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Administrative data

Key value for chemical safety assessment

Toxic effect type:
concentration-driven

Effects on fertility

Description of key information

NOAEL (fertility) = 500 mg/kg bw/day

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1.3 mg/m³
Study duration:
subchronic
Experimental exposure time per week (hours/week):
140
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No experimental data on the effects on fertility of the substance were available, therefore, toxicity to fertility was evaluated using a variety of experimental studies performed on structural analogues, and using a weight of evidence approach. Greater weight was given to studies performed according to the principles of GLP, performed according to relevant OECD Guidelines, performed on the recommended test species (appropriate strains of rat), and performed on the two metabolites of the substance. Justification for the use of a read-across approach is detailed in Section 13 of this Registration Dossier.


The experimental study on one of the metabolites (SC09) was a drinking water study performed according to a method comparable to the OECD Guideline 415 (a One-Generation Reproduction Toxicity Study): no toxicity to fertility (or developmental or general toxicity) was observed up to the highest dose administered of 5000 mg/kg bw/day in either male or female rats following an 8-week pre-mating period, a mating period, and a 20-day gestion period. An experimental study on the other primary metabolite of the substance (SC11) was a GLP, OECD study (OECD Guideline 422: Combined Repeated Dose Toxicity Study with the  Reproduction/Developmental Toxicity Screening Test). In this study, no impact on fertility parameters was observed (or general/developmental toxicity), up to the highest dose of 500 mg/kg bw/day. Rapid and complete hydrolysis of the substance occurs in aqueous medium, rendering both SC09 and SC11, therefore, data on these two substances is sufficient to evaluate this endpoint.


Several supporting studies relevant studies are also available for the assessment of the toxicity of the substance to fertility. The most relevant of these are two non-GLP, non-OECD studies on rats performed a primary metabolite of the substance; the third is a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (GLP; OECD Guideline 422) performed on the other primary metabolite of the substance.


An experimental study on the first primary metabolite of the substance (SC09) was not performed according to an OECD guideline, however, is comparable to an OECD Guideline 416 Prenatal Developmental Toxicity Study via the inhalation route. In this study, although developmental toxicity and general toxicity was observed at 2000 ppm, no toxicity to fertility was observed at this dose and the NOAEL for fertility was subsequently set at 2000 ppm. However, a supporting study on a structural analogue of a primary metabolite of the substance demonstrates a more sensitive NOAEL for sub-chronic inhalation toxicity of 1.3 mg/L, therefore, using a worst-case scenario approach, this NOAEL value is shared also for this substance.


Based on these values, no toxicity to fertility occurs at oral doses of at least 800 mg/kg bw/day, therefore, the lower NOAEL of 500 mg/kg bw/day is considered relevant also for this substance.

Effects on developmental toxicity

Description of key information

NOAEL (developmental) =  300 mg/kg bw/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1.33 mg/m³
Study duration:
subacute
Experimental exposure time per week (hours/week):
159
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

For the evaluation of the developmental toxicity of the substance a prenatal devolpmental toxicity study is available on the substance. It is performed as per the guideline OECD 414 and under GLP conditions.


This study was performed to evaluate the potential prenatal developmental and maternal toxicity of dibutyl phosphonate when administered orally, through gavage, to pregnant female rats as per the OECD 414 and under GLP conditions. The substance was administered orally from gestation day (GD) 5 to 19, through gavage, to 25 mated female rats per group at dose levels 100, 300, and 1000 mg/kg b. wt./day. The control group received the vehicle, corn oil, only.


Results


At 100 and 300 mg/kg b. wt./day: No treatment-related effects were seen in the 100 and 300 mg/kg b. wt./day dose groups for any evaluated parameter.


At 1000 mg/kg b. wt./day


No treatment-related effects were seen in the 1000 mg/kg b. wt./day dose group for the below-mentioned parameters:



  • Mortality and morbidity

  • Salivation was observed approximately 5 to 10 minutes after dosing in all-female rats from around gestation days 9 to 19 and persisted for approximately 20 to 25 minutes post-dosing. Salivation was not seen during morning observation. It is well known that salivation is often observed in gavage studies and may be a reaction to the taste or irritation of the test article rather than an indication of toxicity (Wook-Joon Yu at al, 2011). Therefore, salivation observed in this study was of no toxicological significance.

  • Pregnancy rate

  • Mean relative uterine weights

  • T3, T4, and TSH (Thyroid Stimulating Hormone)

  • External (gross) examination of the terminally sacrificed female rats

  • Internal (gross) examination of terminally sacrificed female rats revealed increased thickness of non-glandular stomach (in 23 out of 25 female rats). This effect was related to the test item treatment but was considered insignificant due to lack of human relevance as the non-glandular stomach is absent in humans.

  • The absolute and relative weight of the thyroid gland

  • Histological examination of the thyroid gland

  • Histological examination of the stomach (with gross lesions) revealed mucosal hyperkeratosis and hypertrophy/hyperplasia as well as infiltrate of inflammatory cells. These lesions were related to the test item treatment but were considered insignificant due to lack of human relevance as the non-glandular stomach is absent in humans.

  • Mean foetal count of male, female, and total foetuses (male + female)

  • Mean numbers of corpora lutea, implantation sites, live foetuses, dead foetuses, resorptions (early, late, and total), pre-implantation loss, and post-implantation loss

  • Mean percent of live foetuses, dead foetuses, pre-implantation loss, post-implantation loss, and total resorptions

  • Anogenital distance of male and female foetuses

  • Male sex ratio

  • Incidence of malformation/variation for external, visceral, and head razor examination of foetuses


The following treatment-related adverse effects were seen in the 1000 mg/kg b. wt./day dose group:



  • A statistically significant decrease in mean body weight of the pregnant female rats was observed on gestation days 17 and 20. Reduced mean body weight was also observed during gestation day 14 without statistical significance. A decrease in 20th day corrected mean body weight was also observed without statistical significance.

  • A statistically significant decrease in the mean body weight change was observed during the gestation days 5-8, 14-17, and 5-20. A reduced mean body weight change was also observed during the gestation days 11-14 and 17-20 without statistical significance.

  • A statistically significant decrease in mean food consumption was observed during the gestation days 5-8, 8-11, 11-14, and 5-20. Reduced mean food consumption was also observed during the gestation days 14-17 and 17-20 without statistical significance.

  • The decrease in the mean body weight, 20th day corrected body weight, and body weight change were correlated with the decreased mean food consumption and were considered as adverse effects of the test item.

  • A statistically significant decrease in mean absolute uterine weight (-13.01% than the control group) was observed. This finding was considered secondary to the maternal toxicity and adverse effect of the test item.

  • A statistically significant decrease in mean foetal weight of male foetuses (-7.43% than the control group), female foetuses (-7.83% than the control group), and the composite of foetuses of both sexes (-6.74% than the control group) was observed when compared to the control group. These lowered foetal body weights were correlated with decreased maternal body weight as well as absolute uterus weight. Hence, these findings were considered secondary to the maternal toxicity and adverse effects of the test item.

  • During foetal skeletal examination, statistically significant increase in the number of foetuses and litters with xiphisternum: unossified was observed. Statistically significant increase in the number of foetuses with 5th sternebrae: unossified was also observed. These variations indicated a delayed ossification associated with reduced foetal weights, i.e., a delay in foetal development rather than a direct effect on bone tissue and considered as secondary to the maternal toxicity and adverse effects of the test item.


Conclusion


NOAEL (maternal toxicity) = 300 mg/kg bw/day, based on the adverse effects observed on body weight, food consumption, and absolute uterine weight at the dose level of 1000 mg/kg bw/day


NOAEL (developmental) =  300 mg/kg bw/day, based on the adverse effects observed on foetal body weight and skeletal variations at the dose level of 1000 mg/kg bw/day.


 


Supporting data are retrived from a variety of experimental studies performed on structural analogues.  Justification for the use of a read-across approach is detailed in Section 13 of this Registration Dossier.


An experimental study on the first primary metabolite of the substance (SC09) was not performed according to an OECD guideline, however, is comparable to an OECD Guideline 416 Prenatal Developmental Toxicity Study via the inhalation route. In this study, the NOAEL for developmental toxicity was considered to be 750 ppm. However, a supporing study on a structural analogue of a primary metabolite of the substance demonstrates a more sensitive NOAEL for deveopmental toxicity via the inhalation route of 1.33 mg/L, therefore, using a worst-case scenario approach, this NOAEL value is shared also for this substance.


The second experimental study on this substance was a drinking water study performed according to a method comparable to the OECD Guideline 414 (a Prenatal Developmental Toxicity Study): the NOAEL for foetal development was set at 300 mg/kg bw/day in the absence of maternal/general toxicity at this dose and up to 5000 mg/kg bw/day. An experimental study on the other primary metabolite of the substance (SC11) was a GLP, OECD study (OECD Guideline 422: Combined Repeated Dose Toxicity Study with the  Reproduction/Developmental Toxicity Screening Test). In this study, toxicity to foetal development was observed at 500 mg/kg bw/day in the absence of maternal toxicity at this dose, therefore, the NOAEL for development was set at the next dose of 250 mg/kg bw/day. Rapid and complete hydrolysis of the substance occurs in aqueous medium, rendering both SC09 and SC11, therefore, data on these two substances is sufficient to evaluate this endpoint. Based on these values, no toxicity to fertility occurs at oral doses of at least 250 mg/kg bw/day, therefore, as both metabolites are expected to be present following ingestion, the lower NOAEL of 250 mg/kg bw/day is considered relevant for this substance.


An increasing trend in toxicity is observed with decreasing ester length (also observed in acute oral toxicity and repeated dose oral toxicity). Specifically, the structural analogues with methanol and octanol esters in place of the butanol esters rendered NOAEL (development, oral) values of 90 and 800 mg/kg bw/day, respectively. 

Justification for classification or non-classification

According to CLP Regulation (EC) No 1272/2008, reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring. For the purpose of classification for reproductive toxicity, substances may be allocated to one of two categories. Within each category, effects on sexual function and fertility, and on development, are considered separately.


-Category 1: Known or presumed human reproductive toxicant. Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).


-Category 2: Suspected human reproductive toxicant. Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1.


Based on the evaluation using the available data on reproductive toxicity, effects on fertility and development were not observed at oral doses exceeding 500 mg/kg bw/day, respectively, or at inhalation concentrations of 1.33 mg/L. Effects on and development on animals were noted at the highest dose applied in the OECD 414 at 1000 mg/kg bw/day. However, these effects were found to be secondary to maternal toxicity.


Therefore, the substance is not classified for reproductive toxicity, according to CLP Regulation (EC) No 1272/2008.

Additional information

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