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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No concern for reproductive toxicity was identified when analysing reproductive organs in subschronic+chronic oral tests with the substance as well as with a closely related substance (read across from THPC).

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Quality of whole database:

The quality of whole data base is limited, but there is enough evidence (e.g. mode of action) that a (systemic) effect on fertility is unlikely up to and including dose levels causing local toxicity.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Quality of whole database:

Limited exposure.

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Quality of whole database:

No data, but there is enough evidence (e.g. mode of action) that a (systemic) effect on fertility is unlikely up to and including dose levels for local toxicity.

Additional information

No data from tests with Tetrakis(hydroxymethyl)phosphonium chloride, oligomeric reaction products with urea.

In a two-generation reproduction study in rats, no reproductive effects were observed at the highest dose tested, which was 15 mg/kg bw/day. However, paternal toxicity characterized by histopathological liver alterations occurred at a dose of 7.5 mg/kg bw/day; the NOEL was 1 mg/kg bw/day. The data basis considers only the oral route of exposure.

Short description of key information:
Chronic oral studies in rats and mice (NTP tests with THPC and THPS) did not show effects on reproductive organ weights.

Justification for selection of Effect on fertility via oral route:
No study available with THPC-urea.

Effects on developmental toxicity

Description of key information

Teratogenicity cannot be excluded based on the foetuses with microphthalmia at 100 mg/kg bw/day. Given animal data considering only the oral route of exposure. 

Link to relevant study records

Reference

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)

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

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

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

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

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

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: fetotoxicity

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: fetotoxicity

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: teratogenicity

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(65-68%)

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

	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)

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

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

The substance caused developmental effects in rabbits at maternally toxic doses in a range-finding and main developmental study after oral administration of 100 mg/kg bw/day. The NOAEL for maternal toxicity in rabbits was 30 mg/kg bw/day based on body weight loss, decreased body weight gain and decreased food consumption. The NOAEL for developmental toxicity (eye and limb malformation) in rabbits was 30 mg/kg bw/day.

Justification for selection of Effect on developmental toxicity: via oral route:
Fully reliable OECD 414 test (GLP)

Justification for classification or non-classification

1) Teratogenicity was found at maternal toxic dose levels in rabbits. Classification of THPC-urea oligomers with Repr.Tox Cat. 1B H360 is not warranted because effects have been observed at high dose levels, where human exposure (worker only) is expected to be very unlikely. With respect to the severe local toxicity of the substance "exposure/risk" for an developmental effect in men is unlikely. Avoiding local toxicity (and subsequent maternal toxicity) will give a sufficient margin of safety (factor 3) for the endpoint teratogenicity.

2) In view of the consumption/life cycle of the substance exposure to men is limited and the oral route is not relevant.

3) When considering a dermal teratogenicity test, exposure to the skin of test animals would be limited according to the inherent corrosivity of the substance.

4) The inhalation route of exposure is not relevant because the substance is an organic salt which cannot evaporate without decomposition. During its life cycle, exclusively in industrial settings, aerosol formation does not occur.

Overall, there is evidence that in men systemic toxicity is rather unlikely for the substance, which is a cytotoxic, electrophilically reactive substance. THPC causes primary local toxicity. Doses used in teratogenicity studies (gavage) are not relevant with regard to the expected conditions of handling and use, respective the limited human exposure.