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Key value for chemical safety assessment

Effects on developmental toxicity

Description of key information
Histopathological examinations in repeated dose toxicity studies indicated no effects on reproductive organs. Consequently no effects on reproduction are anticipated. 
The developmental toxicity of phthalic acid was investigated in a developmental toxicity study ( NOAEL,maternal toxicity: 1.25 % in feed = 1021 mg/kg bw/day; NOAEL, developmental toxicity: 2.5 % in feed = 1763 mg/kg bw/day) (Ema, 1997).
Additional information

Reproductive toxicity:

There is no study that investigates fertility for PA available.

As confirmed by literature histopathological examinations in repeated dose toxicity are of high value and high sensitivity for evaluation of reproductive toxicity.

In a subacute repeated dose oral toxicity study in male Wistar rats the test animals were given a powder diet containing phthalic acid (PA) at a level of 0.5 or 5% for 34 to 36 days, respectively. No histopathologic effect or decrease in testicle weight could be observed (Murakami, 1986).

Additionally in an insufficient documented, oral repeated dose toxicity study in young male 3 -4 weeks old (70 -100g) albino rats of the Sprague-Dawley strain for 4 days, the treatment did not affect the testicular tissues of rats (Cater, 1977).

In a subacute oral toxicity study in male Wistar rats the test animals were fed diets containing 2% of PA for 1 week. Absolute and relative testicular weights were not decreased compared to control (Oishi, 1980).

In addition a two-year chronic feeding study in rats and mice revealed no effects on testes (rats), epididymis (rats and mice) and ovaries (rats and mice) ( Huff, 1984; Kluwe, 1986; NCI, 1979).

As confirmed by recent literature (Mangelsdorf et al 2003, Ulbrich & Palmer 1995, Janer et al 2007a, Dent 2007, Sanbuissho et al. 2009)* in rodents histopathological examinations in repeated dose toxicity studies of reproductive tissues are of high value and high sensitivity for evaluation of reproductive toxicity in males and females. Histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. With this respect repeated dose toxicity studies should be considered sensitive and sufficient information to evaluate toxicity on fertility if histological examination of the reproductive organs is covered.

Based on the considerations above no further testing is required for the fertility assessment as the test substance has not shown specific effects on reproductive organs in male and female rats and there was no evidence of a specific reproductive toxicity of the test substance in the 2-year oral toxicity studies with phthalic anhydride.

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* - Mangelsdorf. et al., 2003: Some aspects relating to the evaluation of the effects of chemicals on male fertility. Regulatory toxicology and Pharmacology 36, 69-98

- Ulbrich & Palmer, 1995: Detection of effects on male reproduction – a literature survey. J am. College of Toxicology 14, 293-327

- Janer et al., 2007: A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reproductive Toxicology 24, 103-113

- Dent, 2007: Strength and limitations of using repeated-dose toxicity studies to predict effects on fertility. Regulatory Toxicology and Pharmacology 48, 241-258

- Sanbuissho et al., 2009: Collaborative work on evaluation of ovarian toxicity by repeated-dose and fertility studies in female rats. J Tox. Sci. 34:Special Issue SP1-SP22

Developmantal Toxicity:

The developmental toxicity of phthalic acid was investigated in a developmental toxicity study. Groups of eleven pregnant Wistar rats were fed a diet containing phthalic acid at a dose of 0, 1.25, 2.5, or 5.0 % ad libitum on GD 7 - GD 16 ( 0, 1021, 1763, 2981 mg/kg bw/day). The administration in the feed was selected because of only slight solubility of phthalic acid in water and oil. The pregnant rats were observed daily for evidence of clinical signs of toxicity, maternal body weight and food consumption. Average daily intake of phthalic acid was calculated. The pregnant rats were sacrificed on day 20 of pregnancy. The peritoneal cavity and uterus were opened and the numbers of live and dead fetuses and resorptions were counted. The gravid uterus was removed and the rats weighed again. The adjusted weight gain, i.e. maternal weight gain throughout pregnancy corrected for gravid uterine weight, was calculated. The live fetuses removed from the uterus were sexed, weighed and inspected for external malformations and malformations within the oral cavity. Approximately two-thirds of live fetuses in each litter, randomly selected, were stained with alizarin red S and examined for skeletal malformations. The remaining live fetuses in each litter were fixed in Bouin´s solution and examined for internal malformations. Maternal toxicity occurred in the 2.5 and 5.0 % groups as demonstrated by decreases in the adjusted maternal bodyweight gain (maternal bw gain excluding the gravid uterus; 30, 42, or 50 g for the 5, 2.5, or control group, respectively) during the administration period. No significant changes in maternal parameters were found in the 1.25 % group (adjusted body weight gain 47 g). No deaths or clinical signs of toxicity were noted in any group. No significant changes induced by phthalic acid were detected in the incidence of postimplantation loss, number and sex ratio of live fetuses. Significant decreases in the weight of male fetuses and decreased numbers of ossified centers of the caudal vertebrae were found only in the 5.0 % group, where significant maternal toxicity also was observed. Morphological examinations of fetuses revealed no evidence of developmental toxicity (NOAEL, maternal toxicity: 1.25 % in feed = 1021 mg/kg bw/day; NOAEL, developmental toxicity: 2.5 % in feed = 1763 mg/kg bw/day) (Ema, 1997).

Justification for classification or non-classification

Based on the available study a non-classification for toxicity to reproduction is justified.