Diisotridecyl phthalate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study is rated a "1" because it applied GLP, used appropriate testing procedures, and followed an accepted test guideline.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Developmental Toxicity Study in Rats with Diisodecyl Phthalate

Author:

Nikiforov AI, et al

Year:

1995

Bibliographic source:

Toxicol Letters 78(Suppl 1):61

Reference 2

Reference Type:

publication

Title:

Developmental Toxicity of Di-isodecyl and Di-isononyl Phthalates In Rats

Author:

Waterman SJ, Ambroso JL, Keller LH, Trimmer GW, Nikiforov AI and Harris SB

Year:

1999

Bibliographic source:

Reproductive Toxicology 13(2):131-136

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Version / remarks:

Cited as Directive 87/302/EEC, part B, p. 24

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

1,2-Benzenedicarboxylic acid, di-C9-11-branched alkyl esters, C10-rich

EC Number:

271-091-4

EC Name:

1,2-Benzenedicarboxylic acid, di-C9-11-branched alkyl esters, C10-rich

Cas Number:

68515-49-1

IUPAC Name:

bis(8-methylnonyl) phthalate

Details on test material:

- Name of test material (as cited in study report): di-isodecyl phthalate
- CAS RN 68515-49-1

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc
- Age at study initiation: 9 weeks
- Weight at study initiation: 210 to 270 g
- Fasting period before study:
- Housing: Single house during the study period, except during mating
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24.4
- Humidity (%): 40 to 70
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:

oral: gavage

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- 1:1 M/F ratio per cage:
- Length of cohabitation: until observation of proof of pregnancy.
Mated females returned to individual cages. New females placed in males'cages until required number of mated females obtained for study.
- Proof of pregnancy: vaginal plug / sperm in vaginal smear, referred to as day 0 of pregnancy

Duration of treatment / exposure:

Gd 6 through 15

Frequency of treatment:

daily

Duration of test:

All females euthanised on GD21

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 500, 1000 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

no males; up to 25 mated females / dose

Control animals:

yes, concurrent vehicle

Details on study design:

Sex: male/female
Duration of test: gestation day 21

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Maternal toxicity was indicated by reductions in body weight gain and food consumption.  There was no evidence of malformations or fetal toxicity.

 

Developmental effects:  There were no significant differences in mean foetal body weight and no statistically significant increases in total or individual external, visceral or skeletal malformations in the treated group when compared with controls.  The only visceral variation observed was a single incidence of dilated renal pelves in the mid group.  Three controls, one low-dose, three mid-dose, and six high-dose foetuses were stunted.  Those observations were considered incidental and unrelated to treatment.  There was a dose-related increase in total foetuses with skeletal variations on both a per foetus basis (38/196, 35/177, 61/193, 123/196) and a per litter basis (18/25, 17/22, 20/24, 23/24) at a dose of 0-100-500-1,000 mg/kg, respectively. 

 

When compared with controls, rudimentary lumbar ribs and cervical ribs were dose-related significantly increased (p 0.01) in the mid and high-dose groups on a per foetus basis (21%, 52% versus 8.2% in control group and 6.2%, 9.2% versus 1% in control group, respectively; the historical control ranges are 3.7-21.6% and 0.54-4.0%, respectively) and in the high-dose group on a per litter basis (23/24 vs. 10/24 for rudimentary lumbar ribs and 10/24 vs. 2/25 for rudimentary cervical ribs). It is currently admitted that the litter is the preferred unit for developmental toxicity studies in order to avoid exaggeration of the level of significance. Therefore, only the effects observed at 1000 mg/kg/day are considered to set a NOAEL. As recognized in the EU Risk Assessment Report for DIDP, the NOAEL for the conceptus can be assumed to be 500 mg/kg/day based on significant increase of skeletal variation on a per litter basis at the high dose of 1000 mg/kg/day. 

Applicant's summary and conclusion

Conclusions:

The results indicate that DIDP was neither a selective developmental toxicant nor an embryotoxic agent.

Executive summary:

In regard with developmental effects, skeletal variations are observed in the developmental studies at 1,000 mg/kg/d concurrently with slight signs of maternal toxicity and lead to a NOAEL of 500 mg/kg/d.