Dimethyl isophthalate

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

Remarks:

other: longer than a one-generation (OECD 414)

Type of information:

experimental study

Remarks:

migrated data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Scientifically-sound study which precedes establishment of guidelines and GLP. Male rats were exposed for 115 days to the test substance before mating. This represents a longer premating exposure time compared to guideline studies, and thus represents an adequate assessment of male reproductive function after exposure.

Justification for type of information:

Data can be read-across to dimethyl isophthalate from DMTP, based on common functional groups. The substances are isomers. The similarities in structure are likely to apply to metabolites as well, with DMIP breaking down to isophthalic acid, just as DMTP is known to break down to terephthalic acid; these are isomers. Similar structures and similar break-down products for the two substances is the basis for the reading-across of data for this endpoint.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
Data can be read-across to dimethyl isophthalate (DMIP) from dimethyl terephthalate (DMTP), based on common functional groups. The substances are isomers. The similarities in structure are likely to apply to metabolites as well, with DMIP breaking down to isophthalic acid, just as DMTP is known to break down to terephthalic acid; these are isomers. Similar structures and similar break-down products for the two substances is the basis for the reading-across of data for this endpoint.

Reason / purpose for cross-reference:

read-across source

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1973

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Long-Evans rats were administered DMTP in corn oil mixed with food for 115 days. They were mated with females who had been fed the same diet for 1 week prior to mating. Females continued eating this diet throughout gestation, parturition and weaning (Postnatal day 21). Percentage of inseminations and pregnancies, average gestation time and litter size, mortalities and pup weight were recorded, along with gross observations of teratogenic effects in offspring.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl terephthalate

EC Number:

204-411-8

EC Name:

Dimethyl terephthalate

Cas Number:

120-61-6

Molecular formula:

C10H10O4

IUPAC Name:

dimethyl terephthalate

Test material form:

solid: crystalline

Details on test material:

dimethyl terephthalate. No information on purity

Test animals

Species:

rat

Strain:

Long-Evans

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male animals were placed in the protocol as weanlings.
Housed in wire-bottom cages, 5 per cage.
Water and the appropriate diet were available ad libitum.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

corn oil

Details on exposure:

DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Test material dissolved in corn oil, and mixed with basal diet of ground Purina Laboratory Chow.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Mazola corn oil
- Amount of vehicle (if gavage): 2.0% (w/w) corn oil in diet
- Purity: no information

Details on mating procedure:

Males were mated with females who had been fed the same diet for 1 week prior to mating. The mating period was 1 week long, after which males were removed from the females and the diet changed to control diet for the remainder of their lives. Females continued eating the DMTP diet throughout gestation, parturition and weaning (Postnatal day 21).

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

PREPARATION OF DOSING SOLUTIONS:
Test material was added to the measured amount of corn oil and put into solution by adding 1000 g of chloroform and heating. This solution was added to the ground chow and homogenized using an automatic food mixer. The diets were spread on shallow, open trays to allow the chloroform to evaporate. A control diet was handled similarly but the addition of the test compound was omitted.

Duration of treatment / exposure:

122 days for males; 49 days for females.

Frequency of treatment:

daily

Details on study schedule:

There were 30 rats per dose group. At the beginning of the study, 10 animals of each group were randomly assigned to a group to be sacrificed on day 90. Another 15 animals were randomly selected for clinical chemistry and haemtological assessment at day 55 and every six months until sacrifice at 1 year. After 115 days, 5 animals of each dose group were placed with females for 1 week to allow mating. after which males were removed from the females and the diet changed to control diet for the remainder of their lives. Females continued eating the DMTP diet throughout gestation, parturition and weaning (Postnatal day 21).

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.25 % (w/w)
Basis:

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.5% (w/w)
Basis:

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1.0% (w/w)
Basis:

No. of animals per sex per dose:

30

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

There were no significant effects of exposure to 1% DMTP in the diet of rats. One treatment-related effect was reduced weight gain in the high dose males (386 g compared to 400 g in controls) at 91 days.

Oestrous cyclicity (parental animals):

No effect of treatement for 1 week prior to mating.

Sperm parameters (parental animals):

There was no adverse effect on the ability of males to inseminate females or for females to become pregnant.

Litter observations:

Pregnancy rate was at least 95%. There were no treatment effects on length of gestation or litter size. There was no mortality of young at birth, or during the period from birth to weaning.

Postmortem examinations (parental animals):

No effects

Postmortem examinations (offspring):

No effects

Statistics:

means, no standard deviation/standard error given. Differences were considered statistically significant at p < 0.05.

Reproductive indices:

No effects

Offspring viability indices:

No effects

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

There was reduced weight gain in the high dose males (386 g compared to 400 g in controls) at 91 days.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

There was reduced weight gain in the high dose males (386 g compared to 400 g in controls) at 91 days.

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1 other: % (w/w)in the diet.

Based on:

test mat.

Sex:

male

Basis for effect level:

other: 1% in the diet is approximately equal to 400 mg/kg bw/day.

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

There was a dose-dependent decrease in mean body weight of pups at weaning in the 1% and 0.5% groups (p < 0.05).

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

There was no treatment-associated mortality throughout the 115 day study in males, or in adults or offspring throughout the reproductive phase of the study. There was reduced weight gain in the high dose males (386 g compared to 400 g in controls). There were no toxicological effects on haematologic or clinical chemistry parameters. There was no effect on organ weights. Microscopic examination of tissues from all organ systems revealed no morphologic evidence of abnormalities which could be attributed to the compound. In the reproduction study, there was no adverse effect on the ability of males to inseminate females. The pregnancy rate was at least 95%. There were no treatment effects on length of gestation or litter size. There was no mortality of young at birth, or during the period from birth to weaning. No teratogenic effects were reported. There was a dose-dependent decrease in mean body weight of pups at weaning in the 1% and 0.5% groups (p < 0.05).

Applicant's summary and conclusion

Conclusions:

Dimethyl terephthalate was administered to male Long-Evans rats for 115 days at levels of 0.25, 0.5 and 1% (w/w) in the diet, prior to mating with females fed the diet for seven days. Pregnant females were maintained on the diet throughout gestation and through weaning on post-natal day 21. Males were assessed for chronic toxicity effects throughout their natural lifetime (up to 2 years), with the finding of no significant adverse effects (except for slightly lower body weight gain). There were no adverse effects of DMTP on male or female fertility or gestation, and no fetotoxicity or teratogenicity. The male and female reproductive NOAELs are 1% in the diet, equivalent to approximately 400 mg/kg bw/d. Data can be read-across to dimethyl isophthalate from DMTP, based on common functional groups. The substances are isomers. The similarities in structure are likely to apply to metabolites as well, with DMIP breaking down to isophthalic acid, just as DMTP is known to break down to terephthalic acid; these are isomers. Similar structures and similar break-down products for the two substances is the basis for the reading-across of data for this endpoint. This is adequate to fulfill the information requirements of Annex IX, to be the basis for classification and labelling decisions, and for risk assessment.