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Key value for chemical safety assessment

Effects on fertility

Description of key information
A study using waste water from a petrochemical plant reports testicular toxicity.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 010.9 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Modern, guideline-compliant multigeneration study, with supporting data
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

TPA: screening study

In a one-generation screening study (Ledoux et al, 1982), administration of terephthalic acid in the diet at concentrations of up to 5% did not affect reproduction or fertility parameters in CD or Wistar rats. TPA exposure decreased Day 1 bodyweight and 21-day survival of offspring at the highest dietary concentration of 5%.  The incidence of renal and bladder calculi at Day 51 in pups fed the same test diets as their mothers was increased at 2% and 5% TPA.

 

TPA: multi-generation study

In a modern, GLP- and guideline-compliant proprietary study (Milburn, 2003), dietary administration of 20000 ppm terephthalic acid for two successive generations of Wistar-derived rats did not result in any effects on reproductive performance.  No gross or microscopic changes were seen in the reproductive system that could be related to terephthalic acid administration.  Irritant changes were observed in the bladder of males and females receiving 20000 ppm terephthalic acid and there was some evidence for an effect on the kidney at this dose level.  These tissues were not examined for the 1000 or 5000 ppm groups.  Reductions in pup bodyweight generally occurred from Day 15 post partum, when the offspring had started consuming solid diet, and are considered to be a direct effect of the test material on the pups rather than an expression of developmental toxicity.  Pup bodyweights in the F2 generation of the 20000 ppm treatment group were lower than controls from birth, but this finding is considered to be related to the larger litter size in this group.  The only effect seen at a dose level of 1000 ppm was a decrease in kidney weight in adults and pups.  The NOAEL for effects on reproduction is therefore 20000 ppm (equivalent to 2010.9-2324.3 mg/kg bw/d achieved pre-mating dose levels), the highest dose level used in this study.

 

The apparent effects on kidney weight seen in this study were considered by the independent UK Committee on Toxicity (COT). The COT used the criteria for distinguishing adverse from adaptive effects outlined in ECETOC Technical report No 85 (Recognition of, and Differentiation between, Adverse and Non-adverse Effects in Toxicology Studies). It was concluded that the effects on renal weight seen at 1000 ppm were without histopathological correlates and were therefore adaptive effects. The COT therefore defined the NOAEL for toxicity as 5000 ppm (approximately 500 mg/kg bw/d).

Published study reporting effects on testicular function 

In a non-standard published study, Cui et al (2004) administered terephthalic acid for 90 days to determine the effects on testicular function in male Sprague-Dawley rats.  Terephthalic acid was mixed with a standard rodent diet at levels of 0, 0.2, 1 and 5%.  Testicular function was assessed by histopathology, testicular sperm head counts, daily sperm production, sperm motility, biochemical indices (marker testicular enzymes) and serum testosterone levels.  There were no effects of administration on body weight gain or food consumption.  Damage of spermatogenic cells and Sertoli cells was observed by electron microscopy; testicular sperm head counts, daily sperm production, and sorbitol dehydrogenase (SDH) activity were decreased significantly in the 5% group.  Sperm motility was significantly reduced in all treated groups, in a dose-dependent manner. The authors conclude that the 90-day daily administration of terephthalic acid at levels of up to 5% in the diet can cause impairment of testicular function in male rats.

The findings of the study of Cui et al (2004) are not considered to be of clear toxicological significance given the clear absence of functional reproductive effects in the one-generation screening study at dietary concentrations of up to 5% and in the two-generation study at dietary concentrations of up to 2000 ppm; and also in the clear absence of effects on sperm parameters in the multi-generation study. Based on findings in the screening study and the 90-day toxicity studies, the highest dose level of 5% in the Cui et al (2004) study would be expected to result in toxicity (bodyweight effects), although no signs of toxicity are noted in this paper.  In contrast, signs of toxicity were apparent in the study of Milburn et al (2003) study. The reported effects on sperm at the lower dose levels in the study of Cui et al are not considered to be relevant given the clear absence of effects at dose levels of up to 5% in the screening study and up to 20000 ppm (2%) in the Milburn study.

Read-across study with DEHT/DOTP

Faber et al (2002) report a 2 -generation study performed with the read-across substance DETP / DOHT. No effects on fertility or reproductive capacity were reported at dietary concentrations of up to 1.0% DEHT (10000 ppm, equivalent to a mean achieved intake of 1200 mg/kg bw/d using a default conversion factor). Takin into account the conversion of DEHT to TPA by hydrolyis, the achieved mean intake at the highest dietary concentration of DEHT is equivalent to approximately 510 mg/kg bw/d. The absence of findings in this study is consistent with reliable reproductive toxicity studies with TPA and supports the read-across approach used for other endpoints.


Short description of key information:
No evidence of reproductive toxicity was seen in a modern two-generation study performed with terephthalic acid.

Justification for selection of Effect on fertility via oral route:
Modern proprietary study performed to current guidelines under GLP.

Effects on developmental toxicity

Description of key information
No evidence of developmental toxicity was seen in an inhalation study in rats exposed to TPA at levels of up to 10 mg/m3 (Ryan et al, 1990).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
318 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
High quality, GLP-compliant and guideline-compliant stuides are available for the read-across substance DEHT/DOPT in the rat and mouse.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
The studyy is reliable, but is limited by the relatively low exposure level used.
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

A weight of evidence approach is taken to address the data requirements for developmental toxicity, using data for terephthalic acid (TPA) and the read-across substance DEHT/DOTP, which is shown to be hydrolysed to TPA following oral administration.

Inhalation developmental toxicity study with TPA

No evidence of developmental toxicity was seen in an inhalation study in rats exposed to TPA at levels of up to 10 mg/m3 (Ryan et al, 1990).

Oral developmental toxicity studies with DEHT/DOTP

A GLP- and Guideline-compliant study with the read-across substance DEHT in the rat showed no evidence of developmental toxicity following exposure to dietary concentrations of up to 10000 ppm DEHT on Gestation Days 0 -20. Maternal toxicity (reduced weight gain and increased liver weight) was seen in this study at the highest dietary concentration of 10000 ppm. An increased incidence of supernumerary rib seen at the highest concentration was considered to be treatment-related but not adverse. The highest dietary concentration of 10000 ppm DEHT is reported to be equivalent to 747 mg/kg bw/d and is calculated to be equivalent to 318 mg/kg bw/d terephthalic acid, based on the hydrolysis of DEHT to TPA.

A GLP- and Guideline-compliant study with the read-across substance DEHT in the mouse showed no evidence of developmental toxicity following exposure to dietary concentrations of up to 7000 ppm DEHT on Gestation Days 0 -18. Maternal toxicity (increased liver weight) was seen in this study at dietary concentrations of 3000 and 7000 ppm. The highest dietary concentration of 7000 ppm DEHT is reported to be equivalent to 1382 mg/kg bw/d and is calculated to be equivalent to 587 mg/kg bw/d terephthalic acid, based on the hydrolysis of DEHT to TPA.

Study of the effects of DEHT/DOTP on sexual differentiation

The effects of a number of phthalate esters on the sexual differentiation of male rats offspring (due to reported anti-androgenic properties) was assessed in a published study (Gray et al., 2000). In contrast to other substances investigated, the administration of DEHT at a dose level of 750 mg/kg bw/d to maternal female rats from Gestation Day 14 to Lactation Day 3 had no effect on sexual differentation, showing the absence of anti-androgenic activity for this substance.

Developmental toxicity studies: toxicokinetic considerations

It is also relevant that toxicokinetics studies (Tyl et al, 1982) indicate only limited placental transport of TPA following intravenous injection, due to the rapid maternal urinary excretion of the substance. Exposure of the developing embryo/foetus to TPA as a result of maternal exposure is therefore likely to be very low.


Justification for selection of Effect on developmental toxicity: via oral route:
A weight of evidence approach is taken to this endpoint, using read-across data from studies in two species (rat and mouse), neither of which reports any developmental toxicity at the highest dose levels tested. The rat study reports the lower NOAEL and is therefore selected. The NOAEL in the rat study (performed with DEHT) is corrected to show the equivalent TPA dose level based on the hydrolysis of DEHT to form TPA.

Justification for selection of Effect on developmental toxicity: via inhalation route:
Only study available for this endpoint

Toxicity to reproduction: other studies

Additional information

Zhang et al. (2010) report adverse effects on the testes of male mice exposed to waste water (containing TPA and a number of other organic and inorganic pollutants) for 35 days. A slight (but statistically significant) reduction in the proportion of viable spermatogenic cells was seen in the treated group. Findings were accompanied by an increased number of abnormal sperm and testicular histopathology including expanded interstitial space, reduced Leydig cell size and reduced numbers of sperm. The results of this study indicate that the wastewater caused effects on the testes of male mice; however due to the complex nature of the material tested, the contribution of terephthalic acid to the observed effects is unknown. Comparing the results of this study to the wider reproductive toxicity dataset, it would seem to be extremely unlikely that the dose level of TPA achieved in this study (~3 mg/kg bw) is responsible for the effects observed. The study is not considered to be of direct relevance to the toxicological assessment of TPA due to the complex nature of the test material and is therefore disregarded.

Justification for classification or non-classification

A published 90 -day rat study (Cui et al, 1984) reports effects on sperm development (identified using electron microscopy) at the highest dose level of 5% in the diet and effects on sperm motility at lower dose levels. In contrast, it is notable that a reproductive screening study (Ledoux et al, 1982) reports no effects on reproductive parameters at dose levels of up to 5% in the diet. The Ledoux et al study notes marked bodyweight effects at the 5% dose level, with a NOAEL for bodyweight effects of 0.125%. Findings are consistent with the results of other 90 -day dietary toxicity studies, which note effects at comparable dose levels. In the 90 -day study of Vogin (1972), the 5% dose level was not tolerated and was subsequently reduced to 3%. In contrast, the paper of Cui et al does not note any bodyweight effects. A modern guideline-compliant 2 -generation study (Milburn et al, 2003) does not report any evidence of reproductive toxicity (including sperm parameters) in rats administered TPA at levels of up to 20000 ppm in the diet.

The findings of Cui et al (1984) were noted at a dietary concentration exceeding the limit concentration (1000 mg/kg bw/d) recommended for a reproductive toxicity study and at a concentration which, in a number of other dietary studies in the rat, has caused marked effects on bodyweight. Effects on sperm parameters were not noted in a guideline-compliant 2 -generation study and no effects on fertility or reproduction were seen in a one-generation and in a two-generation study.

No classification is therefore proposed for effects on fertility or reproduction. Findings in the Cui et al (2004) study were not reproducible and were seen at dose levels above which the production of an adverse effect is considered to be outside the criteria which lead to classification. No classification is proposed for developmental toxicity in the absence of any relevant findings in an inhalation study in the rat (Ryan et al, 1990).