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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Conduction and documentation of study very acceptable
Justification for type of information:
Tin, dioctylbis(2,4-pentanedionato-κO2,κO4)- hydrolyses with humidity into Dioctyltinoxide and 2,4-Pentadione. There is an evidence that the hydrolysis product 2,4-Pentadion cause an adverse effect in worker (US EPA)

Data source

Reference
Reference Type:
publication
Title:
An evaluation of the developmental toxicity of 2,4-pentanedione in the Fischer 344 rat by vapour exposure.
Author:
Tyl et al.
Year:
1990
Bibliographic source:
Toxicol Ind Health. 1990 May-Jul;6(3-4):461-74.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Principles of method if other than guideline:
Timed-pregnant Fischer F-344 rats (Harlan Fischer F-344/HarBR) were exposed to 2,4-pentanedione vapour by inhalation on gestational days (gd) 6 to 15 at exposure target concentrations of 0, 50, 200 and 400 ppm (0, 52.7, 202 and 398 ppm mean analytical concentrations, respectively) to evaluate the embryotoxic and fetotoxic (including tera-togenic) potential of the TS administered during organogenesis. The day a copulation plug was found was designated gestational day (gd) 0. Twenty-five plug-positive fe-males were assigned to each experimental group. Clinical observations were recorded daily, and maternal body weights were taken on gd 0, 6, 9, 12, 15 and 18. At scheduled necropsy on gd 21 (CO2 asphyxiation), dams were evaluated for body weight, liver and thymus weights, gravid uterine weight, and status of implantation sites (i.e. resorptions, dead fetuses, live fetuses). Maternal brains were removed, fixed and examined histopa-thologically. Live fetuses were dissected from the uterus, counted, weighed and sexed and examined for external abnormalities. weighed and sexed and examined for external abnormalities. Approximately one-half of the live fetuses in each litter was examined for visceral abnormalities. These fetuses were then decapitated and their heads fixed in Bouins solution and examined for soft tissue craniofacial malformations. The remaining intact fetuses in each litter were eviscerated, fixed in alcohol, stained with alizarin red S, and examined for skeletal defects and deficits.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
2,4-pentadione
IUPAC Name:
2,4-pentadione
Constituent 2
Reference substance name:
Pentane-2,4-dione
EC Number:
204-634-0
EC Name:
Pentane-2,4-dione
Cas Number:
123-54-6
IUPAC Name:
pentane-2,4-dione
Details on test material:
- Name of test material (as cited in study report): 2,4-Pentanedione
- Physical state: liquid
- Stability under test conditions: stable

Test animals

Species:
rat
Strain:
Fischer 344

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation:
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- Any other deviations from standard protocol:
Duration of treatment / exposure:
gestational days (GD) 6-15
Frequency of treatment:
6 h/day consecutive days
Duration of test:

13 days (treatment), animals were sacrificed on GD 21
No. of animals per sex per dose:
25 females
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEC
Effect level:
200 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEC
Effect level:
400 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: educed fetal weights; reduced fetal ossification in the 200 and 400 ppm group

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEC
Effect level:
50 ppm
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
LOAEC
Effect level:
200 ppm
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEC
Effect level:
400 ppm
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEC
Effect level:
400 ppm
Based on:
test mat.
Basis for effect level:
other: embryotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

.

Applicant's summary and conclusion

Conclusions:
Based on a significantly reduced body weight gain in the 400 ppm exposure group the NOAEC/LOAEC derived for maternal toxicity is 200 and 400 ppm, respectively. The NOAEC/LOAEC for developmental toxicity is 50 and 200 ppm, respectively, which is based on reduced fetal weights in male fetuses at 200 ppm and in male and female fe-tuses at 400 ppm and a consistent pattern of reduced fetal ossification at 400 ppm. The NOAEL for embryotoxicity and teratogenicity is 400 ppm (highest dose tested).
Executive summary:

Groups of 25 timed-pregnant Fischer F-344 rats (Harlan Fischer F-344/HarBR) were exposed to 2,4-pentanedione vapour by inhalation on gestational days (gd) 6 to 15 at exposure target concentrations of 0, 50, 200 and 400 ppm (0, 52.7, 202 and 398 ppm mean analytical concentrations, respectively) to evaluate the embryotoxic and fetotoxic (including teratogenic) potential of the test substance administered during organogenesis. The day a copulation plug was found was designated gestational day (gd) 0. Twenty-five plug-positive females were assigned to each experimental group. Clinical observations were recorded daily, and maternal body weights were taken on gd 0, 6, 9, 12, 15 and 18. At scheduled necropsy on gd 21 (CO2 asphyxiation), dams were evaluated for body weight, liver and thymus weights, gravid uterine weight, and status of implantation sites (i.e. resorptions, dead fetuses, live fetuses). Maternal brains were removed, fixed and examined histopathologically. Live fetuses were dissected from the uterus, counted, weighed and sexed and examined for external abnormalities. weighed and sexed and examined for external abnormalities. Approximately one-half of the live fetuses in each litter was examined for visceral abnormalities. These fetuses were then decapitated and their heads fixed in Bouins solution and examined for soft tissue craniofacial malformations. The remaining intact fetuses in each litter were eviscerated, fixed in alcohol, stained with alizarin red S, and examined for skeletal defects and deficits.

There was no maternal mortality in this study. Significantly reduced body weight gain at 400 ppm; liver weight significantly increased at 200 ppm but no further significant effects were determined. Maternal toxicity was indicated by reduced body weights on gd 9, 12, 15, and 18 but not on gd 21, and reduced weight gain for the intervals gd 6-9, 6-12, 6-15 (exposure period) and gd 6-18, but not for the post-exposure period (gd 15-21). There were no treatment-related effects on maternal liver, thymus or gravid uterine weight, or on body weight (absolute or corrected for gravid uterus) at sacrifice; histologic examination of the maternal brains showed no pathological effects related to treatment. For fetal toxicity significant reduction in female body weight per litter at 400 ppm (all fetuses, males and females approximately 10 %) and at 200 ppm (all fetuses, and males but not females approximately 3 %), one visceral variation (partial fetal atelectasis) significantly increased at 400 ppm were observed. 17 out of 79 observed skeletal variation exhibited significant changes in incidence and indicated a consistent pattern of reduced ossification in the 400 ppm group (for example poorly or unossified phalanges, unossified cervical or poorly ossified thoracic centrum). No differences were observed among the groups in the incidence of external, visceral or skeletal malformations; no further treatment related effects. There were also no effects of treatment on the number of ovarian corpora lutea, of total, non-viable or viable implantations per litter, or on pre- or post-implantation loss or on sex ratio. There were no maternal deaths, early deliveries or abortions. Pregnancy rate was high and equivalent across all treatment groups. One dam each at 0, 50 and 200 ppm carried a totally resorbed litter on gd 21. Two dams at 400 ppm had totally resorbed litters on gd 21. Clinical observations were made daily throughout the study. Most of the observations were limited to the eyes, nose and blood at the vaginal orifice and only in a few dams per group. In addition, urogenital area wetness was present in a few dams only at 0, 50, 200 ppm (not at 400 ppm). At sacrifice on gd 21, there was no effect of exposure on maternal body weight, maternal body weight corrected for gravid uterine weight or on absolute or relative (to corrected body weight) thymus weight. Absolute and relative liver weight was elevated at 200 but not at 400 ppm. Administration of 2,4-pentanedione vapour by inhalation to timed-pregnant Fischer F-344 rats during organogenesis at 0, 50, 200 and 400 ppm resulted in maternal toxicity at 400 ppm. Fetotoxicity was observed at 200 and 400 ppm in terms of reduced fetal weights per litter (approximately 3 and 10 %, respectively) and at 400 ppm in terms of a consistent pattern of reduced fetal ossification. There was no evidence of embryotoxicity or teratogenicity at any exposure concentrations employed, including those which produced maternal toxicity. Based on a significantly reduced body weight gain in the 400 ppm exposure group the NOAEC/LOAEC derived for maternal toxicity is 200 and 400 ppm, respectively. The NOAEC/LOAEC for developmental toxicity is 50 and 200 ppm, respectively, which is based on reduced fetal weights in male fetuses at 200 ppm and in male and female fetuses at 400 ppm and a consistent pattern of reduced fetal ossification at 400 ppm. The NOAEC for embryotoxicity and teratogenicity is 400 ppm (highest dose tested).