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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
sufficient
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Triple Superphosphate (TSP):

In a combined repeated dose - reproductive / developmental toxicity screening test according to OECD 422 (GLP, RL1) (Dent 2002) triple superphosphate (TSP) was administered to Sprague-Dawley rats orally (gavage). Animals were either exposed for 6 weeks (males and females of toxicity subgroup) or 2 weeks before mating, during mating and gestation until postnatal day 3 at doses of 0, 250, 750 or 1500 mg/kg bw/day (doses are calculated as TSP added to feed, natural phosphate in feed not counted). Several haematological and clinical chemistry parameters were changed at the two highest dose levels and neurobehavioural changes in parental animals were observed at the highest dose. Minimal kidney and stomach effects observed at the lowest dose administered were not considered adverse or caused by a locally irritating effect, respectively. No effects on reproductive parameters or developmental toxicity were observed, apart from a slight reduction of pup body weights at the highest dose (1500 mg/kg bw/day). Therefore, a NOAEL of 250 mg/kg bw/day for general/maternal toxicity and a NOAEL of 1500 mg/kg bw/day for reproductive toxicity was derived from this study performed with TSP.

Phosphoric acid:

In a pre-guideline feeding study (Bonting and Jansen, 1956) parental rats and 2 successive generation received phosphoric acid in feed at concentrations of 0, 0.4 or 0.75%. Basal diet contained phosphate in a concentration of 1.47%, summing up to a total phosphate concentrations in the two dose groups of 1.92 and 2.22% in feed. No adverse effects in parental animals or offspring was observed in any of the groups regarding clinical observations, body weights, reproductive parameters, number and viability of offspring, blood cell counts, gross and histopathology. Total phosphate exposure at the highest phosphoric acid dose level amounted to 888 mg/kg bw/day (using ECHA Guidance on IR and CSA, R.8 default values for feed intake and body weights of rats).

Calcium sulfate:

Calcium sulfate dihydrate was tested in a combined repeated dose/reproductive toxicity screening test according to OECD Guideline 422. The test material was administered to male and female Sprague Dawley rats by gavage at daily doses of 0, 100, 300 and 1000 mg/kg bw/day. No relevant observations regarding toxicity in parent animals or offspring were made. Therefore the highest dose tested (1000 mg/kg bw/day Ca sulfate dihydrate, or corrected for Ca sulfate anhydrous: 790 mg/kg bw/day) was considered the NOAEL under the conditions of this study. Calcium sulfate was not considered to be toxic to reproduction or development

Humic acid, potassium salt and humic acid:

Potassium humate was tested in reproductive toxicity screening assay according to OECD Test Guideline No. 421. The test substance was administered daily to male and female Wistar rats by gavage at doses of 250, 500, or 1000 mg/kg body weight/day). Each group consisted of 10 males and 10 females. Body weight, food consumption, clinical status, weight and macroscopic structure of reproductive organs of treated parental males were unaffected by treatment of the test substance. Main observaitions relate to effects in the testes of male parental animals. The test substance negativley affected the sperm quality and morphology of treated males of the middle and high dose group. Histopathological examination of the reproductive system of parental males of these dose groups showed increased incidence of lymphocyte infiltration in interstitium and epithelium of the epididymides in males of the dose levels 500 and 1000 mg/kg/day.

Effects observed in female parental animals were restricted to the high dose group (reduced body weights, hyperplasia of vaginal epithelium, sporadic occurrence of cysts in ovaries). Gestation index was slightly decreased only at the highest dose level (there was one aborted females). The number of pups, sex ratio, average weight of litter, average body weight of pups were unaffected. At the highest dose group slightly increased postnatal loss and decreased viability index was detected in comparison with control.

The NOAEL for reproductive toxicity in male rats in this study was established at 250 mg/kg body weight/day.        

           

Testes toxicity was also observed after intraperitoneal adminstration of humic acids (Lu et al., 1997), but no testes toxicity or detrimental action on sperm was detected after oral administration of high doses (5000 mg/kg) of humic acids to rats (Zimmermann et al., 1991). Hence, the capacity of humate to influence fertility following oral exposure remains unclear. But taking into consideration the NOAEL of 250 mg/kg bw/day observed in the OECD screening study with potassium humate and the very low percentage of the ligand humate in the submission substance (<1% w/w) an effect of the submission substance on fertility can be excluded.

Conclusion:

The NOAEL observed in the key study of Dent (2002) with TSP is taken forward as the NOAEL for fertility effects.

Based on the absence of any relevant reproductive or developmental toxicity observations in the studies reported for phosphate compounds and calcium sulfate (see below), the absence of effects in a pre-guideline multi-generation study with phosphoric acid, the very low percentage of humate in the submission substance, and the fact that the NOAEL for repeated dose toxicity is below the NOAELs for reproductive effects/developmental toxicity, there is no further concern for such effects and a two-generation reproductive toxicity study is not considered necessary.


Short description of key information:
In a OECD 422 screening study with triple superphosphate in rats no effects on fertility or reproductive organs/parameters were seen. Pup weights were slightly reduced in the highest dose used, accompanied by parental toxicity. In an older, published 2-generation study with phoshoric acid again no reproductive or developmental toxictiy was observed. Calcium sulfate did not show reproductive or developmental toxicity in a screening study according to OECD 421. Effects seen on sperm parameters in an OECD screening study with potassium humate at doses >250 mg/kg bw/day are considered to be not of relevance, taking into account the low percentage (<1% w/w) of humate in the submission substance.

Effects on developmental toxicity

Description of key information
Teratogenicity studies in three species (rabbits, rats, mice) are available for monocalcium phosphate and calcium sulfate and did not reveal any concern for developmental toxicity. Two published studies on developmental effects of humic acid did not reveal developmental toxicity at oral doses of 1000 mg/kg bw/day.Furthermore, in an OECD screening study with potassiuim humate (which is contained in the submission substance with 1% (w/w) only, developmental toxic effects were seen only at high doses. Overall, no concern for developmental toxicity could be derived from these reliable studies on the compnents of the submission substance.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
good
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Phosphate:

Monocalcium phosphate, monohydrate, was investigated in teratogenicity studies by the US FDA in rabbits, rats and mice (gavage, in water, equivalent to OECD 414). Neither maternal toxicity nor teratogenic effects or developmental toxicity was observed in these studies at the highest dose administeried (rabbits: 217 mg/kg bw/day; rats: 410 mg/kg bw/day; mice: 465 mg/kg bw/day) (Morgareidge, 1974).

In a combined repeated dose - reproductive / developmental toxicity screening test according to OECD 422 (Dent, 2002) (GLP, RL1) triple superphosphate (TSP) was administered to Sprague-Dawley rats orally (gavage). Animals were either exposed for 6 weeks (males and females of toxicity subgroup) or 2 weeks before mating, during mating and gestation until postnatal day 3 at doses of 0, 250, 750 or 1500 mg/kg bw/day (doses are calculated as TSP added to feed, natural phosphate in feed not counted). Several haematological and clinical chemistry parameters were changed at the two highest dose levels and neurobehavioural changes in parental animals were observed at the highest dose. Minimal kidney and stomach effects observed at the lowest dose administered were not considered adverse or caused by a locally irritating effect, respectively. No effects on reproductive parameters or developmental toxicity were observed, apart from a slight reduction of pup body weights at the highest dose (1500 mg/kg bw/day). Therefore, a NOAEL of 250 mg/kg bw/day for general/maternal toxicity and a NOAEL of 750 mg/kg bw/day for developmental toxicity was derived from this study performed with TSP.

Humic acid:

In a OECD 422 study with humic acid, potassium salt (details: see above under "Effects on fertility") effects on pups were only seen at the highest dose applied (1000 mg/kg d). Absence of significant developmental toxicity was shown in published studies with humic acids: Golbs et al. (1982) did not find developmental toxic effects when sodium humate was administered orally to rats at a dose of 1000 mg/kg. Similarly, Rensburg et al. (2007) failed to detect developmental toxicity when brown coal derived humate was administered to rats between day 5 and 17 of pregnancy via gavage of 500 mg/kg bw/day.

Calcium sulfate:

Teratogenicity studies with rats, mice, and rabbits were performed by the US FDA with oral (gavage) administration of calcium sulfate. No developmental toxicity was observed at any of the doses tested (up to 1600 mg/kg bw/day) in these studies (Morgareidge 1973).

Overall, no concern for developmental toxicity could be derived from these reliable studies on the compnents of the submission substance.


Justification for selection of Effect on developmental toxicity: via oral route:
NOAEL based on observations made in OECD 422 screening study with TSP (effects on pups at maternal toxic doses). No developmental toxicity observed in developmental toxicity studies with other phosphate compounds.

Justification for classification or non-classification

Available studies for the phosphate component and the constituent calcium sulfate showed absence of reproductive or developmental toxicity. Detrimental effects on sperm were seen in a OECD screening study with potassium humate at doses >250 mg/kg bw/day. Taking into account the low presence of humate in the submission substance (<1% w/w), it is concluded that no classification for reproductive and/or developmental toxicity according Regulation (EC) no. 1272/2008 (CLP) or Directive 67/548/EEC (DSD) is required.