[No public or meaningful name is available]

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1982

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

2001

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Terephthalic acid

EC Number:

202-830-0

EC Name:

Terephthalic acid

Cas Number:

100-21-0

Molecular formula:

C8H6O4

IUPAC Name:

terephthalic acid

Details on test material:

Terephthalic acid, TA-33MP, Lot SMR-4687, purified grade), was received In a shipment from Amoco Chemicals Corporation, Chicago, IL, on November 21. 1977 and thereafter stored at room temperature.

Specific details on test material used for the study:

No specific test material supplier or purity of test material was noted.

Test animals

Species:

rat

Strain:

other: CD and Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: feed

Duration of treatment / exposure:

paternal: 90 days prior to and throughout mating
maternal: 90 days prior to mating, throughout mating, gestation, and lactation
offspring: 51 days; from birth through lactation and 30 days post weaning

Frequency of treatment:

daily in feed

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

14 mg/kg bw/day (nominal)

Remarks:

corresponds to 0.03%. Actual in CD strain: 14 and 17 mg/kg bw/d in males, females, respectively. Actual: 14 and 19 mg/kg bw/d in Wistar males, females respectively

Doses / concentrations 2

Dose / conc.:

59 mg/kg bw/day (nominal)

Remarks:

corresponds to 0.125%. Actual: 59 and 67 mg/kg bw/d in CD males, females respectively. Actual: 61 and 78 mg/kg bw/d in Wistar males, females respectively.

Doses / concentrations 3

Dose / conc.:

240 mg/kg bw/day (nominal)

Remarks:

corresponds to 0.5%. Actual: 240 and 282 mg/kg bw/d in CD males, females respectively. Actual: 249 and 307 mg/kg bw/d in Wistar males, females respectively

Doses / concentrations 4

Dose / conc.:

960 mg/kg bw/day (nominal)

Remarks:

corresponds to 0.2.0%. Actual: 960 and 1107 mg/kg bw/d in CD males, females respectively. Actual: 960 and 1219 mg/kg bw/d in Wistar males, females respectively

Doses / concentrations 5

Dose / conc.:

2 480 mg/kg bw/day (nominal)

Remarks:

corresponds to 5.0%. Actual: 2480 and 2780 mg/kg bw/d in CD males, females respectively. Actual: 2480 and 3018 mg/kg bw/d in Wistar males, females respectively.

No. of animals per sex per dose:

30

Control animals:

yes, plain diet

Details on study design:

Experimental conditions were identical for the two different strains of rats. Rats 15-17 weeks of age (n=30) were grouped housed 3/cage for the first 90 days of exposure. Body weight and feed intake were determined weekly during this time period. On Day 91, breeding pairs (n=10/sex) were housed together for 2 weeks prior to being separated. On Day 0 (delivery) the number and viability of offspring were evaluated and grossly examined. Offspring were recounted, sexed, and weighed on Day 1. These measurements were repeated at weaning on Day 21. After weaning, the litters were reduced to 2/sex/dose from each of 5 litters (20 pups/dose/strain) and maintained on test diets for 30 more days (Day 51) prior to sacrifice.

Examinations

Statistics:

Body weight gain and standard reproductive indices were assessed and statistically compared using ANOVA and Dunnett’s-t-test using SAS statistical programs.

Reproductive indices:

Parameters evaluated consisted of: fertility index, number of offspring born per dam; number and proportion of each sex born; number (Day 0, 1, and 21) and proportion (Day 1 and 21) of each sex alive; average weight at Day 1 and 21 of all offspring and of each sex.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Mortality:

mortality observed, treatment-related

Description (incidence):

Prior to mating, there were 5 deaths (3 CD females, and a Wistar male and female) reported during weeks 4-13 among those given 5% TPA in the diet. After mating, 3 CD (1 male at 2.0%, and one male and one female at 5.0%) and 4 Wistar female (2 at 5.0% and 2 at 0.03%) rats died.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weights were statistically decreased after 13 weeks in both sexes of CD rats on 2% and 5% TPA diets, and in males exposed to 0.03%. This effect occurred in Wistars (both sexes) only at the 5% level.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

decreased food consumption in CD females treated with 2% and 5% test material, and in both sexes of high dose Wistars

Reproductive function / performance (P0)

Reproductive performance:

no effects observed

Details on results (P0)

The NOAEL for parental toxicity and the F1 generation was 0.5% TPA in the diet (approximately 240-307 mg/kg/day). During the one-generation component of the study 3 CD (1 male at 2.0%, 1/sex at 5.0%) and 4 Wistar female (2 at 5.0% and 2 at 0.03%) rats died. There was no effect of treatment on fertility index and litter size.

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Effect level:

240 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

gross pathology

reproductive performance

Remarks on result:

other: in CD rats

Remarks:

in Wistar, NOAEL = 960 mg/kg bw/d

Target system / organ toxicity (P0)

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

960 mg/kg bw/day (nominal)

Results: F1 generation

Details on results (F1)

In the highest two doses, there was evidence that generalized toxicity affected dams, resulting in a failure of the dams to allow the offspring to nurse. These dams were consuming dietary levels of TPA known to cause reduced feed consumption and diarrhea, and to induce the formation of renal and bladder calculi. Unscheduled deaths during the postweaning period (Day 21-51) were confined to the 5% TPA group (18 Wistar and 16 CD) and were associated with a very high incidence of renal and bladder calculi. Renal and bladder calculi were noted in all animals exposed to 5% that were necropsied at Day 21. Day 51 necropsy findings also reported a very high incidence of renal and bladder calculi and the histological sequelae of the presence of the calculi.

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 2 480 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Any other information on results incl. tables

The NOAEL for reproductive toxicity was > 5% in the diet (approximately 2480-3018 mg/kg/day).

The NOAEL for parental toxicity and the F1 generation was 0.5% TPA in the diet (approximately 240-307 mg/kg/day).

Applicant's summary and conclusion

Conclusions:

A one-generation reproductive toxicity study of dietary terephthalic acid to both CD and Wistar rats at five doses ranging from 14 mg/kg bw/d (0.03% in the diet) to 2480 mg/kg bw/d (5% in the diet). Parental toxicity was displayed at doses of 960 and 2480 mg/kg bw/d in both strains of rat: bladder calculi and renal toxicity was observed in offspring of these doses which were continued on the diet throughout the F1 post-weaning periods, and maternal post-natal behaviour was adversely affected. The NOAEL for parental toxicity was 240 mg/kg bw/d (0.5%). There were no teratologic effects or other adverse reproductive effects of the test substance. The NOAEL for reproduction was 2450 mg/kg bw/d (5%) in both strains.