Tetrakis(hydroxymethyl)phosphonium chloride, oligomeric reaction products with urea

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-1992

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Experimental data (GLP, per guideline)

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1992

Report date:

1992

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrakis(hydroxymethyl)phosphonium chloride, oligomeric reaction products with urea

EC Number:

500-057-6

EC Name:

Tetrakis(hydroxymethyl)phosphonium chloride, oligomeric reaction products with urea

Cas Number:

27104-30-9

Molecular formula:

C5H16ClN2O5P

IUPAC Name:

Phosphonium, tetrakis(hydroxymethyl)-, chloride (1:1), polymer with urea

Test animals

Species:

rabbit

Strain:

New Zealand White

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

volume: 5 ml/kg bw

Details on mating procedure:

Each female mated with 1 stud male. After coitus females were injected with 10 I.U. chorionic gonadotrophin i.v. The day of insemination is taken as day 0 of gestation.

Duration of treatment / exposure:

day 7 to 19 of gestation

Frequency of treatment:

once daily

Duration of test:

Day 0 to day 29 of gestation

No. of animals per sex per dose:

16

Examinations

Maternal examinations:

mortality (twice daily), clinical signs (daily), body weight (day 0, 7, 8, 9, 12, 19, 24, 29 of gestation), food consumption.
Necropsy data: Liver, Lung, Skin, Foot, Uterus, but no observation of gastrointestinal tract =no local effects reporded).

Ovaries and uterine content:

pregnancy status, numer of corpora lutea, number, status and intrauterine position of implantations.

Fetal examinations:

external foetal malformations, foetal weight, foetal sex.

Statistics:

groups means, standard deviations and reproductive indices where appropriate.

Indices:

reproductive indices where appropriate

Historical control data:

yes

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: fetotoxicity

2

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: fetotoxicity

3

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: teratogenicity

4

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

	Group/Dose Level (mg/kg/day)
	1 (0)	2 (10)	3 (30)	4 (100)
Number of animals mated	16	16	16	16
Number pregnant	16	16	16	15
Pregnancy frequency as %	100	100	100	93.8
Died / Killed	0	0	1	1
With total resorptions	1	1	0	0
With live foetuses at Day 29	15	15	15	14*
Group mean body weight (kg) Day of gestation  0 7 8 9 12 19 24 29 Group mean body weight gain significantly lower than control Days 7 to 9.  * p<.05. Kruskal-Wallis, Wilcoxon rank sum test       12 to 19. ** p<.01, Analysis of variance, Dunnett's test	3.37 3.69 3.71 3.72 3.78 3.96 4.07 4.14	3.41 3.72 3.74 3.75 3.82 3.96 4.02 4.09	3.42 3.77 3.79 3.80 3.87 4.03 4.15 4.14	3.41 3.76 3.73 3.73* 3.75 3.76** 3.90 3.95
% body weight change days 0-29	22.8	19.9	21.1	15.8
% body weight change days 7-19	7.3	6.5	6.9	0.5
Group mean food intake (g/animal/day) days of gestation 0-7 7-8 8-9 9-12 12-19 19-24 24-29 Group mean food intakeoverperiod signif. lower than control AnalysIs of variance, Dunnett's test: Days 7 to 9, * p<.05         9 to 12, * p<.01       12 to 19, *** p<.00l	185 197 185 180 174 166 119	184 194 189 185 172 153 125	192 194 185 189 178 171 109	202 159 153* 134** 109*** 155 129
Mean intake /g/day) days 0-29	168	166	170	148
Mean intake /g/day) days 7-19	179	178	183	123
Mean intake /g/day) days 19-29	143	139	140	142
Number of females with live foetuses on GD 29	15	15	15	14
Number of corpora lutea Mean number per female	134 8.5	134 7.9	142 9.5	129 9.2
Number of implantations Mean number per female	127 8.5	119 7.9	127 8.5	106 7.6
% pre-implantation loss	5.2	11.2	10.6	17.8 DR*
Number of male foetuses	67	69	61	57
Number of female foetuses	56	41	60	45
% male foetuses	54.5	62.7	50.4	55.9
Mean litter weight (g)	355.8	327.4	348.4	317.1
Mean foetal weight (g)	43.0	45.0	43.6	43.7
Mean foetal weight (g) – males only	44.3	45.3	42.9	44.0
Mean foetal weight (g) – females only	43.0	44.2	44.1	43.5
DR* = significant increasing dose response (p<.05, Terpstra-Jonckheere test)

Applicant's summary and conclusion

Conclusions:

The technical substance (65%) caused developmental effects in rabbits at maternally toxic doses in a range-finding and main developmental study after oral administration. The effects observed, included postimplantation loss and eye and limb malformations, justify the NOAEL (maternal, fetotoxicity) = 30 mg/kg bw/day.