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Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no reproductive toxicity studies for HMDTMPxK salts, so good quality data from HMDTMP-H (CAS 23605-74-5) has been used as read across.
Based on the reproductive toxicity study in rats a NOAEL of >256 mg/kg bw/day (rat) as active acid is set for the oral route. Reasonably well conducted reproductive toxicity study conducted before the adoption of OECD test guidelines and GLP.

Link to relevant study records

Referenceopen allclose all

Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See justification for read-across between HMDTMP category members in the attached file.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 ppm
Based on:
test mat.
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 3 000 ppm
Based on:
test mat.
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F2a
Effect level:
> 3 000 ppm
Based on:
test mat.
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Key result
Dose descriptor:
NOAEL
Generation:
F2b
Effect level:
> 3 000 ppm
Based on:
test mat.
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Reproductive effects observed:
no
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
Similar to OECD test method for 2-generation reproductive toxicity study.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Long-Evans
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
Nospecific details were provided in the report regarding the mating of F0. There was a fourteen day rest period between weaning of the first litters and initiation of the second mating period.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
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. Dietary administration of CP 45347 continued to the F1 generation animals (10 males and 20 females/group) through a growth period and a mating, gestation and lactation period for two successive litters.
Frequency of treatment:
Continuously, beginning Day 0 of gestation for the F0 females and continued for the F1 males and females through the F2a and F2b litters. (For a total of 281 days)
Details on study schedule:
Test substance administration of the F0 females was initiated the day signs of mating were observed (Day 0 of gestation) and continued throughout the ensuing gestation and lactation periods. F1 offspring were separated from siblings seven days after the weaning (Day 21 of lactation) of the last litter and were randomly selected to continue as future parents (F1 ). More offspring than needed were selected (12 males and 24 females) for the growth period to ensure the required number of adults (10 male and 20 females) necessary for mating. Following pup selection, remaining offspring and F0 females were sacrificed and discarded after gross external and internal examinations.

F1 animals were raised to maturity and mated to produce the F2a litters. F2a pups were sacrificed, necropsied and discarded at weaning. All F1 females were re-mated after a rest period of at least 14 days to produce the F2b litters. F2b pups were sacrificed and necropsied at weaning. Following completion of the F2b sacrifice, all F1 parents were sacrificed, necropsied and selected tissues preserved.

Litters produced from the mating of the F0 parents were housed together for approximately one week after the last litters had been weaned. Twelve male and twenty-four female offspring were proportionately selected from litters using a random number procedure. The parentage of each selected offspring was recorded to avoid possible brother-sister mating. The F1 generation were housed individually for a growth period of approximately 80 days before being mated to produce the F2a litters.
Dose / conc.:
300 ppm
Remarks:
Dose levels based on 100% active ingredient
Dose / conc.:
1 000 ppm
Remarks:
Dose levels based on 100% active ingredient
Dose / conc.:
3 000 ppm
Remarks:
Dose levels based on 100% active ingredient
No. of animals per sex per dose:
F0 generation females (20/group)
Dietary administration o f CP 45347 continued to the F1 generation animals (10 males and 20 femaleslgroup) through a growth
period and a mating, gestation and lactation period for two successive litters.


Control animals:
yes, concurrent no treatment
Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 ppm
Based on:
labile/free
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 3 000 ppm
Based on:
labile/free
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Generation:
F2a
Effect level:
> 3 000 ppm
Based on:
labile/free
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Key result
Dose descriptor:
NOAEL
Generation:
F2b
Effect level:
> 3 000 ppm
Based on:
labile/free
Remarks:
acid
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Reproductive effects observed:
no

In the F1 generation, no treatment effects were observed in growth, food consumption, fertility-reproduction or litter examination parameters. At terminal sacrifice, a lower mean body weight was observed in the mid-dose males and high-dose female groups. In the female groups, mean thyroid weights (absolute and relative to body weight and brain weight) were lower in the treated groups and spleen/body weight ratios were higher at the mid - and high- dose levels (only at the mid-dose leve1 was spleen/brain weight ratio increased).

 

No treatment effects on organ weight data were observed in the treated male groups. Gross post mortem observations and evaluation of selected tissues from five adult F1 generation males and females of the control (300 and 1000 ppm) and high-dose (3000 ppm) groups indicated no findings considered related to the administration of the test substance.

In the F1 females the only effect seen was a reduction in the mean thyroid weights. However in the absence of histopathological/clinical pathology examination results, it is not clear whether or not the weight change a real effect.

In the absence of adverse clinical /reproductive effects for this substance it is unlikely to be of toxicological significance.

 

Dose level (ppm)

Mean Weight (g) (Thyroid) F1 Female

Mean Ratio (Thyroid) F1 Female

0

0,018

0,0056

300

0,014

0,0046

1000

0,015

0,0047

3000

0,013

0,0043

Executive summary:

In a reproductive toxicity study the test substance was administered continuously via the diet to Long-Evans F0 generation females (20/group) at the onset of gestation and continued throughout the ensuing gestation and lactation periods. Dietary administration was continued to the F1 generation animals (10 males and 20 females /group) through a growth period and a mating, gestation and lactation period for two successive litters.

In the F0 generation, no treatment effects were evident. In the F1 generation, no treatment effects were observed in growth, food consumption, fertility-reproduction or litter examination parameters. In the F1 females the only effect seen was a reduction in the mean thyroid weights. However in the absence of histopathological/clinical pathology examination results, it is not clear whether or not the weight change a real effect. In the absence of adverse clinical /reproductive effects for this substance it is unlikely to be of toxicological significance.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
256 mg/kg bw/day
Study duration:
chronic
Species:
rat
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 reasonably well conducted reproductive toxicity study conducted before the adoption of OECD test guidelines and GLP, the general and reproductive toxicity NOAEL for HMDTMP acid was greater than the highest dose tested, 3000 ppm in the diet, in rats (approximately equal to a dose of 256 mg/kg bw/day in males and 297 mg/kg bw/day for females both as active acid). The result is read-across from HMDTMP-H (CAS 23605-74-5). The test protocol followed was similar to the current OECD 416 test guideline for two generation reproductive toxicity. HMDTMP-xK, HMDTMP-xNa and HMDTMP acid are members of the HMDTMP Category. The use of read-across between members of the category is in accordance with the rationale outlined in the attached justification.

A supporting multigenerational study is available for the analogous substance, ATMP-H, conducted prior to the adoption of OECD test guidelines and pre-GLP (Biodynamics Inc., 1979a). It is judged to be reliable with restrictions. Male and female Long-Evans rats were administered ATMP-H 60 days prior to mating (F0) and continuously thereafter (F1, F2, F3) in the diet at fixed concentrations of 0, 300, 1000 and 3000 ppm for three consecutive generations. The litters from F0, F1 and F2 matings were raised to maturity and also mated. Offspring from the first litter of each generation (F1a, F2a, F3a) were taken for necropsy on lactation Day 21. The parents were re-mated following a 14-day rest period and the offspring randomly selected at seven days post-weaning to continue as the F1b and F2b generation parents. Remaining F1b and F2b animals, as well as the F3a and F3b generation, were taken for necropsy. A gross internal examination was conducted on these animals. Randomly selected offspring from the F3a litters (10 pups/sex/group) were necropsied and selected tissues examined microscopically. Evaluations of adult mortality, mating, pregnancy, fertility, body weight data, food consumption data (growth and rest periods), litter survival, offspring viability at parturition, offspring weight and sex, and necropsy of adults and offspring, did not indicate any treatment-related adverse effects. The NOAEL for general toxicity and reproductive toxicity was greater than the highest dose tested, 3000 ppm. The concentration of the test substance and mean weekly food intake values were used to determine the approximate doses received by the animals. 3000 ppm was approximately equal to a dose of 275 mg/kg bw/day in males and 310 mg/kg bw/day in females. The result is read across to HMDTMP-xK and HMDTMP-xNa as supporting data, as the data for HMDTMP acid predates the requirement for the extended one-generation study (OECD TG 443).

Read-across data on reproductive toxicity from ATMP acid have been used to support evidence for lack of toxicity among members of aminomethylenephosphonates analogue group. ATMP acid and HMDTMP (4 -7K)

are both members of the aminomethylenephosphonates analogue group.

Effects on developmental toxicity

Description of key information

No developmental toxicity studies are available. The basis for possible read-across from organophosphonates with existing reliable studies is under review. A pre-natal developmental study, according to OECD 414, is therefore proposed (only in the event that no read-across from existing available reliable studies is possible). It is proposed to perform the study with the registered substance, HMDTMP (4-7K) (Potassium salts of {hexane-1,6-diylbis[nitrilobis(methylene)]}tetrakisphosphonic acid (4-7:1); EC 701-184-1) (only in the event that no read-across from existing available reliable studies is possible).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available (further information necessary)
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

No developmental data are available for HMDTMP Category members.

Read-across data on reproductive and developmental toxicity from ATMP acid have been used to support evidence for lack of toxicity among members of aminomethylenephosphonates analogue group. ATMP acid and HMDTMP (4 -7K

are both members of the aminomethylenephosphonates analogue group.

In a well documented pre-GLP teratology study (FDA segment II teratological study; reliability score 2) ATMP-H was administered by oral gavage to pregnant Charles River CD rats (24/dose), at dose levels of 100, 500 and 1000 mg/kg bw/day, on gestation days 6 to15. Control animals received the vehicle (water) only. Dams were sacrificed on gestation day 21 and recovered fetuses evaluated for external, soft-tissue and skeletal malformations. Maternal mortality, pregnancy rate, body weight gain, uterine implantation data, fetal size, sex data, ossification variation data and teratological evaluations were evaluated. High dose females gained less weight than the controls during the dosing period. A statistically significant increase in the number of resorptions was observed in the low and high dose animals (not the mid-dose). There was also an increase in the number of dams with two or more resorptions. However, the resorption data were within the range of historical values for the laboratory, so it was concluded that there was not a treatment-related effect. There were no teratogenic effects in the low and mid dose group. In the high dose group six fetuses from a single litter had common multiple malformations that included flexed forepaws, shortened and thickened torso, abdominal distention and exaggerated flexure of the head. Soft tissue examination revealed two of these fetuses had a malformation defect of the heart. The remaining high dose fetuses were generally unremarkable. Soft tissue and skeletal malformation data from the high dose group were similar to the control group. Although a possible teratogenic effect could not be excluded, it was most likely that the effects were secondary to maternal toxicity. Therefore the maternal NOAEL was 500 mg/kg bw/day, and the NOAEL for fetotoxicity and teratogenicity was >1000 mg/kg bw/day.

Justification for classification or non-classification

Based on the available data, no classification is required for HMDTMP-(4 -7K) for reproductive toxicity according to Regulation 1272/2008/EC.

In the absence of data, HMDTMP-(4 -7K) is not classified for developmental toxicity according to Regulation (EC) No 1272/2008.