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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
14 October 2011 (Received for publication)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP compliant study performed according to guideline similar to OECD 416. The study was performed not with DEGDEE but with DEGEE, a substance which like DEGDEE is part of the diethylene glycol monoalkyl and dialkyl ethers category. These substances have been demonstrated to be similar in structure, physical/chemical properties and toxicological profile.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1990
Report Date:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): Diethylene Glycol Monoethyl Ether (DEGEE)
- Molecular formula (if other than submission substance): C6H14O3
- Molecular weight (if other than submission substance): 134
- Analytical purity: >99%

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: UK Breeding Laboratory
- Age at study initiation: 6 weeks old
- Housing: 10 animals per sex per cage ( in solid-bottom polypropylene or polycarbonate cages with stainless·steel wire lids and Ab-Sorb-Dri cage
litter)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): at libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70+/-2
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 10/14

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

The compounds were weight and added to deionized/filtered water and stirred at approximately 300 rpm until the solutions were homogeneous. Such solutions were found to be stable for 3 weeks stored in the dark at room temperature. At approximately 6-week intervals, aliquots of each formulation were analyzed for concentration of the test compound.
The concentrations were within 99 and 104%.
Details on mating procedure:
- M/F ratio per cage: 1 breeding pair
- Length of cohabitation: 14 weeks (98 days) for F0. The pairs were separated and the male and female mice were housed individually and exposed for an additional 3 weeks. F1: After weaning F1 animals were continuously treated, and paired with nonsiblings from the same dose group at 74 +/- 10 days. These animals were cohabitated either for 1 week or until a copulatory plug was detected.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
- premating exposure: 7 days
- mating exposure: 14 weeks
- postmating exposure: 3 weeks
- Total exposure: 126 days
Frequency of treatment:
Continuous
Details on study schedule:
- F1 parental animals not mated until 74+/- 10 days after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 21 days of age.
- Age at mating of the mated animals in the study: 9-12 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.25. 1.25, and 2.5% w/v (corresponding to approximately 0, 0.44, 2.2 and 4.4g DEGEE/kg body wt/day, respectively).
Basis:
nominal in water
No. of animals per sex per dose:
40 per sex (males and females) for untreated controls and 20 per sex (males and females) in each of the following dose groups: 0.25, 1.25, and 2.5% w/v.
Control animals:
yes, concurrent vehicle
Details on study design:
An initial dose finding study was performed in which animals were exposed to 0, 1, 2, 3, 4 and 5% in the drinking water for 14 days.
Positive control:
None

Examinations

Parental animals: Observations and examinations:
- water consumption
- body weights
- mortality
- clinical signs of toxicity
Oestrous cyclicity (parental animals):
Not examined
Sperm parameters (parental animals):
Parameters examined in [P/F1] male parental generations:
testis weight, epididymis weight, sperm concentration in epididymides, sperm motility and sperm morphology in the right cauda epididymisother: percentage abnormal sperm in the right cauda epididymis
Litter observations:
The day of delivery of each litter, the number of litters per breeding pair, the number and percentage of fertile pairs, the number, percentage and sex of live pups per litter, and the mean body weights of live offspring were recorded.
Postmortem examinations (parental animals):
Because reproductive effects were not observed during the 126-day exposure period, the F0 parents were not necropsied.
Postmortem examinations (offspring):
The F1 parents were euthanized and necropsied. Body, liver, brain and pituitary weights were recorded. Selected reproductive tissues from males (left testis with epididymis attached, right testis, right epididymis, prostate and seminal vesicles) and females (ovary with oviduct attached, and uterus) were weighed, fixed and embedded in paraffin, stained and evaluated by light microscopy.
The sperm concentration, percentage of motile sperm, and percentage of abnormal sperm in the right cauda epididymis also were evaluated.
Offspring viability indices:
proportion of pups born alive

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
A total of 6 F0 animals died; one control male and female, one female in the 0.25 and 1.25% groups and two males in the high dose group.
The random distribution of deaths across the treatment groups suggested that they probably were not treatment related.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were small significant decreases in the mean body weights of the males during Weeks 1 and 5 for the 2.5% DEGEE group,
which amounted to a 6% decrease compared to controls.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
During the first week, there was a slight, but statistically significant, decrease in water consumption for the males in the 2.5% group.
However, at Week13 the pairs of animals were consuming significantly greater volumes of water than the control group.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Fertility index: 100%

ORGAN WEIGHTS (PARENTAL ANIMALS)
Not examined

GROSS PATHOLOGY (PARENTAL ANIMALS)
Not examined

HISTOPATHOLOGY (PARENTAL ANIMALS)
Not examined

OTHER FINDINGS (PARENTAL ANIMALS)

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
ca. 1.25 other: % (2200 mg/kg/day)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: systemic toxicity

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings:
no effects observed

Details on results (F1)

BODY WEIGHT (OFFSPRING)
The only statistically significant changes observed were a 3% reduction in the adjusted live pup weights for males at
the 0.25% dose level and a 5% reduction in this parameter for females in the 2.5% DEGEE group.

SEXUAL MATURATION (OFFSPRING)
At necropsy a specific effect on male reproductive function was noted (a decrease in sperm motility for the top dose group). It should be noted that this decrese was not sufficient to affect fertility and reproductive performance and occured at high doses of DEGEE (>4g/kg body wt/day- estimated for adults mice)

ORGAN WEIGHTS (OFFSPRING)
The only signifIcant changes observed were decreases in the absolute brain weights for both sexes, and an increase in the absolute
liver weights of the females. These organ weights were also significantly different from controls when adjusted for body weight. In
addition, the liver weights for the males were found to be significantly increased (15%) when adjusted for body weight.

HISTOPATHOLOGY (OFFSPRING)
No histopathological changes were seen in any of the organs which were examined.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1.25 other: % (2200 mg/kg/day)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 34% decrease in sperm motility at 2.5% (4400 mg/kg/day) and increase in liver weights

Results: F2 generation

Effect levels (F2)

Dose descriptor:
NOAEL
Generation:
F2
Effect level:
ca. 2.5 other: % (4400 mg/kg/day)
Based on:
test mat.
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Fertility and reproductive performace of Diethylene Glycol Monoethyl Ether-treated mice during continuous breeding (Task 2)

            Treatment (% DEGEE)
 Parameter  0  0.25  1.25  2.5

 No. fertile/ No. cohabited (%)

 38/38 (100)  19/19 (100)  19/19 (100)  18/18 (100)

 Litters per pair

 4.89 +/-0.05  4.53 +/-0.25  4.89 +/-0.11  4.72 +/-0.11

 Live pups per liter

 11.82 +/-0.45  11.05 +/-0.62  11.34 +/-0.42  11.23 +/-0.58

 Percentage pups born alive

 99 +/-1  97 +/-2  98 +/-2  99 +/-0

 Percentage males among live pups

 51 +/-1  55 +/-2  51 +/-1  51 +/-2

 Live pup weight (g)

 1.65 +/-0.02  1.61 +/-0.03  1.63 +/-0.02  1.62 +/-0.03

 Adjusted live pup weigt (g)

-male

-female

1.69 +/-0.021.63 +/-0.02 1.64 +/-0.02*1.58 +/-0.02 1.66 +/-0.021.60 +/-0.02  1.65 +/-0.021.55 +/-0.02*

*Significantly different (p<0.05) from 0% DEGEE group.

The effect of Diethylene Glycol Monoethyl Ether on fertility and reproductive performance of F1 generation mice

(Task 4)

    Treatment (% DEGEE)   
Parameters(a)  0  2.5
No. with copulatory plugs/No cohabited (%)   20/20(100)

 

16/19

(84)

No. fertile/No with copulatory plugs (%)  20/20(100)

16/16

(100) 

 Live pups per litter  11.00 +/-0.65

 10.81 +/-0.59

 Percentage pups born alive  100 +/-0

 100 +/-0

 Percentage males among live pups  47 +/-3

 49 +/-3

 Live pup weight (g)  1.54 +/-0.03

 1.53 +/-0.03

(a)Except for the mating index (No with copulatory plugs/No. cohibited) and the fertility index (No. fertile/No. with copulatory plugs), values are means +/-SEM for the one litter delivered per fertile pair. Numer of fertile pairs = 16(2.5% DEGEE) and 20 (controls).

Applicant's summary and conclusion

Conclusions:
The described experiment shows that DEGEE had no effect on fertility and reproductive performance in the F0 or F1 generationmice despite a 34% decrese in cauda epididymal sperm motility in the F1 males at 2.5% DEGEE. The NOAEL for the Parents and F1 generation can be established at 1.25% in the diet (2200 mg/kg) and the NOAEL for the F2 generation at 2.5% in the diet (4400 mg/kg/day).
Executive summary:

DEGDEE and DEGEE, which is in the above study tested for its reproductive toxicity in CD-1 mice, are both part of the diethylene glycol monoalkyl and dialkyl ethers category described and evaluated in the document titled "Category Approach-Read across Bis(2 -ethoxyethyl)ether" (2013).

These substances have been demonstrated to be very similar in structure, physical/chemical properties and toxicological profile . Therefore, a read-across from DEGDEE to data obtained with DEGEE is scientifically justified.