Registration Dossier

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Administrative data

Description of key information

A GLP-study according to OECD guideline 407 is available for dipropylene glycol methyl ether acetate. This data is supported by GLP-studies equivalent to OECD guidelines 407 and 413 for dipropylene glycol methyl ether. Further, several studies according to or similar to OECD guidelines 411 and 413 are provided for propylene glycol methyl ether and dipropylene glycol methyl ether.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study according to OECD guideline 407.
Qualifier:
according to guideline
Guideline:
other: Annex V, Published in the official journal of E.C.(No. L25I, 19 September 1984)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River ( UK )
- Age at study initiation: 5-6 week
- Weight at study initiation: Male -144-150 gms and Female - 107 - 111 gms
- Housing: Rats were housed 2 or 3 of one sex per cage in suspended polypropylene cages with stainless steel wire grid tops and bottoms
- Diet ( ad libitum): SQC Expanded rat and mouse maintenance diet No. 1 supplied by special diet services limited,Stepfield, Witham, Essex, CM8 3 AB.
- Water ( ad libitum):Tap water
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 °C - 22 °C
- Humidity (%): 45 - 65 %
- Air changes (per hr): 15-20
- Photoperiod : (12hrs dark / 12hrs light)


Route of administration:
oral: gavage
Vehicle:
other: Distilled water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared daily using distilled water as vehicle.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See the attachment - 2
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
100 mg/kg
Basis:
other: nominal concentration
Remarks:
Doses / Concentrations:
250 mg/kg
Basis:
other: nominal concentration
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
other: nominal concentration
No. of animals per sex per dose:
5 animals per sex per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Dose levels were selected for this is on the basis of preliminary one week oral range finding study , conducted by Inveresk Research International.
Positive control:
no data
Observations and examinations performed and frequency:
-CAGE SIDE OBSERVATIONS: No
-DETAILED CLINICAL OBSERVATIONS: Yes, Weekly
-BODY WEIGHT: Yes
-Water Consumption : Yes, Weekly
-Time schedule for examinations: Weekly
-FOOD EFFICIENCY: Not Examined
-OPHTHALMOSCOPIC EXAMINATION: No
-HAEMATOLOGY: Yes
- Time schedule for collection of blood: During 4th week of dosing
- Anaesthetic used for blood collection: Yes ( Light Ether Anaesthesia )
- Animals fasted: Yes
- How many animals: 40
- Parameters checked : Hb, RBC, HCT, MCH, MCV, MCHC, WBC, DLC
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:During 4th week of dosing
- Animals fasted: Yes
- How many animals: 40
- Parameters checked : BUN, Glu, AST, ALT, AP,Na, K, Cl, TP, Alb, AG-R, Crea, Ca, Phos, T. Bl.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
none
Statistics:
Hematology, Clinical chemistry, organ weight and body weight data were statistically analysed for homogeneity of variance using the F-max test. If the group variances appeared homogenous a parametric ANOVA was used and pairwise comparisons made via student’s T test using Fischer’s F- protected LSD. If the variances were heterogeneous log or square root transformations were used in an attempt to stabilize the variances. If variances remained heterogeneous then a non parametric test such as Kruskal- Wallis ANOVA was used.
Organ weights were also analysed conditional on body weight. Histological data were analysed by Fisher’s Exact Probability test
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY : Increased breathing and subdued behavior were evident in the majority of animals of both sexes receiving T-4388. There were no deaths found during 4 weeks of dosing period.

BODY WEIGHT AND WEIGHT GAIN : There were no notable intergroup differences in either sex during 4 weeks of oral administration of T-4388.

FOOD CONSUMPTION :There were no notable intergroup differences in either sex during 4 weeks of oral administration of T-4388.

FOOD EFFICIENCY : Not examined

HAEMATOLOGY :There were no notable intergroup differences in either sex .

CLINICAL CHEMISTRY : There were no notable intergroup differences in either sex .

ORGAN WEIGHTS : There was a slight increase in liver in high dose females.

GROSS PATHOLOGY : There were no notable intergroup differences in either sex .

HISTOPATHOLOGY: NON-NEOPLASTIC : There were no findings considered to be due to administration of the test material.






Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (nominal)
Sex:
male/female
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: Slight increase in liver weight of females not accompanied by histopathological changes.
Critical effects observed:
not specified
The only effects observed during this study were increased liver weights and subdue behaviour and increased breathing. The liver weight increase was very slight and only observed in females of the highest dose group. There were no histopathologic changes accompanying this effect. The same effect was observed with other structurally related molecules, e.g. propylene glycol methyl ether has been shown to cause liver weight increases via a phenobarbital-like enzyme induction mode of action and it is highly likely that dipropylene glycol methyl ether acetate liver weight increases occur via the same mode of action. As this is an adaptive effect typical for many glycol ethers, it is not consered as adverse. The toxicological significance of the observed increased breathing and subdue behaviour is unclear. As these observations were not accompanied by any significant effect, they are considered as not relevant.
Conclusions:
Based on the results of this study a dose of 1000 mg/kg/day was identified as no observed adverse effect level. Based on a slight increase in liver weight which was not accompanied by histopathologic changes and observed in females only. The no observed effect level is 250 mg/kg/day.

dosing Sprague-Dawley rats with dose levels of 100, 250, 1000 mg/kg/day T-4388 produced increased breathing and subdued behavior in the majority of animals of both sexes receiving T-4388 and a slight increase in liver weight at 1000 mg/kg/day in females
Only.

Executive summary:

Four groups of Sprague- Dawley rats each containing 5 males and 5 females received T- 4388 (colorless liquid) via oral route by steel cannula at dose levels of 0,100, 250, 1000 mg/kg/day daily for 28 days. Rats were received from Charles River (UK) and housed 2 or 3 of one sex per cage in suspended polypropylene cages with stainless steel wire grid tops and bottoms. Animals were kept for acclimatization for 8 days and provided adlibitum feed and water. Temperature maintained in animal rooms was 18 °C - 22 °C with relative humidity of 45 - 65 % and 15-20 air changes.12 hour dark and 12 hour light photoperiod was maintained.

All animals were monitored for toxic effects which included clinical observations, body weights, organ weights, hematology, clinical chemistry, macroscopic and microscopic evaluations. Increased breathing and subdued behavior were evident in the majority of animals of both sexes receiving T-4388. There were no deaths found during 4 weeks of dosing period.

In body weights and feed consumption, there were no notable intergroup differences in either sex during 4 weeks of oral administration of T-4388. In hematology and clinical chemistry, there were no notable intergroup differences in either sex. In organ weights there was a slight increase in liver in high dose females.

There were no notable intergroup differences in either sex in gross pathology. There were no microscopic findings considered to be due to administration of the test material T-4388.

Based on the results of this study a dose of 1000 mg/kg/day was identified as no observed adverse effect level. Based on a slight increase in liver weight which was not accompanied by histopathologic changes and observed in females only. The no observed effect level is 250 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
good

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study according to OECD guideline 413.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)
GLP compliance:
yes
Limit test:
no
Species:
other: Rat and Rabbit
Strain:
other: Fischer - 344 and New zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Rats :Charles River Breeding Laboratories (Portage, MI and Rabbits : Langshaw Rabbitry (Augusta, MI)
- Age at study initiation: 9 weeks for rats
- Weight at study initiation: Rats (140-195 gms) for male and female and for rabbits approx. 3 kg and above
- Housing: Rats (2/cage) and rabbits (1/cage) were housed in stainless steel cages with wire bottoms
- Diet (ad libitum): A standard laboratory diet (Purina Certified laboratory Chow, Ralson Purina Co., St. Louis. MO)
- Water (ad libitum): ad libitum except during exposure
- Acclimation period: 2 weeks for rats and 4 weeks for rabbits


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 -24°C
- Humidity (%): 40- 60 % (Relative humidity)
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:Stainless steel and glass inhalation chambers
- Method of conditioning air:DPGME was vaporized and metered into the chambers with a compressed air flames heat torch/j-tube assembly as described by Miller.The concentration of DPGME in each chamber was measured approximately once per hour with a Varian 2400 GC with 1/8" by 6 nickel column (8%Triton X-305 on 100/120 chromosorb) and flame ionization detector. Standard bags were made by adding DPGME to a "U-tube" 100 l of dry filtered air was metered through the tube into gas tight bag. Heat was applied to the test material to facilitate vaporirization.A series of standards which included15, 50,200 ppm were made and analyzed at least biweekly to produce standard curve.
- Temperature, humidity, in air chamber: Temperature- Mean maximum in the 4 chambers were 24-26°C
- Air flow rate: 800 l/min


TEST ATMOSPHERE :Measured mean chamber DPGME concentrations were within 1% of target concentrations (15, 50,200 ppm). Mean nominal DPGME concentrations (based on chamber air flow) were good in agreement (within 8%) with mean analytical concentrations, indicating that the test material losses were minimized in the vapor generator and exposure systems. Chamber distribution studies indicated that the test atmosphere concentrations were uniform within 10% inside each chamber.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See the attachment-5
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hr/day, 5 days/week for 13 weeks
Remarks:
Doses / Concentrations:
0, 15, 50, or 200 ppm (0, 91, 303, or 1,212 mg/m3) for rats and rabbits
Basis:
nominal conc.
No. of animals per sex per dose:
Rats : 10/sex/exposure
Rabbits : 7/sex/exposure
Control animals:
other: Yes, room air.
Details on study design:
Post-exposure period: none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly once prior and after exposure.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD EFFICIENCY: Not examined
-WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 12 weeks of exposure
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: Rats :40 male and 40 female Rabbit : 27 male and 28 female
- Parameters checked : PCV, Hgb, RBC, WBC (total and differential), Plat, RBC indices


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples from rats for clinical chemistries were taken at necropsy.
- Animals fasted: Yes
- How many animals: Rats 40 male and 40 female and Rabbits :27 male and 28 female
- Parameters checked : Alb, AP, BUN, TP, Globulin,glucose, SGPT


URINALYSIS: Yes ( For rats only)
- Time schedule for collection of urine: After 12 weeks of exposure
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked : Bilirubin, Glucose,Ketone, Occult blood, pH,Protein, Specific gravity and Urobilinogen

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table) : See attachment 1
HISTOPATHOLOGY: Yes (see table) : See attachment 1
All surviving animals underwent a gross necropsy on the day following last exposure. Rats (but not rabbits) were deprived of food overnight prior to necropsy. Rats were anesthetized with methoxyflurane, and then decapitated. Rabbits were anesthetized with CO2, and then decapitated. The trachea of all animals was clamped after anesthesia to prevent aspiration of blood during decapitation. Each animal was examined internally and externally for gross pathological changes. The heart, liver, kidneys, brain, thymus (rats), and testes (males) were removed from each animal and weighed. Eyes of all animals were examined grossly using a microscope slide technique with fluorescent illumination. Representative portions of the tissues and organs were preserved in buffered 10% formalin.
One male rabbit from the 200 ppm exposure group was sacrificed prior to scheduled termination of the study because of a head tilt and disequlibirium.This animal was examined in a manner similar to the other rabbits, except that organs were not weighed and serum was not collected. A full set of tissues was prepared and examined microscopically.
Liver samples from male rats and rabbits (3.exposure group) were fixed in a phosphate buffered 2% gluteraldehyde and 2% formaldehyde solution, then routinely processed and embedded in EPON 812 resin for possible electron microscopy.
Other examinations:
Organ weights : The heart, liver, kidneys, brain, thymus (rats), and testes (males) were removed from each animal and weighed.
Statistics:
Clinical chemistry, hematology (PCV, Hgb, RBC, WBC and Plat only), urinary specific gravity, organ weight, body weight and organ to body weight ratio data were evaluated by Bartlett’s test for the equality of variances. If group variances were homogeneous; a parametric analysis of variance was conducted to determine if any statistically significant differences exist between groups. If overall parametric ANOVA was significant at <0.10 Dunnett’s test was used to identify statistically significant differences (<0.05) between experimental groups and their corresponding controls.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no apparent clinical effects and mortality due to DPGME exposure. Several minor observations were noted, including a case of ear mites in a male rabbit (treated topically with mineral oil), facial alopecia in 2 female rabbits, and a possible ruptured abscess in a female rabbit. One male rabbit which had been exposed to 200 ppm developed an ear infection and was sacrificed prior to the scheduled necropsy.


BODY WEIGHT AND WEIGHT GAIN: There were no exposure related adverse effects on body weights in either species during the 13 week study. There were no statistically significant differences from control body weight means in male and female rats or in male rabbits. The mean body weights of female rabbits in the 50 ppm group were slightly higher than the controls at the beginning of the study and at various intervals thereafter. This was not considered to be exposure related, due to absence of any effect on body weights of female rabbits in the high exposure group


HAEMATOLOGY: There were no exposure related effects on any measured hematology parameters in either sex of rat and rabbit. There were also no statistically significant differences from control means.


CLINICAL CHEMISTRY: There were no exposure related effects on any measured clinical chemistry parameters in either sex of rat and rabbit The only statistically significant difference was a slight decrease in BUN in female rats exposed to 50 ppm but this has no toxicologic significance.


URINALYSIS: There were no apparent effects on any of urinalysis parameters of male and female rats.


ORGAN WEIGHTS: There were no statistically significant differences in absolute or relative organ weights of rats exposed to DPGME, except for a slight decrease in mean relative liver weight of 50 ppm exposed males. There were several statistical differences in mean organ weights of rabbits but these also did not occur at the highest concentration tested, and were therefore not considered to be exposure related. There was an increase in mean relative kidney weight of female rabbits exposed to 200 ppm. The absolute mean kidney weights of 50 ppm and 200 ppm exposed female rabbits were also increased. However, both the absolute and relative mean kidney weights of DPGME exposed rabbits were within the range of historical control values. Because there was no evidence of nephrotoxicity, the increased kidney weights in the female rabbits were thought to be unrelated to the treatment.


GROSS PATHOLOGY: There were no exposure related changes observed at the necropsy in rats and rabbits. The changes observed during necropsy that were considered to be spontaneous changes of minimal severity which were not treatment related.


HISTOPATHOLOGY: NON-NEOPLASTIC: There were no DPGME exposure related microscopically changes observed in rats and rabbit. All histopathological observations were considered to be spontaneous changes of minimal severity which were not treatment related


Dose descriptor:
NOAEL
Remarks:
(Rat and Rabbit)
Effect level:
200 ppm
Sex:
male/female
Dose descriptor:
NOAEC
Effect level:
1 212.27 mg/m³ air (nominal)
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
Based on the results of this study NOAEL in rat and rabbit was 200 ppm which is the highest attainable concentration due to the low vapor pressure of dipropylene glycol methyl ether.
Executive summary:

Fischer – 344 (10/sex/exposure concentration )  and New Zealand white rabbits ( 7/sex/exposure concentration ) were exposed to 0, 15,50,200 ppm (0,91,303,1212 mg/m3) of dipropylene glycol monomethyl ether (colorless liquid DPGME) for 6 hrs/day, 5 days/week for 13 weeks.

Rats were received from Charles River Breeding Laboratories (, ) and Rabbits were received from Langshaw Rabbitry (, ).Rats and rabbits were kept for an acclimatization period of 2 weeks and 4 weeks respectively. Rats were housed (2/cage) and rabbits (1/cage) in stainless steel cages with wire bottoms. A standard laboratory diet (Purina Certified laboratory Chow, Ralson Purina Co., . MO) was supplied to rats and rabbits. Water also provided ad libitum to rats and rabbits except during exposure. Housing conditions were maintained at temperature of 20 -24 °C with relative humidity of 40-60 %.

Monitored for effects included general observations, body weights, clinical chemistry, hematology, urinalysis (Rats only), necropsy, organ weights and histopathology.

There were no exposure related adverse effects on body weights in either species during the 13 week study. There were no statistically significant differences from control body weight means in male and female rats or in male rabbits. The mean body weights of female rabbits in the 50 ppm group were slightly higher than the controls at the beginning of the study and at various intervals thereafter. This was not considered to be exposure related, due to absence of any effect on body weights of female rabbits in the high exposure group.

There were no apparent clinical effects and mortality due to DPGME exposure. There were no exposure related effects on any measured hematology parameters in either sex of rat and rabbit. There were also no statistically significant differences from control means. There were no apparent effects on any of urinalysis parameters of male and female rats.

Clinical chemistry, hematology (PCV, Hgb, RBC, WBC and Plat only), urinary specific gravity, organ weight, body weight and organ to body weight ratio data were evaluated by ’s test for the equality of variances.

All surviving animals underwent a gross necropsy on the day following last exposure. Rats (but not rabbits) were deprived of food overnight prior to necropsy. Rats were anesthetized with methoxyflurane, and then decapitated. Rabbits were anesthetized with CO2, and then decapitated. The trachea of all animals was clamped after anesthesia to prevent aspiration of blood during decapitation. Each animal was examined internally and externally for gross pathological changes. The heart, liver, kidneys, brain, thymus (rats), and testes (males) were removed from each animal and weighed. Eyes of all animals were examined grossly using a microscope slide technique with fluorescent illumination. Representative portions of the tissues and organs were preserved in buffered 10% formalin.

One male rabbit from the 200 ppm exposure group was sacrificed prior to scheduled termination of the study because of a head tilt and disequlibirium.This animals was examined in a manner similar to the other rabbits, except that organs were not weighed and serum was not collected. A full set of tissues was prepared and examined microscopically.

Liver samples from male rats and rabbits (3 exposure group) were fixed in a phosphate buffered 2%gluteraldehyde and 2% formaldehyde solution, then routinely processed and embedded in EPON 812 resin for possible electron microscopy.

There were no exposure related changes observed at the necropsy in rats and rabbits. There were no DPGME exposure related microscopically changes observed in rats and rabbits. All histopathological observations were considered to be spontaneous changes of minimal severity which were not treatment related.

Based on the results of this study NOAEL in rat and rabbit was 200 ppm.  Under conditions of this study the low vapor pressure of DPGME, and results in this 13 week study DPGME appears to have a low subchronic vapor inhalation toxicity hazard.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 212.27 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
good

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was conducted similar to OECD guideline 410.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Principles of method if other than guideline:
Method: other
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation: 170-240 gms
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):


IN-LIFE DATES: From: To:
Type of coverage:
other: occlusive and open
Vehicle:
water
Details on exposure:
Route of Administration: dermal
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not specified in the publication
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
4 hours/day; 5 days/week
Remarks:
Doses / Concentrations:
0, 100, 1000 mg/kg/d(occlusive and open)
Basis:
nominal per unit body weight
No. of animals per sex per dose:
8/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: No

DERMAL IRRITATION (if dermal study): No

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes


FOOD EFFICIENCY: No data


WATER CONSUMPTION: No data


OPHTHALMOSCOPIC EXAMINATION: No



HAEMATOLOGY: Yes


CLINICAL CHEMISTRY: Yes

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
At the postmortem examination, fragments of bone marrow were removed from the left femur of each rat and placed in tubes containing one drop of 20 % bovine serum albumin in saline. The tubes were placed on a vortex mixer for a few seconds to disperse the marrow fragments. Marrow films were then prepared, air dried and fixed in solvent methanol before staining for 10 min each in May-Grunwald and Giemsa stains. The films were then differentiated for 10 min in dilute phosphate buffer and blotted dry. Additionally one femur from each animal was decalcified with a 10 % solution of formic acid in formalin for 1 week and processed and stained with hematoxylin and eosin.
HISTOPATHOLOGY: Yes
At 28 days, all the rats were killed by intraperitoneal injection of pentobarbitone sodium. The animals were examined post-mortem and testes weighed. Samples of liver, kidney, skin, stomach, small and large intestine and testes were taken for histological processing. Additionally lungs were processed where there was evidence gross abnormality. After fixation in neutral buffered formalin, 5µm sections were cut and stained with hematoxylin and eosin
Other examinations:
Organ weights
Statistics:
The differences between body weight gain, food intake, clinical chemistry, hematology and bone marrow film data between test and control groups were analyzed using the unpaired student t-test to compare values in a test group with those in the corresponding control group at the same stage of the study. Thus combined weight of both testes was used in the analysis in which the weight of both testes animals from test animals was compared with that from the corresponding control animals, with the unpaired student t-test. Histological data were analyzed Fischer's test.
Clinical signs:
not specified
Dermal irritation:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY: All animals were survived during 28 day exposure period.

BODY WEIGHT AND WEIGHT GAIN: There were no significant differences in body weights between control and exposed animals


FOOD CONSUMPTION: There were no significant differences in food consumption between control and exposed animals


HAEMATOLOGY: There were no statistically significant differences from control values with respect to hematology.

CLINICAL CHEMISTRY: There were no statistically significant differences from control values with respect to clinical chemistry.

ORGAN WEIGHTS: There were no statistically significant differences organ weights of rats exposed to DPGME


GROSS PATHOLOGY: Macroscopic examination of the tissues revealed no significance findings attributable to DPGME exposure in rats


HISTOPATHOLOGY: NON-NEOPLASTIC: Macroscopic examination of the tissues revealed no significance findings attributable to DPGME exposure in rats


Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day
Sex:
male
Basis for effect level:
other: overall effects
Critical effects observed:
not specified
Conclusions:
Based on results of the study NOEL for rats via dermal route was >1000 mg/kg/day.
Executive summary:

Wistar rats (8 animals/sex/dose) were exposed to 0,100 and 1000 mg/kg/day (occluded and open) of DOWANOL DPM (colorless liquid) 5 days/week for 28 days.

Monitored for effects included clinical observations, body weights, food consumption, hematology, blood chemistry and, necropsy, organ weights, gross pathology and histopathology.

All animals were survived during 28 day exposure period.There were no significant differences in body weights, food consumption between control and exposed animals.There were no statistically significant differences from control values with respect to hematology and clinical chemistry DPGME exposed rats.

Macroscopic and microscopic examination of the tissues revealed no significance findings attributable to DPGME exposure in rats.

Based on results of the study NOEL for rats via dermal route was > 1000 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
good

Additional information

Based on toxicokinetics data summarized in IUCLID section 7.1.1, dipropylene glycol methyl ether acetate (DPMA) rapidly hydrolyzes to yield dipropylene glycol methyl ether in vivo. Thus, it is appropriate to conclude that the acetate behaves in a similar way to the parent ether due to the rapid conversion. Therefore, data on dipropylene glycol methyl ether are used to characterise the hazards of DPMA. Supporting data on PM and PMA are also provided.

 

Short-term repeated dose toxicity studies in rats (28-day), via oral gavage, are available for propylene glycol methyl ether (PM), propylene glycol methyl ether acetate (PMA), dipropylene glycol methyl ether (DPM) and DPMA. The NOAELs (oral) are > 919 mg/kg bw/day for all 4 substances. No adverse effects have been observed at the highest dose level tested. For the inhalation route, range-finding studies (up to 14-days) are available for PM and DPM. Repeated dose toxicity studies (28- and 90-day) via the dermal route are available for PM and DPM.

 

Sub-chronic (90-day) inhalation studies in rats and in rabbits are available for PM and DPM. The NOAEL for PM is 1000 ppm (3686 mg/m3), in rats and rabbits. The NOAEL for DPM is 200 ppm (1212 mg/m3, the highest attainable concentration), in rats and rabbits.

 

The only effects observed during the repeated dose toxicity study with DPMA were increased liver weights, subdued behaviour and increased breathing. The liver weight increase was very slight and only observed in females of the highest dose group. There were no histopathological changes accompanying this effect. There were no changes in clinical chemistry (ALP, ASP) indicating any liver damage.

The same liver effects were observed with other structurally related molecules, e.g. PM has been shown to cause liver weight increases via a phenobarbital-like enzyme induction mode of action and it is highly likely that DPMA liver weight increases occur via the same mode of action. As this is an adaptive effect typical for many glycol ethers, it is not considered as adverse. The toxicological significance of the observed increased breathing and subdue behaviour is unclear. As these observations were not accompanied by any significant effect, they are considered as not relevant.

PM, PMA and DPM have been subjected to repeated dose toxicity studies by at least one route of exposure. All studies indicate low repeated dose toxicity for these glycol ethers. The NOAELs obtained in the 90-day inhalation studies with PGME and DPGME were 1000 ppm (3686 mg/m3) and 200 ppm (1212 mg/m3, the highest attainable concentration), respectively. For DPMA, this would (theoretically) be equivalent to inhalation NOAELs of 7779 mg/m3 and 1556 mg/m3, respectively. Extrapolation to the oral route would result in NOAELs of 2256 and 451 mg/kg bw/day, respectively. Conducting repeated dose toxicity studies with DPMA via the oral route up to the limit dose of 1000 mg/kg bw/day will unlikely results in any adverse effects. Therefore, the data from DPM should be used to read-across, based on the rapid hydrolysis of acetate moiety from DPMA to yield DPM.

Further support for read across is attached at section 13 of the IUCLID.

For the purposes of risk assessment, the inhalation 90 -day study peformed using DPM with a NOEC of 200ppm will be taken as the starting point for DNEL derivation. Converting this to mg/m3 of DPMA, this is equivalent to 1556 mg/m3.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A well conducted 28-day oral toxicity study (reliability 1, GLP)

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
A well conducted guideline 90-day inhalation study on a structural analogue.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
most recent, reliable study performed on a strucrutal analogue

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

The no observed adverse effect levels for dipropylene glycol methyl ether acetate exceed the values triggering classification via all routes of exposure. Therefore no classification for prolonged exposure is required.

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