[2-(2-methoxymethylethoxy)methylethoxy]propanol

Endpoint summary

Description of key information

Two GLP-studies according to OECD guideline 401 are available supported by two non-GLP studies equivalent to OECD guideline 401. For the inhalation route a non-GLP study equivalent to OECD guideline 403 is available, which is supported by a study published in the peer-reviewed literature. Two non-GLP studies equivalent to OECD guideline 402 are available for tripropylene glycol methyl ether.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1986

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-study according to OECD guideline 401.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Sprague-Dawley CFY

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Interfauna (UK) limited, Wyton, Huntingdon
- Age at study initiation: Males: 121-151 g and females: 101-136 g
- Weight at study initiation: Approximately five to eight weeks old
- Fasting period before study: overnight fasting immediately before dosing
- Housing: The animals were housed in groups of up to five by sex in polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): Rat and Mouse Expanded Diet No. 1, Special Diet Services Limited, Witham, Essex, U. K.
- Water (e.g. ad libitum): Drinking water ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22º C
- Humidity (%): 45-65 %
- Air changes (per hr): 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours darkness


IN-LIFE DATES: not specified

Route of administration:

oral: gavage

Vehicle:

other: none

Details on oral exposure:

Four groups of Sprague-Dawley rats (5/sex/dose level) received single  oral doses of 2300, 3000, 3900, or 5000 mg/kg polypropylene glycol methyl  ether (PPM), administered undiluted using a stainless steel stomach cannula attached to a syringe.  Animals were fasted overnight prior to  dosing. The specific gravity was determined and used to calculate the appropriated dose volumes for the required dose levels.

Doses:

2300, 3000, 3900 and 5000 mg/kg

No. of animals per sex per dose:

5 rats/sex/dose

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed 1 and 4 hours after dosing and subsequently once daily for 14 days. Individual body weights were recorded on the day of treatment (day 0), days 7 and 14 and at death.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathological examinations

Statistics:

LD50's and 95% confidence limits were calculated for both sexes  individually and combined using the method of Weil (Biometrics 8:249,  1952).

Preliminary study:

A preliminary study was performed using groups of two rats (one male and one female) to determine suitable dose levels for the main study. The doses were 500, 1000, 2000, 4000 and 8000 mg/kgbw. Animals were observed 1 and 4 hours after dosing and then daily for five days, or until all evidence had subsided, whichever was longer. Bodyweights were recorded on the day of dosing. No necropsies were performed. Mortalities occured at the dose level of 8000 mg/kgbw (2/2). The mortalities indicated an oral LD50 of between 4000 and 8000 mg/kg.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 500 mg/kg bw

95% CL:

>= 3 100 - <= 3 900

Sex:

male

Dose descriptor:

LD50

Effect level:

3 600 mg/kg bw

95% CL:

>= 3 100 - <= 4 200

Sex:

female

Dose descriptor:

LD50

Effect level:

3 400 mg/kg bw

95% CL:

>= 2 900 - <= 4 100

Mortality:

Males:-
2300 mg/kg: 0/5
3000 mg/kg: 1/5
3900 mg/kg: 3/5
5000 mg/kg: 5/5

Females:-
2300 mg/kg: 0/5
3000 mg/kg: 2/5
3900 mg/kg: 3/5
5000 mg/kg: 5/5

Clinical signs:

other: Symptoms in survivors exhibited a dose-response relationship and included  hunched posture, lethargy, piloerection, decreased respiratory rate,  ptosis, body tremors, and red/brown staining around the eyes or snout at  all dose levels.  Other more severe 

Gross pathology:

Necropsy of survivors revealed congested lungs in 4 males  and 4 females from the 2300 mg/kg group but not in the 3000 or 3900 mg/kg  groups.

Other findings:

None

Mortality is shown in the table below:

Dose Level(mg/kg)	Mortalities
	Male	Female	Both Sexes	Percentage
2300	0/5	0/5	0/10	0
3000	1/5	2/5	3/10	30
3900	3/5	3/5	6/10	60
5000	5/5	5/5	10/10	100

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

With an oral LD50 of 3500 mg/kg, polypropylene glycol methyl ether shows a low degree of acute toxicity. This test material is appears to be comprised largely of tripropylene glycol methyl ether.

Executive summary:

Twenty five male and twenty five female Sprague Dawley CFY strain rats were used. Animals were acclimatized for a minimum period of five days. At the start of the main study the males weighed 121-151 g, and the females 101-136 g, and were approximately five to eight weeks old. The animals were housed in groups of up to five by sex in polypropylene cages with sawdust bedding. With the exception of an overnight fast immediately before dosing and for approximately two hours after dosing, free access to mains drinking water and food was allowed throughout the study.

The animal room was maintained at a temperature of 19-22º C and relative humidity of 45-65%. The rate of air exchange was approximately 15 changes per hour.

Following an initial range-finding study, four groups, each of ten rats (five males and five females) were given a single oral dose of test material at dose levels of 2300, 3000, 3900 and 5000 mg/kg bodyweight.

Animals were observed 1 and 4 hours after dosing and subsequently once daily for 14 days. Mortalities and evidence of overt toxicity were recorded at each observation. Individual bodyweights were recorded on the day of treatment (day 0), days 7 and 14 and at death. All animals were subjected to gross necropsy examination for any microscopic abnormalities. No tissues were retained.

Symptoms in survivors exhibited a dose- response relationship and included hunched posture, lethargy, piloerection, decreased respiratory rate, ptosis, body tremors and red/ brown staining around the eyes or snout at all dose levels. Other more severe symptoms occurring more often at higher dose levels included coma and gasping respiration. By day 2, symptoms had disappeared in the two lower dose levels and by day 3 in survivors from the 3900 mg/kg group.

Deaths occurred in a dose related manner (3/10 at 3000 mg/kg, 6/10 at 3900 mg/kg and 10/10 at 5000 mg/kg). All rats which died did so within 24 hours of dosing and survivors recovered from the non-specific signs of toxicity within 3 days of dosing. Some survivors were reported to have congested lungs at necropsy after 14 days observation but most were unremarkable.

The LD50 in rats for Dowfroth 250E was 3600 mg/kg for males, 3400 mg/kg for females and 3500 mg/kg for the sexes combined (3100-3900 mg/kg 95% confidence limits). As the LD50 of the test material was greater than 2000 mg/kg, Dowfroth 250E was not classified as toxic as per EU classification.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 400 mg/kg bw

Quality of whole database:

Good (Klimisch 1)

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1977

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted prior to GLP and guidelines. The report contains sufficient amount of data for the interpretation of the results. Non-GLP study equivalent to OECD guideline 403.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:Glass Exposure chamber
- Exposure chamber volume: 9 litre
- Source and rate of air:Substantially saturatted vapor
- Method of particle size determination: Dynamically
- Temperature, humidity, pressure in air chamber: 24C

Duration of exposure:

8 h

Concentrations:

30 ppm at 25C

No. of animals per sex per dose:

6

Control animals:

not specified

Sex:

not specified

Dose descriptor:

LC0

Effect level:

> 30 ppm

Exp. duration:

8 h

Remarks on result:

other: No signs of toxicity observed

Mortality:

No

Clinical signs:

other: No

Body weight:

Increase i.e., 53 to 77 grams

Gross pathology:

Nothing remarkable

Other findings:

No

Procedure A	Time	Concentration	Dead/Dosed	Death	Weight Change	Signs and/or symptoms
A	8 hr	Substantially saturated vapor	0/6	-	53 to 77 gm	-

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

No hazard is anticipated from the infrequent inhalation of substantially saturated vapor generated at room temperature under normal handling conditions.

Executive summary:

Six rats were exposed to concentrated vapors for 8 hours. Concentrated vapor was generated in a gas washing bottle by passing dried air at 2.5 liters/min through a fritted glass disc immersed to a depth of at least 1 -1/2 inches in the chemical which is delivered to rats in a 9 -liter glass exposure chamber. Mean vapor concentration was calculated from the loss in weight of the liquid or estimated from the vapor pressure at the acutal temperature of the chemical during aeration.

No signs/symptoms of toxicity observed during the observation. Gross pathology shows no remarkable changes in it. There was a gradual increase inthe body weight range observed in all the rats. Out of six rats, all animals servived without any changes. No hazard is anticipated from the infrequent inhalation of substantially saturated vapor generated at room temperature under normal handling conditions.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

Good (Klimisch 2)

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1977

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP study equivalent to OECD guideline 402.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

other: Albino (strain not specified)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 3 to 5 months old
- Weight at study initiation: weight not specified

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

For a period of 24 hour, TPM was applied under occlusion (impermeable  wrap - polyethylene sheeting) to the clipped, intact skin of the trunk of  male albino rabbits at dose levels of 8.0 or 16 milliliters TPM per kg  body weight.  These dose volumes correspond to 7.72 or 15.4 g/kg (7720 or  15400 mg/kg).  Rabbits were restrained in an undefined manner.  At the  end of the 24-hour application period, excess TPM was removed and the  rabbits were observed for mortality and signs of toxicity for an  unspecified period thereafter (presumably up to 14 days).

Duration of exposure:

24 hour

Doses:

8.0 and 16.0 ml/kgbw. These dose volumes correspond to 7.72 or 15.4 g/kg (7720 or 15400 mg/kg).

No. of animals per sex per dose:

4 per group

Control animals:

not specified

Statistics:

no data

Sex:

male

Dose descriptor:

LD50

Effect level:

15 440 mg/kg bw

Mortality:

16 ml/kg: 2/4
8 ml/kg: 0/4

Clinical signs:

other: The high dose of 16 ml/kg (15400 mg/kg) caused death in 2 of 4 rabbits on  days 2 and 3.  Non-survivors lost 80 and 113 grams of weight and one  subject from this group had an unsteady gait and another was prostrate at  24 hours.  At 8 ml/kg (7720 mg/kg),

Gross pathology:

At necropsy, non-survivors showed mottled livers,  mottled spleens, and full bladders.  Survivors exhibited pale and mottled  kidneys.

Other findings:

None

LD50: 16 ml/kg or 15440 mg/kg

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The dermal LD50 of TPM is 16 ml/kg or 15400 mg/kg with a very broad 95% confidence interval ranging from 4.48 to 57.2 ml/kg, according to the authors, of the fractional mortality at the high dose. TPM shows a low order of acute dermal toxicity.

Executive summary:

A sample of Propasol Solvent TM (sample no. 40-130) was evaluated for acute toxicity potential in male albino rabbits. 4 rabbits per group of 3 to 5 months old were used in the study.

For a period of 24 hour, TPM was applied under occlusion (impermeable wrap - polyethylene sheeting) to the clipped, intact skin of the trunk of male albino rabbits at dose levels of 8.0 or 16 milliliters TPM per kg body weight. These dose volumes correspond to 7.72 or 15.4 g/kg (7720 or 15400 mg/kg). Rabbits were restrained in an undefined manner. At the end of the 24-hour application period, excess TPM was removed and the rabbits were observed for mortality and signs of toxicity for an unspecified period thereafter (presumably up to 14 days)

The high dose of 16 ml/kg (15400 mg/kg) caused death in 2 of 4 rabbits on days 2 and 3. Non-survivors lost 80 and 113 grams of weight and one subject from this group had an unsteady gait and another was prostrate at 24 hours. At 8 ml/kg (7720 mg/kg), no rabbits died and no symptoms were reported.

At necropsy, non-survivors showed mottled livers, mottled spleens, and full bladders. Survivors exhibited pale and mottled kidneys.

The dermal LD50 of TPM is 16 ml/kg or 15400 mg/kg with a very broad 95% confidence interval ranging from 4.48 to 57.2 ml/kg, according to the authors, of the fractional mortality at the high dose. TPM shows a low order of acute dermal toxicity.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

15 440 mg/kg bw

Quality of whole database:

Good (Klimisch 2)

Additional information

Oral - Four acute oral toxicity studies in rats reported LD50 values ranging from 3400 to 5462 mg/kg bw. The lowest LD50 is taken forward for the risk assessment. The key study identified for acute oral toxicity is the Dow (1986) study in rats and the LD50 (male and female) is 3500 mg/kg body weight. In the other supporting studies - Lyondell (Arco, 1984) and another Dow/UCC (1977) study, the LD50 was greater than 5000 mg/kg body weight.

Inhalation - At the highest attainable vapor concentration (30 ppm) of tripropylene glycol methyl ether, no signs of toxicity have been observed. The key study identified is the Dow/UCC (1977) study in rats with a LC0 of greater than 30 ppm (saturated vapor study, duration 8 hours), equivalent to approximately 257.26 mg/m3 (based on conversion equation at 20 degree celsius and 1 atmosphere). Using Haber's law for converting this 8 -hour exposure to a 4 -hour exposure, the equivalent LC0 value is 0.32 mg/l.

In the supporting (aerosol) study - Dow (1975) study, the LC0 values were in excess of 200 mg/l (duration 1 -hour). This concentration is far in excess of the theoretical vapor concentration and hence the animals were exposed to tripropylene glycol methyl ether as an aerosol. Using Haber's law for converting this 1 -hour exposure to a 4 -hour exposure, the equivalent LC0 value is greater than 50 mg/l. In both the studies, there were no mortalities observed.

Dermal - Two acute dermal toxicity studies in rabbits reported LD50 values of 15440 and greater than 19300 mg/kg bw. The lower LD50 value is taken forward to the risk assessment.

Justification for selection of acute toxicity – oral endpoint
The study was conducted according to OECD TG 401 and in accordance with the Principles of GLP

Justification for selection of acute toxicity – inhalation endpoint
The study was conducted prior to GLP and guidelines. The report contains sufficient amount of data for the interpretation of the results. Non-GLP study equivalent to OECD guideline 403.

Justification for selection of acute toxicity – dermal endpoint
The study methodology followed was equivalent or similar to OECD TG 402

Justification for classification or non-classification

All acute toxicity studies via the oral and dermal route reported LD50 values greater than 2000 mg/kg bw. No toxicity was observed at the highest attainable vapor concentration. Hence, no classification for acute toxicity is required according to EU criteria for classification and labelling requirements for dangerous substances as laid down in Annex VI of the EEC Council Directive 67/548 EEC (amended by Directive 83/467 EEC).

Also, as per Globally Harmonized System of classification and labelling of chemicals (GHS), tripropylene glycol methyl ether will not be classified for acute oral and acute inhalation toxicity, as no mortality was noted in doses tested up to 2000 mg/kg body weight via the oral and dermal routes and similarily, no mortality was noted in the saturated vapor study (Dow/UCC, 1977) and the aerosol study tested in excess of 200 mg/l.