Tetrakis(hydroxymethyl)phosphonium chloride, oligomeric reaction products with urea

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Short description of key information:
No data are available on fertility effects of THPC-urea.

Effects on developmental toxicity

Description of key information

See "Discussion"

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

19.5 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

GLP guideline study well conducted (Kr: 1).

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

Developmental effects of THPC-urea have been assessed through one OECD 414 study (Barker, 1992), under GLP.

Summary of key information on THPC

Range-finding study

In a range finding study in rabbits, maternal animals were given 0, 32.5, 65 or 97.5 mg Active Ingredient (AI) /kg bw/day. Maternal toxicity was noted at 65 and 97.5 mg AI/kg bw/day and included reduced body weight and food consumption. No changes in foetal or litter weights were observed. From external examination and tissue examination of abnormal foetuses and one control litter, malformations were observed in one foetus at 65 mg AI/kg bw, which included oligosyndactyly, microphthalmia and retinal dysplasia. Four foetuses from one litter at 97.5 mg AI/kg bw/day showed also malformations, including oligosyndactyly, brachymelia, microphthtalmia and retinal dysplasia. As these malformations were seen in only one litter and only at doses which enhanced maternal toxicity these malformations were considered to be secondary non-specific effects.

Main study

In a teratogenicity study in rabbits, maternal animals were given 0, 6.5, 19.5 or 65 mg AI/kg bw/day.

Maternal effects were noted at 65 mg AI/kg bw/day and included coloured urine, reduced body weight gain and reduced food consumption.

No toxicological significant changes in foetal weight were noted. Decreased mean litter weight was observed at 65 mg AI/kg bw/day, but was considered to be due to a lower number of foetuses due to increased pre-implantation loss. No clear treatment related changes in the number of foetuses showing external, visceral or skeletal malformations were noted. At 65 mg AI/kg bw/day, only one foetus showed retinal dysplasia, absent forelimb phalanges and fused sternebrae. At the same dose level an increased incidence in foetuses showing external and visceral variations was noted, and included abnormal common carotid and agenesis of the intermediate lung lobe. As these latter observations are known to occur spontaneously in this strain of rabbit, they were considered not to be related to treatment.

In addition, eye and limb malformations were noted at the high dose level in which maternal toxicity was seen in the rabbit. We believe that maternal toxicity as measured by food consumption and body weight in this study was likely underestimated because repeated dose toxicity studies in rats revealed significant liver toxicity at similar or lower dose levels.

Indeed, animals of the 90-day toxicity rat study showed also liver toxic effects at lower dose levels (i.e. 13.1 mg/kg/day) compared to doses selected for the teratology studies. Given the important role of the liver ensuring the maternal homeostasis, the possible influence of the hepatotoxic effect of Perform CC deserves further investigation. This indicates that the observed developmental effect could be secondary to hepatotoxic effects. In public literature, other substances showing similar eye and limb malformations were identified (cyanazine, 2,4-dichlorophenoxyacetic acid and flurprimodol are examples). These effects were only observed in excess of maternal toxicity and were assessed not to be a proven direct effect of the test substance.

 

Perform CC is corrosive to the skin following topical administration in rabbits. Similar effects probably occurred during the gavage application of the test substance in the rabbit teratology study. This effect might not always have been detected due to the post treatment period and the rapid renewal capability of the intestinal tract. This irritation might have affected intestinal function and combined with the reduced food intake might have resulted in a low absorption of nutrients critical to the foetus. These observations suggest that maternal toxicity is the main driver of these abnormalities. 

A slightly increased incidence of bilateral and unilateral insertion of pelvic girdle on the 2^ndsacral vertebra was noted at 19.5 and 65 mg AI /kg bw/day. As this latter finding is also observed in the same proportion of controls, it is considered not to be related to treatment. In addition,the slightly increased incidence of extra thoraco-lumbar ribs noted at 6.5, 19.5 and 65 mg AI/kg bw/day was considered to be due to a low incidence in control animals, when compared to historical control data.

 

This body of evidences leads to consider that THPC-urea should be classified for reproductive toxicity as Category 2 Presumed human reproductive toxicant (H361d -Suspected of damaging fertility or the unborn child).

Justification for selection of Effect on developmental toxicity: via oral route:
Only one study was available.

Justification for classification or non-classification

Considering the studies from Barker (1991, 1992 - OECD 414), showing that the registered substance induced eye and limb malformations at 65 and 97.5 mg AI/kg bw/day, in presence of maternal toxicity, considering the results form OECD 414 studies on other THP+ salts, demonstrating the same pattern of effects, eye and limb malformations in presence of maternal toxicity, these observations suggest that maternal toxicity is the main driver of these abnormalities. Therefore, additional experiments are proposed with another substance from the same THP+ family member (see note below) to elucidate how secondary non-specific effects are occurring. Indeed Solvay is currently building a research project to consolidate the supporting evidence. In addition, there is a clear toxicological threshold for the developmental effect, below which no effects would be expected. It was concluded that THPC-urea should be classified for reproductive toxicity as Category 2 - Suspected of damaging fertility or the unborn child (H361d - Suspected of damaging fertility or the unborn child), according to CLP regulation (No) 1272/2008.

Note: Information from other THP+ salts is judged relevant because as an ionic salt THPC-urea is completely dissociated into THP+ and Cl- in aqueous solutions and the equivalent is true for most of the THP+ salts, including sulphate salt. As a consequence hazard properties evaluated in aqueous solution could reasonably be predicted using data from the equivalent sulphate salt. Therefore a read-across approach could be done for certain hazard properties between THPC-urea (chloride salt) and other THP+ salts.