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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study under conditions similar to OECD Guideline 415; Study under GLP Regulation

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1988
Report date:
1988
Reference Type:
publication
Title:
Unnamed
Year:
1998

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
yes
Remarks:
- Inhalation exposure. - Male rats were also exposed until end of lactation period. - Female rats were not exposed from gestation day 19 through postpartum day 3.
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.34 (One-Generation Reproduction Toxicity Test)
Deviations:
yes
Remarks:
- Inhalation exposure. - Male rats were also exposed until end of lactation period. - Female rats were not exposed from gestation day 19 through postpartum day 3.
Principles of method if other than guideline:
- Inhalation exposure.
- Male rats were also exposed until end of lactation period.
- Female rats were not exposed from gestation day 19 through postpartum day 3.
GLP compliance:
yes
Limit test:
no
Justification for study design:
Inhalation is a likely route of exposure and therefore suitable for a reproduction test.

Test material

Constituent 1
Reference substance name:
Reaction mass of dimethyl adipate and dimethyl glutarate and dimethyl succinate
EC Number:
906-170-0
IUPAC Name:
Reaction mass of dimethyl adipate and dimethyl glutarate and dimethyl succinate
Test material form:
other: liquid
Details on test material:
See information in the field "Confidential details on test material"
Specific details on test material used for the study:
test substance contained 65.1 % w/w dimethyl glutarate, 17.8 % w/w dimethyl adipate and 16.8 % w/w dimethyl succinate.

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Kingston, NY;
- Age at study initiation: (P) 4 wks
- Housing: individually, except during mating (1 male, 1 female)
- Diet (e.g. ad libitum): a libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 40 - 70%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
other: inhalation of vapor at lower (0.0, 0.16 and 0.40 mg/L) doses; inhalation of aerosol at highest dose (1mg/L)
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1.4 m³ stainless steel and glass NYU-style inhalation chamber
- System of generating particulates/aerosols: vapour generation: flash-evaporation in a tube maintained at 250-300°C; aerosol vapour: nebulizer
- Air flow rate:300 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: sample collection: in acetone-filled impingers; analysis method: GC-FID
- Samples taken from breathing zone: yes
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 5 days
- Proof of pregnancy: vaginal plug day 1 of pregnancy
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of atmospheric DBE were taken from the rat breathing zone at approximately 60-minute intervals by drawing calibrated volumes of chamber atmosphere through fritted glass midget impingers containing acetone. Samples were analyzed using a Hewlett-Packard Model 5710 Gas Chromatograph (GC) equipped with a flame ionization detector. DBB was chromatographed isothermally at 150°C on a 3 ft x 2 mm ID glass
column packed with 10% SP-1000 on Chromasorb W-AW 100/120 mesh.

Chamber concentrations were determined by comparing the chamber sample GC response with that obtained from standard samples prepared by quantitative dilution of DBE in acetone. The DBE chamber concentration was calculated after measuring the peak area of the largest DBE component, dimethyl glutarate. In addition, the relative amounts of the 3 largest DBE components (dimethyl-glutarate, -adipate, and -succinate) were qualitatively
compared for each sample.
Duration of treatment / exposure:
pre-breeding: 6 h per day
breeding, gestation, lactation: 6 h per day;
Frequency of treatment:
pre-breeding: 5 days per week, 14 weeks;
breeding, gestation, lactation: 7 days per week, 8 weeks;
Doses / concentrations
Remarks:
Doses / Concentrations:
0.0 (control), 0.16, 0.40, 1.0 mg/L
Basis:
nominal conc.
No. of animals per sex per dose:
20 males;
20 females;
Control animals:
yes, concurrent no treatment

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

OTHER:
Mating performance, fertility, gestation length, and lactation performance were assessed.
Oestrous cyclicity (parental animals):
no data
Sperm parameters (parental animals):
no data
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, viability, weight

Postmortem examinations (parental animals):
All parental animals were sacrificed by exanguation under chloroform anesthesia and examined for gross anatomic abnormalities.
Additionally, the nasal tissues were examined histologically; other tissues were examined grossly and saved.
Mean organ and organ-to-body ratios were calculated for the brain, heart, lungs, liver, spleen, kidneys, testes and thymus.
Postmortem examinations (offspring):
Ten 21-day old arbitrarily selected pups of each sex per dose group were sacrificed by exanguination under chloroform anesthesia and examined for gross anatomic abnormalities.
Mean organ and organ-to-body ratios were calculated for the brain, liver, kidneys, and testes.
Statistics:
For parental organ and body weight analyses, data were statistically analyzed by a one-way ANOVA. When the ratio of variance (F) indicated a significant group variation, test groups were compared with appropriate control group by least significant difference test for body weight data and by Dunnett's test for organ and final body weight data.
Litter data were analyzed by Mann-Whitney U-test.
Significance for statistical tests was judged at the 0.05 probability level.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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

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)

BODY WEIGHTS AND CLINICAL SIGNS
Body weights were decreased in the 0.40 mg/L group female rats during the last week of the study. Weights were slightly decreased in male and female rats in the 1.0 mg/L group starting around the seventh week of the study.
No unusual signs or behaviours that could be associated with exposure to DBE were seen in rats in any of the treated groups. Parental rats in the 1.0 g/L group showed wet fur during exposures from aerosol deposition. The fur dried about 2 hours after exposure.

REPRODUCTION PARAMETERS
No treatment-related differences were observed between the control and test groups with regard to male or female fertility, gestation length, litter sizes, viability, or lactation performance. A slight but statistically significant decrease in viability index at birth (number of pups born alive per number of pups born) was observed in the 0.16 mg/L DBE group but this was considered to be unrelated to DBE exposure because it was not seen at either of the two higher exposure concentrations. All pups delivered by both DBE-exposed and control rats appeared outwardly normal. Body weights at birth and weaning (21 days pp) were significantly lower in the 1.0 mg/L group.
The fertility rate in the control group was lower than that of the test groups (60% versus 75 to 90% for the test groups) and is low compared to historical rates for this laboratory. One potential contributing factor to the low fertility rate in the control group is that there were some males that never had the opportunity to mate with a subsequently proven fertile female; three of these males were in the control group, three in the 0.4 mg/L group, and two were in the 0.16 mg/L group. On the other hand all the males in the 1 mg/L group were mated with females who were subsequently proven to be fertile. Although the cause is uncertain, the control group low fertiIity rate did not impact the toxicity evaluation since the fertility rate in the DBE-exposed groups was well within historical limits.

PATHOLOGY
No gross pathologic changes were seen in any of either the parental rats or their offspring. Histopathologic evaluation of parental generation rat nasal tissues showed squamous metaplasia primarily in the olfactory epithelium in all groups exposed to DBE. The nasal effect was minimal in the 0.16 mg/L group rats and of mild to moderate severity in the 0.40 and 1.0 mg/L groups. The squamous metaplasia was characterized by a flattening and pavementing of epithelial cells which replaced the normal architecture of olfactory epithelium. In some cases, particularly in the 0.40 and 1.0 mg/L rats, this squamous change was accompanied by a very minimal to mild suppurative inflammation.
The squamous metaplasia was present primarily in the olfactory epithelium of the dorsal meatus, along the dorsal portion of the nasal septum, and on the tips of the ecto- and endoturbinates in the nasal cavity. There was also an increase in squamous metaplasia of the respiratory epithelium in the nasal cavity in the high-dose rats. The severity of the lesions ranged from absent-to-minimal up to moderate in some rats.
One male rat in the 1.0 mg/L group had a meningeal sarcoma surrounding the olfactory region of the brain. Because the tumor did not communicate with the nasal cavity and the tumor cell type was unrelated to any nasal epithelial cell types, the tumor was considered to be unrelated to inhalation of DBE.

ORGAN WEIGHTS
In parental rats, liver-to-body weight ratios were slightly lower than the controls in the rats exposed to either 0.40 and 1.0 mg/L. Other incidental differences between test and control rats included slight decreases in absolute heart and kidney weights in female rats in the 0.40 and 1.0 mg/L groups. A slight decrease in absolute spleen weight and a slight increase in relative brain weight were observed in females in the 1.0 mg/L group. These differences were not dose-related and may have been related to the slight body weight differences between the test and control groups and were considered of minimal biological significance.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEC
Remarks:
for systemic toxicity effects
Effect level:
> 1 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on the nasal histopathology data
Remarks on result:
not determinable
Remarks:
no NOAEC identified
Dose descriptor:
NOEC
Remarks:
for reproductive parameters
Effect level:
1 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: maximum level tested
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

A slight decrease in relative kidney weight was seen in female pups whose parents were exposed to 0.40 mg/L of DBE; however, in the absence of a dose-response relationship, the decreased relative kidney weights were not considered to he related to DBE exposure. No differences were seen in the liver weights of DBE-exposed pups.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 1 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No dose reproductive effects were observed. The NOAEL is above the highest test concentration

Overall reproductive toxicity

Reproductive effects observed:
not specified
Lowest effective dose / conc.:
1 mg/L air
Treatment related:
no

Any other information on results incl. tables

Reproduction parameters in rats exposed to DBE by inhalation

Parameter

DBE Concentration [mg/L]

0 (control)

0.16

0.40

1.0

Male fertility

[%]

12/20

60

16/20

80

15/20

75

18/20

90

Female fertility

[%]

17/20

85

17/20

85

17/20

85

20/20

100

Viability index at birth

100

94.6 *

99.6

99.0

Viability index day 0-4

99.5

93.7

99.2

98.2

Lactation index

100

100

97

99

Gestation index

100

100

100

100

Pups / litter [mean]

13.1

12.5

12.6

12.9

Gestation duration [days]

22.1

22.1

22.1

21.8

Pup weight at birth [g]

6.4 (0.6)

6.4 (0.8)

6.1 (0.1)

5.9 (0.1) *

Pup weight at day 21 [g]

           Male

           Female

 

44.3 (2.6)

41.0 (3.9)

 

44.9 (4.3)

41.7 (4.7)

 

45.5 (4.1)

44.3 (4.2)

 

41.8 (2.8) *

40.8 (2.0) *

 * Significantly different to control, p < 0.05

Values in parentheses report standard deviation

Applicant's summary and conclusion

Conclusions:
Reproduction in rats was not altered by repeated inhalation exposure to up to 1.0 mg/L DBE, a concentration that produced both body weight and histologic effects in parental rats.
Executive summary:

Dibasic Esters (DBE) has been tested in a reproduction toxicity study on Crl:CD(SD)BR rats after inhalation exposure using a protocol similar to OECD guideline no 415 and EU method B34 in compliance with US TSCA Good Laboratory Practice.

Groups of 20 male and 20 female rats were exposed to DBE at concentrations of 0 (control), 0.16, 0.40 (maximum attainable vapor), or 1.0 mg/L (aerosol) in whole-body inhalation chambers. Exposures were conducted for 6 hours/day, 5 days/week for 14 weeks (pre-breeding) then 7 days/week for 8 weeks (through breeding, gestation, and lactation). The exposures were interrupted for female rats between gestation day 19 and postpartum day 3.

Parental examinations included clinical and cage side observations, body weight determination, and assessment of mating performance, fertility, gestation length, and lactation performance. The number and sex of pups, viability, and weight were determined. At the end of the lactation period, all parental rats and ten 21-day old pups of each sex were per group were killed and examined for gross abnormalities. Parental nose tissues were examined histopathologically.

 

No significant differences were observed between control and test rats with respect to mating performance, fertility, length of gestation, or progeny numbers, structure, and viability. Body weights of parental rats and of their offspring were reduced at 1.0 mg/L. The only histopathologic changes detected in the nasal tissues of the parental rats, was an exposure-related increase in squamous metaplasia in the olfactory epithelium. There was an increase in liver-to-body weight ratios in the two higher parental exposure groups and an increase in the lung-to-body weight ratio also seen at 1.0 mg/L.

From the results obtained, it can be concluded that reproduction in rats was not altered by repeated inhalation exposure to up to 1.0 mg/L DBE, a concentration that produced both body weight and histologic effects in parental rats. See further discussion in IUCLID Section 7.12.

 

Dibasic Esters (DBE) is not classified for reproduction according to the criteria of Directive 67/548/EC and EU Regulation No. 1272/2008 (CLP).