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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
This IUCLID for dimethyl adipate is compiled using data from the substance itself, a structuraly related compound (dimethyl glutarate) and a mixture of dibasic esters (dimethyl adipate, succinate and glutarate). The toxicity of each of these susbtances is similar and the document attached justifies why data on the category members can be used to support the data gaps for dimethyl adipate.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
See information in the field "Confidential details on test material"

Test animals

Species:
rat
Strain:
other: Crl:CD BR
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc., Kingston, NY
- Age at study initiation: females: 63 days, males: 84 days
- Weight at study initiation: females: 146-198g; males: 303-396g
- Housing: individually in stainless steel wiremesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25°C
- Humidity (%): 40-60%
- Photoperiod (hrs dark / hrs light): 12/12

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: 1.4 m3 stainless steel and glass NYU-style inhalation chamber
- Method of holding animals in test chamber: in cages
- System of generating particulates/aerosols: 0.16 and 0.4 mg/L: liquid DBE was metered into a furnace maintained at 50-300°C; for the 1.0 mg/L concentration, mixed aerosol/vapour athmospheres were generated using a Spraying Systems Nebulizer
- Temperature, humidity, pressure in air chamber:
- Air flow rate: about 300 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: GC-FID
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were analyzed using a Hewlett-Packard Model 5710 Gas Chromatograph (GC) equipped with a flame ionization detector. DBE was chromatographed isothermally at 150°C on a 3' x 2 mm ID glass column packed with 10% SP-1000 on Chromosorb W-AW 1001120 mesh.
Details on mating procedure:
The female rats were cohabited overnight with mature males (1:1). Mating was verified each morning by detection ol a copulation plug in the vagina or on the cage hoard. The day a plug was found was designated Day 1 of gestation (Day 1G). Mated females were stratified by body wcight and assigned to groups by random sampling within each stratum (24 per group).
Duration of treatment / exposure:
In the definitive study, groups of 24 pregnant rats were targeted for exposure to 0 (control), 0.16, 0.4, and 1.0 mg DBE /L. Rats were exposed to whole-body inhalation for 6 hr per day from Days 7 through 16 (10 exposures). The control dams were exposed to air only.
Frequency of treatment:
6h per day
Duration of test:
Day 7 to 16 (10 exposures)
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/L air (nominal)
Remarks:
Measured concentration 0.0 mg/L air
Dose / conc.:
0.16 mg/L air (nominal)
Remarks:
Measured concentration 0.15 mg/L air
Dose / conc.:
0.4 mg/L air (nominal)
Remarks:
Measured concentration 0.38 mg/L air
Dose / conc.:
1 mg/L air (nominal)
Remarks:
Measured concentration 0.99 mg/L air
No. of animals per sex per dose:
24 pregnant rats per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: based on results of a pilot study

Examinations

Maternal examinations:
Body weights and clinical signs were recorded on the day after arrival and before mating; observations for morbidity and mortality were made daily. Females selected for the study were weighed on Days 1, 7, 9, 11, 13, 15, 17, and 21G. Feed was weighed on Days 1, 3, 9, 11, 13, 15, 17, 19 and 21G and each afternoon on Days 7-16G (the exposure period). Just before euthanasia on Day 21G. each dam was coded, so personnel involved did not know the exposure group to which any dam or fetus belonged. Dams were euthanized by cervical dislocation, a gross pathologic examination was made, and the liver was weighed. The ovaries were removed and the number of corpora lutea were counted at a magnification of 2.5 x (Ednalite).
Ovaries and uterine content:
The uterus was opened and the number and position of all live, dead, and resorbed conceptuses were recorded. Both gravid and empty uteri were weighed. The uterus of each apparently nonpregnant dam was stained with ammonium sulfate solution to determine whether any very early resorption could be identified.
Fetal examinations:
All fetuses were weighed and examined for external alterations at a magnification of 2.5x. About one-half of the live fetuses in each litter (plus all stunted and malformed fetuses) were examined for visceral alterations. For each litter, the maximum stunted weight (MSW) was calculated by subtracting the lightest weight from the total weight dividing by the remaining number of fetuses, and multiplying by 0.666. A fetus weighing the same or less than the MSW was considered stunted, and its weight was omitted after the mean litter weight was calculated. The heads of these fetuses were fixed in Bouin’s solution and examined. All fetuses were sexed internally and then they were fixed in 70% ethanol, eviscerated, macerated in 1% aqueous KOH, and stained with alizarin red S to permit examination of the skeletons for alterations.
Statistics:
The litter was considered the experimental unit for the purpose of statistical evaluation. The level of significance selected was 0.05.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical observations of perinasal staining (15 rats) and wet fur (20 rats) were seen in the 1.0 mg/L group; while these findings were not seen in the controls. Perinasal staining was seen in 1 rat from the 0.16 mg/L group and in 4 rats from the 0.4 mg/L group; wet fur was also seen in 1 rat from the 0.4 mg/L group. Other clinical observations including alopecia, sores, periocular and facial staining, and swollen extremities were seen but infrequently and with no suggestion of a relationship to DBE exposure.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
All female rats survived the testing period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight changes in maternal rats exposed to either 0.4 or 1.0 mg/L, were reduced, whereas those from the 0.16 mg/L were not.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Feed consumption was reduced in the 0.4 and 1.0 mg/L group rats during the first 6 days of exposures (means of 23.3, 20.5, and 20.1 g/day, 0, 0.4, and 1.0 mg/L groups, respectively).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No significant differences in absolute or relative liver weight was found but a significant trend in absolute weight was evident; a trend not seen when related to the body weight where values for all test groups were lower (but not significantly) from that of the controls.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The only histopathologic changes were detected in the nasal tissues of the parental rats, was an exposure-related increase in squamous metaplasia in the olfactory epithelium.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
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.

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
The number of pregnant rats/group was not altered by exposure to DBE, with the numbers being 24, 21, 20, and 24, control to high concentration groups, respectively.
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not examined
Details on maternal toxic effects:
All female rats survived the testing period. The number of pregnant rats/group was not altered by exposure to DBE, with the numbers being 24, 21, 20, and 24, control to high concentration groups, respectively. Body weight changes in maternal rats exposed to either 0.4 or 1.0 mg/L, were reduced, whereas those from the 0.16 mg/L were not. Feed consumption was reduced in the 0.4 and 1.0 mg/L group rats during the first 6 days of exposures (means of 23.3, 20.5, and 20.1 g/day, 0, 0.4, and 1.0 mg/L groups, respectively). Clinical observations of perinasal staining (15 rats) and wet fur (20 rats) were seen in the 1.0 mg/L group; while these findings were not seen in the controls. Perinasal staining was seen in 1 rat from the 0.16 mg/L group and in 4 rats from the 0.4 mg/L group; wet fur was also seen in 1 rat from the 0.4 mg/L group. Other clinical observations including alopecia, sores, periocular and facial staining, and swollen extremities were seen but infrequently and with no suggestion of a relationship to DBE exposure. No significant differences in absolute or relative liver weight was found but a significant trend in absolute weight was evident; a trend not seen when related to the body weight where values for all test groups were lower (but not significantly) from that of the controls.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
>= 1 mg/L air (nominal)
Based on:
test mat.
Basis for effect level:
other: no treatment-related effects observed on developmental toxicity parameters
Key result
Dose descriptor:
NOAEC
Effect level:
0.16 mg/L air (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Remarks on result:
not determinable
Remarks:
no NOAEC identified

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
No adverse reproductive effects related to DBE exposure were detected. There was no effect on fetal weights at any exposure level. There was no significant difference between the control and experimental groups in the incidence of external, visceral, or skeletal malformations. Developmental variations among fetuses derived from DBE-exposed female were not significantly different from those of the controls.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Effect level:
> 1 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment-related effects observed

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
DBE exerts no adverse effect on prenatal development in the rat following inhalation exposures as high as 1.0 mg/L DBE during the period of organogenesis.
Executive summary:

Dibasic Esters (DBE) has been tested in a developmental toxicity study on Crl:CD(SD)BR rats after inhalation exposure using a protocol similar to OECD guideline no 414 in compliance with Good Laboratory Practice. Pregnant Crl:CD BR rats (7-8 per group) were exposed to either 0.16, 0.4, or 1.0 mg/L DBE by inhalation for 6 hr/day from Days 7 through 16 of gestation (day in which copulation plug was detected was designated Day 1G) in whole-body inhalation chambers. A control group of pregnant rats was exposed simultaneously to air only. Parental examinations included clinical and cage side observations, body weight determination, and determination of feed consumption. Gross pathologic examination was performed on day 21G and included counting of the corpora lutea and determination of number and position of all live, dead, and resorbed conceptuses in the uterus. Liver, gravid and empty uteri were weighed. All fetuses were weighed and examined or external alterations. About one-half of the live fetuses were examined for visceral alterations. All fetuses were sexed and examined for alterations of the skeleton after maceration.

 

A suppression of both food consumption and the rate of body weight gain was seen in the 0.4 and 1.0 mg/L groups during the first 6 exposure days. Staining on the fur and perineal area was seen in rats exposed to 1.0 mg/L and liver weight decreases, although not statistically significant, occurred in the 2 high exposure groups. None of the reproductive parameters were altered in any of the groups and no fetal effects were detected. DBE exerts no adverse effect on prenatal development in the rat following inhalation exposures as high as 1.0 mg DBEL during the period of organogenesis.

Based on the given data, Dibasic Esters (DBE) is not classified for developmental effects according to the criteria of Directive 67/548/EC and EU Regulation No. 1272/2008 (CLP).