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EC number: 205-011-6 | CAS number: 131-11-3
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- The study is reliable with restrictions and was conducted aquivalent or similar to OECD TG 414 (Prenatal development toxicity study). Restriction: the study was performed according to guideline recommendations using exposure from GD 5-16, but the critical time-window for phthalate developmental toxicity is from GD 16-18.
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Reference Type:
- secondary source
- Title:
- No information
- Author:
- Price CJ et al.
- Year:
- 1 989
- Bibliographic source:
- Teratology 39: 473-474; abstract |no. P66
- Reference Type:
- secondary source
- Title:
- Developmental Toxicology: Status of the Field and Contribution of the National|Toxicology Program
- Author:
- Schwetz BA and Harris MW
- Year:
- 1 993
- Bibliographic source:
- Env. Health Persp., 100: 269-282
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Dimethyl phthalate
- EC Number:
- 205-011-6
- EC Name:
- Dimethyl phthalate
- Cas Number:
- 131-11-3
- Molecular formula:
- C10H10O4
- IUPAC Name:
- 1,2-dimethyl benzene-1,2-dicarboxylate
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Dimethyl phthalate (DMP)
- Physical state: clear, colorless liquid
- Analytical purity: >99% (gas chromatography)
- Lot/batch No.: 2113CM
- Stability under test conditions: yes, analyzed by the Research Triangle Institute supported by NTP
- Storage condition of test material: in amber bottles fitted with teflon-lined screw caps at -20°C
- other: DMP manufactured by the Aldrich Chemical Company and supplied by the Radian Corporation
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD (SD)Br VAF/Plus outbred Sprague-Dawley rats
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Caesarean-originated, barrier sustained outbred Crl:SD (CD)BR VAF-Plus albino rats; supplier: Charles River Laboratories Inc., Raleigh, NC
- Age at study initiation: 8-12 weeks
- Weight at study initiation: not reported
- Fasting period before study: not reported
- Housing: random, M (single) and F (max. 3 per cage) in solid bottom polycarbonate cages (Laboratory Products, Rochelle Park, NJ)
- Diet: Purina Certified Rodent Chow, #5002, pelltized (for M breeders) or ground (F at beginning, switch to ground chow during cohabitation)
- Water: ad libitum (deionized, filtered water)
- Acclimation period: 7 days quarantine period prior to study
ENVIRONMENTAL CONDITIONS
- Temperature (°C): mean 22.1-22.3
- Humidity (%): mean 54+-4
- Air changes (per hr): 12-14
- Photoperiod (hrs dark / hrs light): 12/12 (7.00p.m./7.00a.m.)
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: food
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
- DMP was weighed and added to an aliquot of Purina Certified Ground Rodent chowe (#5002) in a beaker and mixed with a spatula; premixed sample was thoroughly stirred by hand and it was added to the preweighed sample of ground feed from which the initial aliquot was taken and blended in a Patterson-Kelley Liquid-Solids Twin Shell Blender.
DIET PREPARATION
- Rate of preparation of diet (frequency): because of the limited stability of DMP under animal feeding conditions, animals were given a fresh supply of feed every third day throughout the dosing period.
- Mixing appropriate amounts with (Type of food): preweight ground food
- Storage temperature of food: formulated DMP/feed mixtures were refrigerated in light-protected containers - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - All feed formulations administered to the animals assayed within 90-110% of the theoretical concentration with the exception of the high dose (5.0%) in the preliminary study which was measured at 88.34%
- HPLC analysis - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight in the cages of the single housed M
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear, referred to as day 0 of pregnancy - Duration of treatment / exposure:
- days 6-15 of gestation
- Frequency of treatment:
- continuous
Doses / concentrationsopen allclose all
- Dose / conc.:
- 200 mg/kg bw/day (actual dose received)
- Remarks:
- calculated based on average food intake and a dietary concentration of 0.25 % (nominal concentration)
- Dose / conc.:
- 840 mg/kg bw/day (actual dose received)
- Remarks:
- calculated based on average food intake and a dietary concentration of 1.0 % (nominal concentration)
- Dose / conc.:
- 3 570 mg/kg bw/day (actual dose received)
- Remarks:
- calculated based on average food intake and a dietary concentration of 5.0 % (nominal concentration)
- No. of animals per sex per dose:
- 14-15 sperm-positve F per treatment in replicates
- Control animals:
- yes, concurrent no treatment
- yes, historical
- Details on study design:
- Duration of test: gestation days 6-15
- Dose selection rational: dose selection after range finding study; highest dose was expected to cause limited adverse effect in the dam
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: GD 3,6-9, 9-12, 18-20
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations: GD 3,6,9,12,15,18,20
WATER CONSUMPTION : Yes
- Time schedule for examinations: 0-3, 3-6, 6-9, 9-12, 12-15, 15-18. 18-20
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterine, liver, kidney - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Middle resorption: Yes (some fetal tissue, in addition to early resorptions) - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter - Statistics:
- ANOVA; Williams and Dunnett; Multiple Comparison Test, Fishers exact probability test
- Historical control data:
- Yes, historical control data in the appendix of the final report (teratologic investigations in the CD rat at Research Triangle Institute)
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
see table 1+2 (remarks on results including tables and figures)
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 840 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: No adverse effects at this dose
- Dose descriptor:
- LOAEL
- Effect level:
- 3 570 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- organ weights and organ / body weight ratios
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
see table 1+2 (remarks on results including tables and figures)
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 3 570 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects at the highest tested dose
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Table1: responses to DMP exposure
DMP in food (g/kg bw/day) |
||||
0.0 |
0.2 |
0.84 |
3.57 |
|
MATERNAL |
||||
Maternal body weight gd 9 + 12 |
-- |
-- |
-- |
↓ |
BW gain (treatment) |
-- |
-- |
-- |
↓ |
Relative liver weight |
-- |
-- |
-- |
↑ |
Food consumption (g/kg bw/day) gd 6-9 + 9-12 gd 15-18 |
-- -- |
-- -- |
-- -- |
↓ ↑ |
Water consumption (g/kg bw/day) gd 6-9 + 9-12 gd 18-20 |
-- -- |
-- -- |
-- -- |
↓ ↑ |
Embryo/fetal |
||||
% nonlive implants/litter |
-- |
-- |
-- |
-- |
% malformed fetuses/litter |
-- |
-- |
-- |
-- |
Average fetal bw/litter |
-- |
-- |
-- |
-- |
-- indicates no significant difference (p= 0.05) difference from control value
↓ or ↑ indicates significant difference (p= 0.05) difference from control value
Table2: Raw data from Fields et al. (1989) all data in (g) if not indicated different
DMP in food (g/kg bw/day) |
|||||
0.0 |
0.2 |
0.84 |
3.57 |
||
DMP % in feed |
0 |
0.25 |
1.0 |
5.0 |
|
MATERNAL TOXICITY |
|||||
Animals treated |
30 |
30 |
29 |
30 |
|
No. Dead |
0 |
0 |
0 |
0 |
|
No. (%) pregnant at sacrifice |
26(90) |
25(89) |
26(90) |
28(93) |
|
Maternal bw GD0 |
234.98+-2.75 |
236.25+-3.05 |
232.68+-2.30 |
239.96+-2.47 |
|
Maternal bw GD at sacrifice |
378.72+-5.17 |
386.69+-6.68 |
381.25+-4.58 |
378.12+-5.82 |
|
Maternal weight gain (gestation) |
143.74+-3.32 |
150.44+-4.54 |
148.57+-3.20 |
138.16+-4.68 |
|
Maternal weight gain (corrected for gravid uterine weight) |
64.38+-1.58 |
67.36+-3.02 |
67.07+-2.34 |
58.97+-2.34 |
|
Gravid uterine weight |
79.36+-3.20 |
83.08+-2.26 |
81.50+-3.24 |
79.19+-3.79 |
|
Maternal liver weight |
61.40+-0.23 |
17.03+-0.41 |
16.76+-0.35 |
17.33+-0.34 |
|
Maternal relative liver weight (% bw) |
4.31+-0.06 |
4.40+-0.06 |
4.39+-0.06 |
4.59+-0.06** |
|
Maternal right kidney weight |
1.153+-0.020 |
1.149+-0.026 |
1.114+-0.018 |
1.174+-0.024 |
|
Maternal left kidney weight |
1.112+-0.016 |
1.086+-0.040 |
1.077+-0.017 |
1.149+-0.020 |
|
Maternal food consumption (g/kg bw/day) 0-3 3-6 6-9 9-12 12-15 15-18 18-20 0-20 |
|||||
88.3+-3.1 |
91.9+-2.9 |
86.1+-2.1 |
83.6+-2.1 |
||
88.0+-1.7 |
92.8+-2.3 |
87.5+-2.4 |
95.4+-3.9 |
||
83.0+-1.2 |
79.4+-1.7 |
82.9+-2.5 |
59.5+-3.2** |
||
81.5+-3.5 |
82.6+-2.2 |
83.8+-1.5 |
70.1+-2.8** |
||
80.7+-1.6 |
81.1+-1.7 |
87.0+-2.8 |
85.1+-2.0 |
||
73.3+-1.3 |
79.8+-2.1 |
85.2+-2.2** |
90.8+-2.0** |
||
67.1+-2.4 |
68.5+-3.6 |
71.8+-3.2 |
76.5+-2.9 |
||
79.1+-1.0 |
80.6+-0.9 |
81.6+-1.4 |
78.7+-1.1 |
||
DEVELOPMENTAL TOXITITY |
|||||
Number corpora lutea/dam |
14.35+-0.62 |
13.88+-0.49 |
13.96+-0.51 |
13.93+-0.54 |
|
Implantation sites/litter |
14.85+-0.53 |
14.68+-0.41 |
14.58+-0.66 |
14.00+-0.61 |
|
% preimplantation loss |
3.39+-1.11 |
2.53+-1.52 |
5.44+-3.33 |
5.38+-2.35 |
|
Resorptions/litter |
0.46+-0.14 |
0.28+-0.09 |
0.50+-0.18 |
0.32+-0.12 |
|
% Resorptions/litter |
3.76+-1.21 |
1.85+-0.61 |
3.25+-1.15 |
5.29+-3.58 |
|
No. litter with resorptions (%) |
9(34.6) |
7(28.0) |
8(30.8) |
7(25.0) |
|
Late fetal deaths/litter |
0.00+-0.00 |
0.00+-0.00 |
0.04+-0.04 |
0.00+-0.00 |
|
(%) Late fetal deaths/litter |
0.00+-0.00 |
0.00+-0.00 |
3.85+-385 |
0.00+-0.00 |
|
No. litter with fetal death (%) |
0(0.0) |
0(0.0) |
1(3.8) |
0(0.0) |
|
No. nonlive implants/litter |
0.46+-0.14 |
0.28+-0.09 |
0.54+-0.18 |
0.32+-0.12 |
|
(%) nonlive implants/litter |
3.76+-1.21 |
1.85+-0.61 |
7.10+-3.89 |
5.29+-3.58 |
|
No. litter with nonlive implants (%) |
9(34.6) |
7(28.0) |
9(34.6) |
7(25.0) |
|
No. liiters with live fetuses |
26 |
25 |
25 |
27 |
|
Live fetuses per litter |
14.38+-0.59 |
14.40+-0.40 |
14.60+-0.39 |
14.19+-0.44 |
|
Males per litter |
7.23+-0.47 |
6.54+-0.51 |
7.28+-0.34 |
6.96+-0.50 |
|
Females per litter |
7.15+-0.45 |
7.76+-0.52 |
7.32+-0.36 |
7.22+-0.47 |
|
% Males per litter |
50.17+-2.34 |
46.06+-3.28 |
49.96+-2.07 |
48.80+-2.96 |
|
Average fetal bw |
3.439+-0.056 |
3.583+-0.053 |
3.625+-0.054 |
3.573+-0.046 |
|
Average male fetal bw |
3.515+-0.054 |
3.689+-0.057 |
3.713+-0.057 |
3.628+-0.049 |
|
Average female fetal bw |
3.366+-0.061 |
3.502+-0.047 |
3.540+-0.050 |
3.512+-0.045 |
|
Gross malformations/litter |
0.00+-0.00 |
0.00+-0.00 |
0.04+-0.04 |
0.07+-0.05 |
|
Visceral malformations/litter |
0.15+-0.07 |
0.12+-0.07 |
0.12+-0.09 |
0.07+-0.05 |
|
Skeletal malformations/litter |
0.12+-0.12 |
0.08+-0.08 |
0.16+-0.12 |
0.07+-0.07 |
|
Fetuses malformed/litter |
0.27+-0.13 |
0.20+-0.13 |
0.32+-0.15 |
0.22+-0.12 |
|
(%) litter with malformations |
19.23 |
12.00 |
20.00 |
14.81 |
|
(%) males malformed/litter |
1.19+-0.83 |
1.19+-0.82 |
1.67+-1.18 |
2.13+-1.09 |
|
(%) females malformed/litter |
1.96+-1.19 |
1.78+-1.39 |
2.62+-1.30 |
0.74+-0.74 |
|
** p-value = 0.01(Dunnett´s test)
Applicant's summary and conclusion
- Conclusions:
- The NOAEL for maternal toxicity was 1.0% (840 mg/kg bw/day) DMP.
The NOAEL for developmental toxicity was 5.0% (3570 mg/kg bw/day) DMP. - Executive summary:
The study is reliable with restrictions and was conducted equivalent or similar to OECD TG 414 (Prenatal development toxicity study). Dimethyl phthalate (DMP) was evaluated for developmental toxicity in timed-pregnant Sprague-Dawley (CD) rats. On gestational days (GD) 6 through 15, dietary concentrations of 0.0, 0.25, 1.0 and 5.0% (nominal concentration) DMP were administered, resulting in an estimated average food intake of 0.0, 0.2, 0.8 and 3.6 g/kg bw/day. This study was conducted to clarify the conflicting situation in the literature. Singh et al. (1972) reported embryo lethality and malformations in the rat after DMP exposure whereas Plasterer et al. (1985) reported no substance related effects in the mouse. This study was conducted in the rat to check rat specific developmental toxicity; additionally the positive study by Singh et al. (1972) was not assignable due to small sample size and limited fetal examinations. However, the study was performed according to guideline recommendations using exposure from GD 5-16, but the critical time-window for phthalate developmental toxicity is from GD 16-18.
High-dose DMP resulted in transient reductions in food and water consumption and body weight during early treatment. When treatment ended, food and water consumption rose above controls. Animals fed 5.0% DMP also exhibited reduced body weight gain during the treatment period and increased relative liver weight. Neither 0.25% nor 1.0% DMP treatment had significant maternal effects, with the exception of reduced water consumption during early treatment and increased food and water consumption following treatment (1.0% only). These results suggest that the apparent toxic effects of high-dose DMP on body weight may reflect the unpalatability of DMP in feed.
DMP treatment during organogenesis produced no apparent effects on measured endpoints of embryo/fetal viability, growth or development. The implantation sites and percentages of resorptions, dead fetuses, nonlife implants or malformed fetuses per litter were similar among dose groups. DMP treatment had no effect on the number of live fetuses per litter or average fetal body weight per litter. There was no effect of treatment on the incidence of external, skeletal or visceral malformations.
In summary, in this study in CD rats, maternal toxicity was observed at a dietary treatment level of 5.0% DMP. No developmental endpoints were affected under the conditions of this study.The NOAEL for maternal toxicity was 1.0% (840 mg/kg bw/day) DMP.
The NOAEL for developmental toxicity was 5.0% (3570 mg/kg bw/day) DMP.
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