Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
50 mg/kg bw/day
Additional information

There are only limited data available to assess the toxicity of reproduction of IPPD.

Data from a limited reproduction/developmental toxicity screening test (Duslo 2009) and histopathological data of a subchronic feeding study (Monsanto Co. 1990) are used in a weight of evidence approach.

The data from the available reproduction/developmental toxicity screening test (Duslo 2009) are limited, because requirement from recent guidelines (OECD TG 421) are not fulfilled. The number of pregnant females evaluated in this study is under the minimum acceptable number of pregnant females required to assure a meaningful evaluation of the potential of the substance to affect fertility, pregnancy, maternal and suckling behaviour, and growth. Thus, the findings from this study are only used for supporting reasons in a weight of evidence approach.

In the screening reproduction toxicity study (Duslo 2009) groups of 10 male and 10 female rats were administered by gavage to IPPD in dosages of 0, 20, 50, 125 mg/kg bw/day. Male rats were treated for 48 days and female rats were treated from 14 days before mating until day 3 of lactation. Males were sacrificed on day 48 and females on day 4 of lactation. No unscheduled death occurred in this study. Clinical signs were observed sporadic in low and mid dose group animals. Clinical signs related to test substance application were observed in high dose group males and females (125 mg/kg). The clinical signs observed in males were diarrhoea, red or pink secretion around nose or eyes, piloerection and salivation. In females piloerection (10/10), red or sorrel secretion around nostrils, hunch posture and apathy were noted. A slight decrease in body weights were noted in mid dose group males and a statistically significant decrease (p<0.05) in high dose group males. Only slight and transient effects on body weights were noted in treated females during pre-mating period, pregnancy and lactation period compared to control. Food consumption of treated males and females were lower compared to the corresponding control animals. No treatment-related effects on organ weights (males: testes, epididymis, prostate glands and pituitary glands; females: ovaries, uterus, and pituitary gland) were noted. Sporadic macroscopic and histopathological changes in ovaries and uterus were observed in control and treated females. Sporadic macroscopic changes in testes and epididymis were noted in control and treated males. A higher incidence of whitish strata was noted in high dose males (4/10). The relevance of this finding is questionable. Histopathological changes of male reproduction organs were sporadic observed in control and low dose group; whereas higher incidences of changes were noted in mid and high dose males. Inflammation of prostate gland was observed in control and treated animals, however, the incidences were increased in mid and high dose males (control: 1/10, low: 1/10, mid: 5/10, high 3/10). Atrophic changes of germinative epithelium were observed in control and treated animals. The incidences were slightly increased in high dose males (control: 1/10, low: 2/10, mid: 1/10, high: 3/10); however the severity of findings was not dose dependent and insignificant in treated males. Insignificant damage of spermiogenesis was noted in control and treated males. The incidence was increased in high dose males (control: 2/10, low: 0/10, mid: 1/10, 5/10). However, no treatment-related effects on sperm motility and sperm vitality were observed. Changes in sperm morphology was observed in the low dose group (increased incidence of flattened head and bent neck); whereas in the mid and high dose groups morphology of sperm was comparable to control.

No adverse effects were seen in terms of copulation and fertility results. These results should be used only for supporting reasons because of the limitations discussed above. The gestation index was reduced in the high dose group (80%) compared to the control (100 %), because of two aborted high dose females. No difference in gestation index was noted in low and high dose females compared to the corresponding control. An increase in pregnancy period in high dose group females was discussed by the authors (control: 22.25 days, low: 22.67 days, 22.71 days, high dose: 22.75 days). The relevance of the finding is questionable, because the number of pregnant rats evaluated was very low (6 to 8 females per group, for single females the duration of pregnancy could not be determinate). In addition, no historical control data are given.

Pre-implantation loss and post-implantation loss were comparable in control and treated animals. The number of pups delivered, sex ratio, average litter weights and average pups weights were comparable to control at parturition (first check of litters). A significant decrease in pup body weights and average litter weights were noted on day 4 of lactation. A significant decrease in viability index was observed in high dose group pups resulted from high post partum mortality.

Based on the finding of this study the authors suggested a parental and developmental toxicity NOAEL of 50 mg/kg bw and day, which based on body weight reduction in high dose males, and clinical signs in high dose males and females, aborted females and high post-natal loss of offspring.

There are only limited data available to assess the toxicity of reproduction of IPPD (as discussed above). The histopathological data from the 90 day feeding study (Monsanto Co. 1990) are used in a weight of evidence approach to support the limited findings from the screening reproduction toxicity study.

As confirmed by literature (Mangelsdorf et al. 2003, Ulbrich & Palmer 1995, Janer et al. 2007 and Dent 2007, Sanbuissho et al. 2009) histopathological examinations in repeated dose toxicity are of high value and high sensitivity for the evaluation of reproductive toxicity. Therefore at least for fertility assessment a repeated dose toxicity study showing no adverse effect should be taken into account. Also it is agreed that histopathological changes on the reproductive organs in repeated dose studies (subacute or longer exposure, see e.g. Ulbrich & Palmer 1995, Mangelsdorf et al. 2003) are indicative of effects on fertility. Therefore repeated dose toxicity studies should be considered as sufficient information for a DNEL calculation for fertility if histological examination of the reproductive organs is covered by repeated dose toxicity studies and the mode of action of the test substance does not give evidence for a specific toxicity.

A three-months feeding study with IPPD was conducted to assess the potential subchronic toxicity of IPPD (Monsanto Co. 1990). Sprague Dawley rats (10 per dose and sex) were administered orally, via dietary admixture, at dose levels of 0, 180, 360 and 720 ppm (males: 0, 13.5, 26.5, 54.0; females: 0, 15.6, 30.0, 59.0 mg/kg/d) for a period of three months (for more details see chapter repeated dose toxicity). Histopathological evaluation of selected tissues was performed after study termination. Testes, prostates and seminal vesicles were evaluated in control males and high dose males. Ovaries and uterus were evaluated in control females and in low, mid and high dose females. No treatment-related changes in reproduction organs were observed in any of the treated animals.

In conclusion:

There are only limited data available to assess the toxicity of reproduction of IPPD. The data from the limited screening reproduction toxicity study (TG 421) (Duslo 2009) and the histopathological data from a 90 day feeding study (Monsanto Co. 1990) are used in a weight of evidence approach to assess the toxicity of reproduction of IPPD. Significant reduction of body weights and clinical signs were observed in males of the highest dose group (125 mg/kg bw/d). In addition, histopathological changes of prostate in mid and high dose males and insignificant changes of spermatogenesis were observed in high dose males. However, no treatment-related effects on sperm vitality and sperm morphology were noted. In addition, the histopathological evaluation of testes, prostates and seminal vesicles in the 90 day feeding study revealed no treatment-related changes in histopathology (54 mg/kg bw/day highest dose evaluated). Thus, the relevance of the histopathological changes noted in prostates and spermatogenesis is questionable. Females of the highest dose group (125 mg/kg bw/d) showed clinical signs and abortion. The maternal toxicity observed in high dose group females was also accompanied with decreased postnatal viability of offspring and pathological changes in offspring. However, findings from the repeated dose toxicity studies (discussed under chapter repeated dose toxicity) revealed a LOAEL of 13.5 mg/kg bw, which based on changes of the liver; thus indicating the liver as the most sensitive target organ.


Short description of key information:
In conclusion, the reproduction toxicity of IPPD was evaluated in a weight of evidence approach. Based on the limited findings from the screening reproduction toxicity study and the histopathological data from the 90 day feeding study a parental and developmental toxicity NOAEL of 50 mg/kg bw and day is suggested, which based on body weight reduction and clinical signs in males at 125 mg/kg bw and clinical signs and abortion in females at 125 mg/kg bw. Fetotoxicity was indicated at 125 mg/kg bw by postnatal reduced viability index and pathological changes in offspring in the range of maternal toxicity.

Effects on developmental toxicity

Description of key information
The developmental toxicity of the test substance IPPD was evaluated in a developmental toxicity study (Monsanto Co. 1994).  Pregnant Sprague-Dawley rats (24 per group) were used to determine the teratogenic potential of the test substance. Dosage levels of 0, 12.5, 62.5 and 125 mg/kg bw and day were administered orally by gavage as a single daily dose on day 6 through 15 of gestation. Individual clinical observations, body weight and food consumption were recorded during the study. The females were killed on day twenty of gestation, examined macroscopically and the uterine contents examined. Treatment of pregnant females with IPPD at dose level of 125 mg/kg bw/day resulted in maternal toxicity indicated by salivation, soft dark faces and decreased food consumption on day 6 to 9. No dose or treatment related differences were observed on number of live foetuses per litter, early or late resorptions, post-implantation loss, total litter weights, mean foetal weights, or total number of foetuses delivered. There was no evidence of any teratogenic effect of treatment with 2 abnormal foetuses in the control group, 2 abnormal foetuses in the low dose group (12.5 mg/kg bw/d) and 1 abnormal foetus in the mid dose group (62.5 mg/kg bw/d). There were no malformed foetuses in the high dose group (125 mg/kg bw/d). The only adverse effect noted in the foetuses and related to treatment was a retardation of ossification in the high dose group (125 mg/kg bw/d); and a low percentage of wavy ribs, 3.8% compared with 0.6% in the controls. Wavy ribs are a commonly observed effect in studies, especially in presence of maternal toxicity, and normally disappears post-natal and is not considered as a malformation but as a variation.  There are no adverse effects in low and mid dose pups. 
Based on the findings from this study a NOAEL maternal of 62.5 mg/kg bw/day and a NOAEL developmental toxicity of 62.5 mg/kg bw/day is suggested.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
62.5 mg/kg bw/day
Additional information

The developmental toxicity of the test substance IPPD was evaluated in a developmental toxicity study (Monsanto Co. 1994. Pregnant Sprague-Dawley rats (24 per group) were used to determine the teratogenic potential of the test substance. Dosage levels of 0, 12.5, 62.5 and 125 mg/kg bw and day were administered orally by gavage as a single daily dose on day 6 through 15 of gestation. The control group received the vehicle (polyethylene glycol 400) only. Individual clinical observations, body weight and food consumption were recorded during the study. The females were killed on day twenty of gestation, examined macroscopically and the uterine contents examined. The number of corpora lutea, implantation number, position and type, foetal weights, foetal sex and external appearance were recorded. All live foetuses were preserved, processed and subsequently examined for skeletal or visceral anomalies.

No death occurred during the study. Clinical signs observed at 125 mg/kg bw/day were limited to pre-dosing salivation noted in 10/23 animals and soft dark faces noted for 6/23 animals. At 62.5 mg/kg bw/day transient noisy respiration was noted in one animal. There were no treatment related effects on body weight noted during pregnancy.

Food consumption was statistically significant reduced from day 6 to day 9 of gestation in females of the 62.5 mg/kg bw/day (p<0.01) and 125 m/kg bw/day (p<0.001) groups. After day 9 of gestation food consumption in these two groups was comparable with control animals. At the low dose group (12.5 mg/kg bw/day) no significant effects on food consumption were noted.

There were no treatment-related macroscopic findings for adult females at necropsy. There were no treatment-related effects on uterine/implantation data. The number of corpora lutea, number of live foetuses, foetus sex ratio, embryonic/foetal deaths (early and late), implantation loss, total litter weights and mean foetal weight were comparable between treated animals and control animals.

Throughout all groups there were three foetuses with significant structural anomalies. At 12.5 mg/kg one foetus, (dam 35, foetus 1) had an encephalocele with a further foetus (dam 44, foetus 7) having an interventricular septal defect. At 0 mg/kg one foetus (dam 14, foetus 5) had an interventricular septal defect, an atretic left atrium and mitral valve, right sided aorta, aortic arch and ductus arteriosus, no brachiocephalic trunk, no pulmonary trunk with a modified ductus arteriosus exiting from the right ventricle.

There were no intergroup differences in the incidence of foetal external findings.

The overall incidence of visceral findings for foetuses was considered comparable for all groups. Intergroup variations for specific visceral findings were not considered to be significant.

The authors of this study discussed a significant increase of skeletal findings at 125 mg/kg bw and day. Increased incidences of irregularly and incompletely ossified cranial and facial bones (p < 0.001 - P < 0.05) were noted. Small but statistically significant increased incidences of no ossification of hyoid (p < 0.001), unilaterall bilateral wavy ribs (p < 0.05) and semi bipartite vertebral centra (p < 0.01) were also observed. Incomplete ossification of more than one cranial bone (p < 0.05) was noted at 62.5 mg/kg bw/day. A statistically significant increase in incomplete ossification of more than one facial bone (p < 0.05) was noted at 12.5 mg/kg bw/day. However, small increase of retarded ossification and wavy ribs are common observations in studies, especially in presence of some toxicity in the dams.

Based on the findings of this study the authors suggested a NOAEL of 62.5 mg/kg bw/day, which based on the slight maternal toxicity seen at 125 mg/kg bw/day. A NOAEL for offspring of 62.5 mg/kg bw/day was suggested, which based on the small increase of retarded ossification and wavy ribs noted at 125 mg/kg bw/day.

Justification for classification or non-classification

No classification is required according to the classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).