance, the length of the treatment period (organogenesis) was sufficient, and evaluation criteria and statistical methods were typical for this type assay and adequately recorded.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

[2-(2-methoxymethylethoxy)methylethoxy]propanol

EC Number:

247-045-4

EC Name:

[2-(2-methoxymethylethoxy)methylethoxy]propanol

Cas Number:

25498-49-1

Molecular formula:

C10H22O4

IUPAC Name:

[2-(2-Methoxymethylethoxy)methylethoxy]propanol

Details on test material:

Identity: DOWANOL TPM, Tripropylene glycol methyl ether (TPM)
CAS: 25498-49-1 or 20324-33-8
Appearance: Translucent liquid.
Batch No.: 18-8876.
Shipping container: 45 gallon drum containing 125 kg TPM.
Source: Dow Chemical Canada via Van Waters Rodgers.
Expiration Date: Not specified.
Purity: 98.5% TPM isomers.
Specific Gravity: 0.965
Solubility in water: Miscible (from other reports).
Stability: Stable up to 200°C (from other reports).
Boiling point: 242.8°C at 760 mmHg (from other reports).
Vapor pressure: 0.017 mmHg at 25°C (from other reports).
Storage: Room temperature in shipping container.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories
- Age at acclimation: 13-14 weeks (females)
- Weight at study initiation: 223-262 g
- Housing: individual housing in stainless steel mesh-bottomed cages
- Diet (e.g. ad libitum): ad libitum, except during exposure
- Water (e.g. ad libitum): ad libitum, except during exposure
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 2°C
- Humidity (%): 50 ± 20%
- Photoperiod (hrs dark / hrs light): 12 hours (light/dark cycle)


IN-LIFE DATES: From: August 30, 1983 To: September 24, 1983

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Four 32-inch cubed (600-liter volume) stainless steel whole-body exposure chambers (Rochester type)
- Method of holding animals in test chamber: Individually housed
- Source and rate of air: ambient room air
- Temperature, humidity, pressure in air chamber: measured hourly during exposure (mean chamber temperature - 20-24°C, mean relative humidity - 60-90 %)
- Air flow rate: 60 L/min
- Treatment of exhaust air: Exhaust air was drawn from the chambers at a a slight negative pressure and was passed through charcoal and HEPA filters before being eliminated from the facility.

Four 32-inch cubed (600-liter volume) stainless steel whole-body exposure chambers (Rochester type) were utilized. The animals were restrained in stainless steel wire mesh compartmentalised cage with each of 28 compartments measuring 7x4x3 inches. Air was drawn through the chambers by means of a low pressure vacuum pump, flow rate (60L/min) through the chamber was measured in the exhaust line of each chamber by measuring the pressure differential across an orifice plate on a magnehelic plate, calibrated against a conventional ball-type flowmeter. A Thermo Systems Inc. (TSI) 6-jet atomizer was used for each test group to generate an aerosol of the test article. One jet was used at individually set air pressures for each treatment conditions such that the targeted concentration of the test article was achieved in each inhaltion chamber.


TEST ATMOSPHERE
- Brief description of analytical method used: gravimetric and particle size analysis performed for each chamber and analysed at sponsor's site.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The mean achieved gravimetric concentrations were 0.10, 0.29 and 1.02 mg/l and the average mass median particle diameter ranged from 2.47 - 3.75 µm

Details on mating procedure:

- Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 1:1/2 (male:female)
- Length of cohabitation: overnight
- Further matings after two unsuccessful attempts: [no]
- Proof of pregnancy: [sperm in vaginal smear] referred to as [day 0] of pregnancy

Duration of treatment / exposure:

Day 6 through 15 of gestation

Frequency of treatment:

Daily

Duration of test:

10 days

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/l of air
Basis:
nominal conc.
analytical concentration (0 mg/m3-0 ppm)

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.1 mg/l of air
Basis:
nominal conc.
analytical concentration (100 mg/m3-27 ppm)

Doses / concentrations 3

Remarks:

Doses / Concentrations:
0.3 mg/l of air
Basis:
nominal conc.
analytical concentration (300 mg/m3-81 ppm)

Doses / concentrations 4

Remarks:

Doses / Concentrations:
1.0 mg/l of air
Basis:
nominal conc.
analytical concentration (1000 mg/m3-271 ppm)

No. of animals per sex per dose:

25 mated female Sprague Dawley rats/dose

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: Based on the results of a range finding study
- Rationale for animal assignment: Following mating the female rats were randomly assigned to groups using a computer-generated set of random numbers.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weighed on days 0, 6, 9, 12, 15, 18 and 20 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: detailed gross examinations (including examination of the abdominal and thoracic cavities and of the cranium) and their livers, lungs, kidneys, brains and gravid uteri examined.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes / No / No data
- Number of corpora lutea: Yes / No / No data
- Number of implantations: Yes / No / No data
- Number of early resorptions: Yes / No / No data
- Number of late resorptions: Yes / No / No data
- Other: The uteri of the non-pregnant females were stained with a solution of ammonium sulfide for 20 minutes and were then stained with implantations.

Fetal examinations:

- External examinations: Yes:
- Soft tissue examinations: Yes: [2/3 per litter ]
- Skeletal examinations: Yes: [1/3 per litter ]
- Head examinations: Yes: [2/3 per litter ]

Statistics:

Refer to table 1 for further details

Indices:

Pre-implantation and post-implantation losses were calculated

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal toxicity in the 1.0 mg/l group was evidenced by a high incidence of muzzle staining.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

0.3 mg/L air (nominal)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
At dosage levels of up to 1.0 mg/l, DOWANOL TPM did not cause embryolethality, teratogenicity or fetotoxicity.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 1 mg/L air (nominal)

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

DOWANOL TPM did not cause embryo-, fetal, or developmental toxicity in fetuses at any exposure level. Maternal toxicity was evident in the high exposure level only, based on an increased incidence of red staining of the muzzle compared to controls. The NOAEL for maternal toxicity is 0.29 mg/liter and the LOAEL is 1.02 mg/liter, based on stained muzzles. The NOAEL for developmental effects is 1.02 mg/liter and the LOAEL is > 1.02 mg/liter.

Executive summary:

Four groups of 25 mated female Sprague-Dawley rats were exposed to an aerosol of DOWANOL TPM (tripropylene glycol methyl ether) by the whole-body exposure technique for 6 hours a day from day 6 to day 15 of gestation inclusive at target chamber concentrations of 0, 0.1, 0.3 or 1.0 mg/l of air.

No deaths occurred during the study.

There was an increased incidence of red staining of the muzzle at the 1.0 mg/l level.

Body weight of the DOWANOL TPM-treated rats was similar to that of the control rats.

The gross pathology of the DOWANOL TPM-treated rats was normal and there was no significant intergroup differences in the weights of selected organs.

The uterine parameters (numbers of corpora lutea, live fetuses, dead fetuses, resorptions, implantations, the pre- and post-implantation losses, fetal weights and the sex ratios) were not affected by treatment. In all groups the pregnancy rate was at least 80 per cent.

The overall incidences of fetal findings, major malformations and minor visceral and skeletal anomalies in the treated groups were not significantly different from control values. Significantly decreased incidences of thoracic vertebral skeletal variants at the 0.1 and 1.0 mg/l levels were considered to be unrelated to treatment. The incidences of sternebral variants were unaffected by DOWANOL TPM treatment.

In conclusion, maternal toxicity in the 1.0 mg/l group was evidenced by a high incidence of muzzle staining. At dosage levels of up to 1.0 mg/l, DOWANOL TPM did not cause embryolethality, fetotoxicity or teratogenicity.