Tetrakis(hydroxymethyl)phosphonium chloride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

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

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

Additional information

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

Summary of key information on THPC

Range-finding study

In a range finding teratogenicity study in rabbits, maternal animals were given 0, 4.8, 14.4 or 48 mg Active Ingredient (AI)/kg bw/day. Maternal effects were noted at 14.4 and 48 mg AI/kg bw/day and included reduced body weight gain and food consumption. Each foetus was subjected to external observation and a tissue examination was carried out on foetuses exhibiting malformations and on one control litter. Mean foetal and litter weights were decreased at 14.4 and 48 mg AI/kg bw/day. At 48 mg/kg bw/day, eye and limb malformations were observed in foetuses from all litters. No treatment-related malformations were seen at 6 and 14.4 mg AI/kg bw/day. As eye and limb malformations were observed at maternal toxic doses, it was considered that these findings were secondary non-specific effects.

 

Main study

In a teratogenicity study in rabbits, maternal animals were given 0, 1.6, 4.8, 14.4 or 28.8 mg AI/kg bw/day. Maternal effects were noted at 4.8, 14.4 and 28.8 mg AI/kg bw/day and included reduced food consumption and body weight gain. At 28.8 mg AI/kg bw/day, one female aborted and was killed; one female died during the study. In addition, two high dose females appeared not to be pregnant, resulting in 11 pregnant animals at the end of the study, versus 15/16 pregnant animals in the other dose groups.

No changes in mean litter or foetal weight were observed. An increased incidence of foetuses with slightly lower insertion of the pelvic girdle was noted at 4.8, 14.4 and 28.8 mg AI/kg bw/day. An increase in supernumerary ribs was noted in foetuses at 28.8 mg AI/kg bw/day. No clear teratogenic changes were noted in any dose level, with the exception of 3 foetuses with microphthalmia at 28.8 mg AI/kg bw/day. All three foetuses were from one litter; the maternal animal showed slight effects on body weight gain or food consumption, but with no specific clinical signs.

 

The maternal and developmental NOAEL are set at 1.6 mg AI/kg bw/day, based on decreased body weight and food consumption in maternal animals and an increased incidence of foetuses with slightly lower insertion of the pelvic girdle.

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. 15 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 THPC 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.

 

THPC is corrosive to the skin following topical administration in rabbits. Similar effects 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. 

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 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 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 (chloride salt) and other THP+ salts.