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Key value for chemical safety assessment

Effects on fertility

Description of key information

(For more details please read CSR available in section 13).- Confidential CSR

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
11.7 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
OECD guideline study well conducted (Kr. 2)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a two generation study in rats (Wood, 1999), adult males and females exhibited a similar significant treatment-related increased incidence of liver changes to those reported in other repeated-dose studies (see section 8.9.1).
There was no effect of THPS treatment on sperm motility scores, on the proportion of abnormal sperm, on the oocyte numbers or on the proportion of oocytes classified within the different stages of maturation for either generation.

The reproduction phases of the study, particularly in the P generation, showed a higher than expected incidence of early pup death, mainly due to a significant number of females with total litter loss prior to Day 4 of lactation, in all groups including controls. This finding was related to nutritional deficiency of the dietary intake. Substituting the diet eliminated the problem. The F1 generation showed lower levels of total litter loss.

Based on these results, THPS does not cause adverse effects on fertility.


Short description of key information:
One study is available for effect on fertility; it was performed according to OECD 416 test method, with female and male rats. The dose level of THPS was 0.78, 5.84 and 11.7 mg/kg bw/day as active ingredient, administered orally during 89 days (males) and 135 days (females) for the P generation and during 120 days (males) and 165 days (females) for the F1 generation. No adverse effects on male or female reproductive performance were reported in this study.

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

Effects on developmental toxicity

Description of key information

Two reliable data are available for developmental toxicity. There are two studies performed in rat and rabbit (equivalent to OECD 414 test method) by gavage from day 6 to 15 (rat) or 7 to19 (rabbit) post mating. Eye defects and limb malformations were induced in the rabbit, but linked to the maternal toxicity. Based on these results, the NOAEL for teratogenicity (eye and limb malformation) = 13.6 mg/kg bw/day as main ingredient (18 mg/kg bw/day as active substance) in the rabbit.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
13.6 mg/kg bw/day
Study duration:
subacute
Species:
other: rabbit
Quality of whole database:
Two studies are available, well conducted (equivalent to OECD 414 test method, 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

 In teratology studies in rats (Barker, 1991a and b) and rabbits (Barker, 1991 and 1991c), maternal toxicity was observed only at the highest tested doses and was characterised by clinical signs, variation of bodyweight gain and necropsy findings similar to those observed during the repeated dose studies, such as hair loss, fur staining, decrease of bodyweight or bodyweight loss, coloured/discoloured organs. In addition, food consumption was markedly affected in animals treated at the high dose (mainly in rabbit species).

This maternal toxicity in the high dose group was not associated with effects on the pre/post implantation rate, number of living foetuses, on the sex ratio, or, on the foetal weight. Foetal malformations were observed at the highest tested dose for rabbits: eye defects in 35% and limb abnormalities in 15% of the living pups (Barker, 1991c). An eye malformation (only 1 foetus with anophthalmia) was observed in rats (Barker, 1991a); as the frequency of this observation in treated animals is comparable to historical control data in this strain and always at a dose level eliciting marked maternal toxicity, it can be concluded that this observation is not caused by THPS.

Moreover, at the same dose levels and in both species, the number of extra thoraco-lumbar ribs (defined as a developmental variation) was significantly increased. This variation was not considered to adversely affect survival or health of the offspring. In addition, these findings were significantly increased at a dose which was considered to be toxic in both species. Supernumary ribs findings are described as being of low to moderate concern in the ECETOC monograph n°31. In addition, this finding is considered related to maternal stress (Beyer et al., 1986), therefore we do not consider it as being a direct effect of THPS on the foetus.

Eye and limb malformations were noted at the high dose level in which marked maternal toxicity was seen in the rabbit. In the mid and low-dose groups, where no maternal toxicity was observed, no developmental toxicity was seen.  There appears to be an association between the high dose individual maternal toxicity in terms of changes in food consumption and incidence of major abnormalities in the foetuses in the corresponding litters. Moreover, 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, the 28-day toxicity rat study (see section 8.9) showed clearly that a dose level of 60 mg/kg/day enhanced hepatotoxic effects (i.e. 3/10 animals had pale and mottled livers). In addition, animals of the 90-day toxicity rat study (see section 8.9) showed also liver toxic effects at lower dose levels (i.e. 10 mg/kg/day) than 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 THPS deserves further investigations. 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, flurprimodol). These effects were only observed in excess of maternal toxicity and were assessed not to be a proven direct effect of the test substance.

Pharmacokinetic studies (see section 8.8) described that THPO and formaldehyde are the main metabolites of THPS. We may therefore suppose that foetus are exposed to both molecules. Nevertheless, available literature on formaldehyde (Reach dossier disseminated by ECHA) does not show an association with enhanced eye and limb malformations. Limited data is available on THPO, but available data suggest that THPO is a molecule with a low reactivity and when conducting an analysis based on structural similarity, no alerts for developmental toxicity were observed (QSAR tool box 3.2).

THPS is corrosive to the eye and causes severe dermal irritation following repeated topical administration in rats (see sections 8.2 and 8.9). Similar effects probably occurred during the gavage of the rats and rabbits teratology studies. 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 to a low absorption of nutrients critical to the foetus. Indeed, female n° 96 of the rat teratogenicity study which delivered a foetus with anophthalmia showed a marked food consumption decrease and had also a duodenal ulcer/abnormal ingesta noted at necropsy.

 

These observations suggest that maternal toxicity is the main driver of these abnormalities. Therefore, additional experiments are proposed 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. As findings were only observed in the presence of significant maternal toxicity in rabbits, THPS active substance has been self-classified into category 2 H361d. (Suspected of damaging the unborn child)

Justification for selection of Effect on developmental toxicity: via oral route:

Two reliable data are available for developmental toxicity. There are two studies performed in rat and rabbit (equivalent to OECD 414 test method, Kr.1). These two studies were chosen as the key studies for this endpoint.

Justification for classification or non-classification

THPS did not cause adverse effects on fertility.

As cited above in discussion, THPS 100% or 75% were classified into category.2 H361d (Suspected of damaging the unborn child) according to CLP (1272/2008) criteria.

Additional information

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