Registration Dossier

Administrative data

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)
Reference:
Composition 0
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Test material information:
Composition 1
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.