Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In line with ECHA Final Decision number CCH-D-2114495836-29-01/F an extended one-generation reproductive toxicity study in rats, according to OECD Test Guideline 443, has been planned for the Category member DTPMP (5-7Na). The deadline for submitting the requested information is 22 May 2023.

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

In line with ECHA Final Decision number CCH-D-2114495836-29-01/F an extended one-generation reproductive toxicity study in rats, according to OECD Test Guideline 443, has been planned for the Category member DTPMP (5-7Na). The deadline for submitting the requested information is 22 May 2023.

In a supporting one-generation reproductive study (BioDynamics Inc., 1979), conducted prior to OECD Test Guidelines and GLP, DTPMP-H was administered continuously via the diet to Long-Evans rats at concentrations of 300, 1000 and 3000 ppm through one complete generation. Test substance administration to the F0 generation females (20/group) was initiated at the onset of gestation and continued throughout the ensuing gestation and lactation periods. Administration then continued to the F1 generation animals (10 males and 20 females/group) through a growth period and mating, gestation and lactation period for two successive litters. In the F0 generation, no treatment-related effects in the low and mid dose groups were evident. In the high dose group, females delivered litters containing fewer live pups and more dead pups (not statistically significant) resulting in a lower live birth index. Pups also had a lower weight at birth (not statistically significant). No other treatment-related effects were observed. In the F1 generation, no treatment-related effects were evident in the low dose group. No such effects were observed in the second litters and no other treatment-related effects were observed during the remainder of the study. Gross pathological examination of five adult F1 generation males and females of the control and high dose groups did not reveal any abnormal findings. The NOAEL was concluded to be 3000 ppm, equivalent to 294 mg/kg bw/day for males and 312 mg/kg bw/day for females.


Effects on developmental toxicity

Description of key information

In the prenatal developmental toxicity study with DTPMP-7Na (Monsanto, 1982), conducted according to a protocol similar to OECD Test Guideline 414 and in compliance with GLP, clear maternal toxicity (approx. 30% decrease in body weight gain, soft stools) was noted in pregnant Sprague-Dawley rats given 2000 mg/kg bw/day DTPMP-7Na (expressed as active acid) on gestation days 6-19, therefore the NOAEL for maternal toxicity was concluded to be 1000 mg/kg bw/day. The NOAEL for developmental toxicity was concluded to be 2000 mg/kg bw/day (active acid) based on no adverse developmental effects at the highest dose tested.

In line with ECHA Final Decision number CCH-D-2114495836-29-01/F a prenatal developmental toxicity study in second species (rabbit), according to OECD Test Guideline 414, has been planned for the Category member DTPMP (5-7Na). The deadline for submitting the requested information is 22 May 2023.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21.05.1980 to 09.06.1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
No record of gravid uterine weight, number of corpora lutea not recorded, no analytical confirmation of dosing solutions.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: No data
- Weight at study initiation: 180-200 g
- Fasting period before study: No data
- Housing: Individually in suspended stainless steel mesh cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: None, animals were received mated and allocated to cages.


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72 ±2
- Humidity (%): 40-60
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 26.05.1980 To: 09.06.1980
Route of administration:
oral: gavage
Vehicle:
other: Aqueous solution
Details on exposure:
No data
Analytical verification of doses or concentrations:
no
Details on mating procedure:
No data. Animals were received on gestational day 1, having already been mated.
Duration of treatment / exposure:
GD 6 - 19
Frequency of treatment:
daily
Duration of test:
20 days
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
25
Control animals:
other: 0.9% (w/v) aqueous NaCl
Details on study design:
- Dose selection rationale: No data
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for visible toxic effects.


DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: Gestational days 3, 6, 8, 10, 13, 15, 17 and 20.


FOOD CONSUMPTION: No


WATER CONSUMPTION: No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Gross examination of all animals that included examination of external surfaces and thoracic and abdominal cavities.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
Comparison of body weights between treatment and control groups was performed using Dunnett's test. Counted data (corpora lutea, implants, resorptions, live and dead fetuses) and data expressed as percentage were analysed, when appropriate with the Mann-Whitney U test. Response data (pregnancy rates, number of litters with post-implantation loss, and fetuses or litters with abnormalities and variants) were analysed, when appropriate, with Fisher's exact test and the chi-square test.
Indices:
None
Historical control data:
No data
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
9/25 dams had soft stools in the 2000 mg/kg bw/day group beginning on gestation day 14 (9th day of the treatment) and persisted through to gestation day 17. This finding was not observed in the other treated groups or the controls.
Mortality:
no mortality observed
Description (incidence):
No deaths occurred prior to the scheduled sacrifice.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The only statistically significant (P<0.01) effect observed was lower body weight gain (mean value approximately 68% of the control mean) between gestation day 6 and 20 for dams in the 2000 mg/kg bw/day group (33.6/27.6/27.5/22.9). However, terminal body weights were not statistically significantly affected (mean terminal body weights with uterine contents by dose: 360.1/368.1/357.0/346.1 and mean terminal body weights without uterine contents: 265.8/264.5/260.1/257.2).
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related findings in the gross necropsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the number of pre- or postimplantation losses.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the resorptions.
Early or late resorptions:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the resorptions.
Dead fetuses:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the mean number of live fetuses.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
There was no effect on pregnancy rate.
Other effects:
no effects observed
Description (incidence and severity):
There was no effect on the mean number of corpora lutea.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
act. ingr.
Remarks:
active acid
Basis for effect level:
body weight and weight gain
Abnormalities:
effects observed, treatment-related
Localisation:
other: body weight gain
Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no effects on fetal body weight.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the mean number of live fetuses.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There were no effects on sex ratios (males/litter: 5.6/5.8/5.9/4.8. Females/litter: 5.9/6.5/5.4/6.4).
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related gross external malformations present.
Subcutaneous haematomas were present in controls and all treated groups, however the incidence increased at 500 mg/kg bw/day (P<0.05) and was considered unrelated to treatment by the study authors (no dose relationship was present). The occurrence of one female fetus that was hydrocephalic and one female with gastroschisis in the 1000 mg/kg bw/day group was considered by the study authors to be spontaneous. The hydrocephalic female also exhibited a developmental variation (underdeveloped renal papilla) that was not considered to be related to treatment.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Skeletal examination revealed single incidences of dwarfism (one female fetus of 500 mg/kg bw/day group) and fused sternebrae (one female fetus of the 2000 mg/kg bw/day group), which were considered spontaneous. Two fetuses from different litters in the 2000 mg/kg bw/day group and one fetus of the 1000 mg/kg bw/day group had vertebral anomalies (missing, reduced or fused vertebral arches). Although the incidence of these anomalies was not statistically significant compared with the control group, the rare spontaneous occurrence of such anomalies and the pattern of incidence indicated that they might have been treatment-related. Various skeletal variations occurred, but none showed a clear dose-response and so were considered spontaneous. Review of these results for the REACH assessment concluded that the effects should not be considered adverse as they were not statistically significant and were only observed in the presence of maternal toxicity. The limit dose for a prenatal developmental toxicity study conducted to OECD 414 is 1000 mg/kg bw/day, therefore the high dose used in this old study was double the limit dose. When findings up to the limit dose are considered, vertebral anomalies were observed in only one fetus. Therefore, this finding is not considered adverse.
Visceral malformations:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day
Based on:
act. ingr.
Remarks:
active acid
Sex:
male/female
Basis for effect level:
other: No adverse developmental effects observed.
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
In the prenatal developmental toxicity study with DTPMP-7Na, conducted according to a protocol similar to OECD Test Guideline 414 and in compliance with GLP, clear maternal toxicity (approx. 30% decrease in body weight gain, soft stools) was noted in pregnant Sprague-Dawley rats given 2000 mg/kg bw/day DTPMP-7Na (expressed as active acid) on gestation days 6-19, therefore the NOAEL for maternal toxicity was concluded to be 1000 mg/kg bw/day. The NOAEL for developmental toxicity was concluded to be 2000 mg/kg bw/day (active acid) based on no adverse developmental effects.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
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 the prenatal developmental toxicity study with DTPMP-7Na (Monsanto, 1982), conducted according to a protocol similar to OECD Test Guideline and in compliance with GLP, mated female Sprague-Dawley rats (25/dose) were given daily oral gavage doses of 500, 1000, 2000 mg/kg bw/day DTPMP-7Na (expressed as active acid) during gestation days 6 to 19. Control animals were given 0.9% sodium chloride solution. On day 20 all surviving animals were sacrificed and foetuses were examined. There were no deaths prior to scheduled sacrifice. The highest dose produced marginal toxic effects in the dams, as evidenced by lower mean body weight gain between gestational days 6 and 20, and soft stools in some animals. No treatment-related lesions were detected at gross necropsy of the dams of any treatment group. There were no statistically significant treatment-related effects on post-implantation loss or foetal weight at any dose. Vertebral anomalies were observed in single foetuses in two litters of the 2000 mg/kg bw/day group and one of the 1000 mg/kg bw/day group. The incidence was not statistically significant and the effect was only observed in the presence of maternal toxicity. In addition, the limit dose for a prenatal developmental toxicity study conducted to OECD Test Guideline 414 is 1000 mg/kg bw/day, therefore the high dose used in this old study was double the limit dose. When findings up to the limit dose are considered, vertebral anomalies were observed in only one fetus. Therefore, this finding is concluded not to be adverse. The NOAEL for maternal toxicity was concluded to be 1000 mg/kg bw/day based on the lower body weight gain, while the NOAEL for developmental toxicity was concluded to be 2000 mg/kg bw/day (active acid) based on no adverse developmental effects.

Information is also available on DTPMP-H from a one-generation reproductive toxicity study (Biodynamics, 1979b), conducted prior to OECD Test Guidelines and GLP, in which DTPMP-H was administered continuously via the diet to Long-Evans rats at concentrations of 300, 1000 and 3000 ppm through one complete generation. Test substance administration to the F0 generation females (20/group) was initiated at the onset of gestation and continued throughout the ensuing gestation and lactation periods. Administration then continued to the F1 generation animals (10 males and 20 females/group) through a growth period and mating, gestation and lactation period for two successive litters. In the F0 generation, no treatment-related effects in the low and mid dose groups were evident. In the high dose group, females delivered litters containing fewer live pups and more dead pups (not statistically significant) resulting in a lower live birth index. Pups also had a lower weight at birth (not statistically significant). No other treatment-related effects were observed. In the F1 generation, no treatment-related effects were evident in the low dose group. No such effects were observed in the second litters and no other treatment-related effects were observed during the remainder of the study. Gross pathological examination of five adult F1 generation males and females of the control and high dose groups did not reveal any abnormal findings. The NOAEL was concluded to be 3000 ppm, equivalent to 294 mg/kg bw/day for males and 312 mg/kg bw/day for females.

Justification for classification or non-classification

Based on the available data, no classification for reproductive and developmental toxicity is required for DTPMP (5-7Na) according to Regulation (EC) No 1272/2008.

Additional information