O-(4-bromo-2-chlorophenyl) O-ethyl S-propyl phosphorothioate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Reference 1

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10 February 1992 to 13 November 1992

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on mating procedure:

Stated below in 'Details on Study Schedule'

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

70 days of treatment prior to mating, then through to weaning

Frequency of treatment:

Continuous

Details on study schedule:

Following ~70 days of treatment, male and females within each dose group were randomly paired and cohabitated (1:1) for up to 3 weeks to yield F1 littes of the first generation (P0). On postpartum day 4, litters were culled to 8 pups leaving where possible equal number of male and female offspring. At 21 days of age pups were weaned. 30 male and 30 females within each dose level were randomly selected from among as many F1 litters as possible and continued on treatment as the P1 animals The P0 males were necropsied at 177-180 days of age after 134-137 days of dietary treatment. After weaning of F1 pups, the P0 females were necropsied at 183-186 days of age after 140-143 days of dietary treatment.After an additional 69 days of dietary treatment (at~109 days old), P1 animals were mated as described to yield the F2 litters. P1 males were necropsied at 171-177 days of age. After weaning of F2 pups, the P1 females were necropsied at 178-185 days of age.

Remarks:

Doses / Concentrations:0, 5, 100, 400 ppmBasis:nominal in diet

Remarks:

Doses / Concentrations:P0 Males: 0, 0.22, 4.5, 18 mg/kg dietBasis:actual ingested

Remarks:

Doses / Concentrations:P0 Females: 0, 0.31, 6.1, 25 mg/kg dietBasis:actual ingested

Remarks:

Doses / Concentrations:P1 Females: 0, 0.28, 5.5, 22 mg/kg dietBasis:actual ingested

Remarks:

Doses / Concentrations:P1 Males: 0, 0.21, 4.2, 17 mg/kg dietBasis:actual ingested

No. of animals per sex per dose:

30 animals/sex/group

Control animals:

yes, plain diet

Dose descriptor:

NOEL

Remarks:

Toxicity

Effect level:

ca. 100 ppm (nominal)

Sex:

male/female

Basis for effect level:

other: (equivalent to ~7 mg/kg/day). Decreased bodyweight , bodyweight changes and food consumption at 400 ppm

Remarks on result:

other: Generation: Parental and pup (migrated information)

Dose descriptor:

NOAEL

Remarks:

Reproductive toxicity

Effect level:

ca. 400 ppm

Sex:

female

Basis for effect level:

other: (equivalent to ~35 mg/kg/day). No effects on reproductive parameters observed up to a maximum dose of 400 ppm

Dose descriptor:

NOEL

Generation:

F1

Effect level:

7.38 mg/kg bw/day

Based on:

not specified

Sex:

not specified

Basis for effect level:

body weight and weight gain

Reproductive effects observed:

no

Lowest effective dose / conc.:

29.81 mg/kg bw/day

Treatment related:

not specified

PARENTAL ANIMALS:                                                       

Clinical signs and mortality:

No test material related clinical signs of toxicity were observed in males or females from either generation.

 

Bodyweight:

Significant reductions (p<0.05 or p<0.01) were observed at the 400 ppm males P₀ group throughout the study. A similar effect was observed in P₁ males at the same dose.

 

For P₀ females mean body weights were statistically lower over the gestational period. For P₁ females in the 400 ppm group interval body weight change was significantly lower on day 68 (end of mating phase) and there were no differences in cumulative weight changes.

 

Food consumption:

For P₀ males food consumption was similar for the 5 and 100 ppm groups. Mean food consumption values for the 400 ppm group were consistently below the values for the 0 ppm group throughout the study with statistically significant reductions occurring for those intervals ending on days 3, 73 and 94. Similar observations were seen in the P₁ male generation

 

For P₀ females food consumption values for the control and the 5 and 100 ppm dose levels were generally similar throughout this generation. At 400 ppm food consumption values for the 400 ppm dose level were consistently slightly lower during the pre-mating phase, with statistically significant decreases observed only for study day 0 to 3 interval. Again, similar observations were seen in the P₁ female generation.

 

Overall mean test material consumption for both generations throughout the study was equivalent to 0.36, 7.38 and 29.81 mg/kg/day for dietary levels of 5, 100 and 400 ppm respectively.

 

Reproductive function and performance:

There were no treatment related effects on mating behaviour as the precoital interval was similar among all groups in both generations. For P₀ evidence of mating was observed in 70, 87, 87 and 87% of the females in the 0, 5, 100 and 400 ppm dose levels respectively within the first 4 days of cohabitation. For the P₁ generation evidence of mating was observed in 83, 80, 83 and 90% for females in the 0, 5, 100 and 400 ppm dose levels respectively.

 

Litters with liver born pups was similar across all dose groups, in both generations. Mean gestation length, mating index fertility and gestation indices were comparable among all groups, in both generations.

 

Parental post mortem results:

No gross necropsy observations suggestive of a relationship to treatment with CGA 15324 Technical. There were no histological lesions, either non-neoplastic or neoplastic considered to be related to dietary administration of the test material.

 

There were no treatment related effects on male reproductive organs.

 

OFFSPRING:

Bodyweight:

Mean body weight gain of F₁ and F₂ pups at 400 ppm were statistically reduced (p<0.05) on day 14 and 21, which coincided with the direct ingestion of diet containing test material. This onset was indicative of signs of toxicity from ingestion of test material and not a reproductive effect.

 

Pup survival indices

The % of total pups born alive and remaining alive on day 4 (total born viability), of live born pups on day 4 (live born viability) and of the pups after culling surviving to weaning were comparable among the control and treated groups for both F₁ and F₂ litters.

 

Offspring post mortem results:

F₁ and F₂ pups: There were no test material related effects on the number of preweaning losses calculated runts or external observations. No test material related macroscopic findings were observed in incidental (preweaning) deaths, day 4 culled pups or weanlings. There was no significant increase in the number of pups with malformations in the treated groups. All malformations were considered incidental.

Conclusions:

In conclusion, the results of this study clearly demonstrate the absence of any adverse effects on reproductive parameters. The NOAEL for reproductive toxicity was at least 400 ppm (29.81 mg/kg/day). Based on reduced body weight gains and food consumption at 400 ppm, the NOEL for parental and pup toxicity was 100 ppm (7.38 mg/kg/day).

Executive summary:

CGA 15324 Technical was administered in the diet to rats at concentrations of 0, 5, 100 and 400 ppm (corresponding to 0, 0.4, 7 and 35 mg/kg/day) through two generations. Administrations started 10 weeks prior to the P₀ generation being paired and mated. Rats were randomly paired within dose groups to yield the F₁ generation. On lactation day 4 litters were culled to four male and for females where ever possible. Culled pups underwent a soft tissue examination with the focus on the brain and heart.

 

F₁ pups were weaned at 21 days of age. Within each dose level rats were randomly selected to continue on treatment as parent animals of the F₂ generation. They underwent the same study phases as P₀ animals. Adult animals were necropsied and reproductive tissues examined histologically.

 

At the 400 ppm dose level, reduced body weight gains and food consumption were noted in parental animals and pups of both sexes. There were no treatment related clinical signs, necropsy findings or histopathological observations at any dose level. Reproduction performance was not affected. There were no effects on mating, behaviour, gestation length, the number of litters with live born pups, the total number of pups/litter, preweaning losses, survival indices. No macroscopic findings were noted in pups.

 

In conclusion, the results of this study clearly demonstrate the absence of any adverse effects on reproductive parameters. The NOAEL for reproductive toxicity was at least 400 ppm (29.81 mg/kg/day). Based on reduced body weight gains and food consumption at 400 ppm, the NOEL for parental and pup toxicity was 100 ppm (7.38 mg/kg/day).

Reference 2

Endpoint:

three-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: IBTL study, non-GLP, non-guideline compliant. Study not validated by EPA, therefore data considered not reliable

Qualifier:

no guideline followed

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on mating procedure:

Females caged in pairs and mated with a male from within the same treatment group. Males were rotated within their dietary group at 10 day intervals until conception was confirmed or until the female had been paired with a maximum of 3 males. The 1st litters obtained were weaned at 21 days post partum, sacrificed and discarded. Parental females were then givena 10-day rest period and again mated. Females failing to become pregnant during the first mating period were not rebred. Eight males and 16 females from the second litters of each group were retained at weaning as parental animals for the suceeding generation.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

continuous (diet)

Frequency of treatment:

continuous (diet)

Remarks:

Doses / Concentrations:0, 0.2, 1, 20 ppmBasis:nominal in diet

Remarks:

Doses / Concentrations:0, 0.01, 0.07, 1.33 mg/kg dietBasis:other: Calculated from a time weighted conversion factor of 15

No. of animals per sex per dose:

8 males and 16 females/dose

Control animals:

yes, plain diet

Dose descriptor:

NOEL

Remarks:

toxicity

Effect level:

ca. 20 ppm

Sex:

male/female

Basis for effect level:

other: (equivalent to 1.33 mg/kg diet). No effects observed

Remarks on result:

other: Generation: All generations (migrated information)

Dose descriptor:

NOEL

Remarks:

Reproductive

Effect level:

ca. 20 ppm

Sex:

male/female

Basis for effect level:

other: (equivalent to 1.33 mg/kg diet). No effect on reproductive parameters observed

Remarks on result:

other: Generation: P0, P1 (migrated information)

Reproductive effects observed:

not specified

Table 7.8.1 -1: AChE % inhibition

Dose	Time	Plasma				RBC				Brain
(ppm)	(weeks)	Male	Sig	Female	Sig	Male	Sig	Female	Sig	Male	Sig	Female	Sig
F0 Parental Generation
0.2	Term.	-17	NS	-53	*	-2	NS	13	NS	1	NS	0	NS
1	Term.	-27	NS	-53	*	-1	NS	11	NS	-4	NS	-3	NS
20	Term.	15	NS	64	*	23	*	29	**	1	NS	-1	NS
F1 Parental Generation
0.2	Term.	-19	NS	1	NS	34	NS	-3	NS	18	NS	8	NS
1	Term.	-55	*	-27	NS	34	NS	6	NS	-49	N	-72	NS
20	Term.	-9	NS	48	NS	62	**	41	**	-53	NS	-98	NS
F2 Parental Generation
0.2	Term.	-43	NS	-36	NS	2	NS	-2	NS	2	NS	-20	NS
1	Term.	-28	NS	-14	NS	7	NS	9	NS	-10	NS	-13	NS
20	Term.	14	NS	65	NS	41	**	44	**	-18	NS	-9	NS

Term. - Termination

 

No test material consumption data was presented in the report. Therefore in accordance with the JMPR (2000) guidelines for pesticide residues a time-weighted conversion factor of 15 was applied. Therefore approximate levels of test material consumption were 0.01, 0.07 and 1.3 mg/kg/day for dietary levels of 0.2, 1 and 20 ppm respectively.

 

Gross pathology and histopathology did not reveal any test material related pathologies. Whilst erythrocyte cholinesterase activity was significantly inhibited in all 3 generations at doses of 1 ppm and greater, this did not have any affect on the activity of brain cholinestrase, with no inhibition observed with this enzyme.

Profenofos did not affect organ weights, body weights, surivial or reproductive performance.

 

Reference:

JMPR (2000). Pesticide residues. Guidelines for the preparation of toxicological working papers for the WHO core assessment group of the Joint Meeting on Pesticide Residues. Geneva, Switzerland, December 2000. 

Conclusions:

In conclusion, brain cholinesterase activity, reproductive performance or the development and survivial of the offspring through three generations were unaffected. The NOEL for reproductive effects was at least 20 ppm (1.3 mg/kg/day).

Executive summary:

In a three generation reproduction study, CD rats were fed Profenofos at levels of 0, 0.2, 1 and 20 ppm did not affect brain cholinesterase activity, reproductive performance, or the development and surivial of the offspring through three generations. The NOEL for reproductive performance was at least 20 ppm (1.3 mg/kg/day), the highest dose tested.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

29.8 mg/kg bw/day

Study duration:

subchronic

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

The multi-generation key study conducted showed that Profenofos has no effect on reproduction at doses up to the maximum dose tested, 400 ppm (equvialent to a mean test material consumption of 29.8 mg/kg/day^a ). For both paternal and pup toxicity the NOAEL was considered to be 100 ppm (equivalent to 7.81 mg/kg/day) due to reduced body-weight gains and food consumption at 400 ppm.

 

The supporting study confirmed the results of the key study. In addition, plasma, erythrocyte and brain cholinesterase activitiesd were measured in all three generations. Whilst statistically significant erthyrocyte inhibition was observed at doses of 0.1 or 10 ppm in all three generations in excess of 20% inhibition, this was not reflect in the brain cholinesterase activity, with no inhibition observed. Therefore, the NOEL for this study was considered 20 ppm (1.3 mg/kg/day^b), the highest dose tested.

 

a - In the JMPR review on Profenofos, NOAEL values for reproductive and parental/pup toxicity were stated to be 35 and 7 mg/kg/day respectively. In accordance with the JMPR Guidance (2000) a time weighted conversion factor of 15 was used to convert from ppm to mg/kg/day. As no such guidance exisits in REACH, group test material consumption values stated in the report for both generations throughout the life of the study have been averaged to provide a single set of test material consumption values for males and females from both generations.

b - For the supporting study no test material consumption values were calculated or reported. Therefore, in order to provide a mg/kg/day reference dose the JMPR guidance was referred to, as REACH does not recommend any default time-weighted conversion factors.

 

References:

JMPR (2007). Pesticide residues in food. Joint FAO/WHO meeting on pesticide residues. Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide Residues. Geneva, Switzerland, 18 -27 September 2007.

Short description of key information:
Section 7.8.1:
KS -2 gen (rat). Gilles, 1994. KL.1. NOAEL 400 ppm (~29.8 mg/kg/day);
SS - 3 gen (rat). Unknown 1978. KL.3. NOAEL 20 ppm (~1.3 mg/kg/day)

Effects on developmental toxicity

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2 March 1983 to 6 May 1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not applicable

GLP compliance:

no

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Analytical verification of doses or concentrations:

no

Details on mating procedure:

Rabbits were paired 1:1, with does placed in the buck's cage. When mating was observed the dose was weighed and lutenizing hormone was injected into the marginal ear vein. The doe was then returned to her cage.

Duration of treatment / exposure:

GD 6 -18/ oral gavage

Frequency of treatment:

daily

Duration of test:

12 days

No. of animals per sex per dose:

16 females

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

ca. 90 mg/kg bw/day (nominal)

Based on:

not specified

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

ca. 175 mg/kg bw/day (nominal)

Based on:

not specified

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Dose descriptor:

NOAEL

Effect level:

175 mg/kg bw/day

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: the test material was devoid of embroyonic or teratogenic activity in New Zealand White rabbits up to a maximum dose of 175 mg/kg/day

Developmental effects observed:

no

Lowest effective dose / conc.:

175 mg/kg bw/day

Treatment related:

not specified

Conclusions:

In conclusion, CGA 15324 technical was devoid of embroyonic or teratogenic activity in New Zealand White rabbits up to a maximum dose of 175 mg/kg/day. The maternal NOAEL was deemed to be 90 mg/kg/day due to reduced food consumption at 175 mg/kg/day.

Executive summary:

The embryotoxic and teratogenic potential of CGA-15324 Technical was evaluated in albino rabbits. The test material was administered by gavage to inseminated female rabbits at dose levels of 0, 30, 60, 90 or 175 mg/kg/day from day 6 through to 18 of gestation. Each dose level consisted of 16 does. On GD 30 does were euthanised and laparohysterectomies were performed.

 

Maternal mortality was observed in the control (1); 60 (2) and 175 (9 does) mg/day groups. Changes in clinical signs were observed in all groups. These changes were observed consistently in the high dose group and consisted of anorexia (reduced food intake), diarrhoea,soft stool and oral and perianal discharges.

 

The lesions observedin the animals that died on the study were necropsied, primarily involved yellow discolouration of the mesentery in the gastric region and pinpoint haemorrhages in the stomach. No gross lesions were observed in any of the animals suriviving to laparohysterectomy.

 

No statisitically significant differences were observed between the control and treated groups for bodyweight gain during gestation, maternal mortality, or mean copora lutea. Because the 175 mg/kg/day group constituted the maternal multi-dose LD50, the mortality observed in the high dose group was considered biologically relevant.

 

No significant differences were observed for the following measures of prenatal toxicity: mean number of implantations; litter size; foetal body weight; or embryolethality. No significant differences were detected between the control and treated groups for malformations or variations.

 

In conclusion, CGA 15324 technical was devoid of embroyonic or teratogenic activity in New Zealand White rabbits up to a maximum dose of 175 mg/kg/day. The maternal NOAEL was deemed to be 90 mg/kg/day due to reduced food consumption at 175 mg/kg/day.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6 June 1982 to 14 June 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP. Dosing was for 10 consectutive days from 6 - 15 post mating (rather than 5 - 15 as per the guidelines)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not applicable

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Analytical verification of doses or concentrations:

no

Details on mating procedure:

2 randonly selected females were cohoused with a male. The breeding period lasted for 9 days. The morning following cohabitation females were examined for vaginal plugs and /or sperm in vaginal fluid. If positive findings were returned, the female was removed from the males cage, weighed and this was designated as GD 0. The female was then randonly assigned to a treatment group.

Duration of treatment / exposure:

Treated from GD 6 - 15 via oral gavage

Frequency of treatment:

once daily

Duration of test:

10 days

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

ca. 90 mg/kg bw/day (nominal)

Based on:

not specified

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

ca. 120 mg/kg bw/day (nominal)

Based on:

not specified

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Dose descriptor:

NOAEL

Effect level:

120 mg/kg bw/day

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: There were no indications that the test material was embryotoxic or teratogenic at dose levels up to 120 mg/kg/day in the rat.

Developmental effects observed:

no

Lowest effective dose / conc.:

120 mg/kg bw/day

Treatment related:

not specified

MATERNAL TOXICITY:

Mortality and clinical signs:

A significant increase in maternal mortality was observed between the control and the high dose (120 mg/kg/day) dose group, where 3/25 females died prior to the scheduled laparohysterectomy.

 

Clinical signs of toxicity in the animals that died or were terminated included tremors, hypoactivity, ocular porphyrin discharge, hypothermia, diuresia, laboured breathing. No other signs of toxicity were observed.

 

Bodyweight:

Mean body weight increased in dams treated at dosed of 35 and 70 mg/kg/day on days 20 and/or 21.

 

Food and water consumption:

Dams treated at 70 mg/kg consumed more food than controls on days 14, 20 and 21. Water consumption was increased in the 35 mg/kg/day group (day 17) and in the 70 mg/kg/day group (days 20 and 21).

 

Organ weights:

35 mg/kg/day: group mean right ovary, heart liver, spleen significantly (p<0.05) heavier than control group.

70 mg/kg/day:group mean right kidney significantly (p<0.05) heavier than control group. In comparison these changes were small and not considered biologically relevant.

 

Gross pathology:

No abnormal findings in the internal organ, uterus or ovaries were observed.

 

Caesarean section data:

No significant differences in the mean numbers of implantation sites,corpora lutea, the rat of early or late deaths, sex ratio, body weights, body length, placental weights were observed between the treated groups and the control group. Notable changes in the distribution of foetuses in the uterine horns were observed.

 

DEVELOPMENTAL TOXICITY:

External examinations:

Unremarkable, within the historical control.

 

Visceral examinations:

Unremarkable, within the historical control.

 

Skeletal examinations:

Unremarkable, within the historical control.

Conclusions:

Measures of prenatal toxicity were not significantly different between the control and treated groups. A few malformations and a variety of developmental variants were observed in control and treated foetuses, but none were statistically significant.In conclusion the NOAEL for developmental toxicity was deemed to be 120 mg/kg/day (the maximum dose tested). Due to increase in maternal mortality at 120 mg/kg/day, the NOAEL for maternal toxicity was deemed to be 90 mg/kg/day.

Executive summary:

The purpose of this study was to evaluate the teratogenic potential of CGA-15324 Technical in albino rats. The test material was administered by oral gavage to groups of 25 inseminated females at dose levels of 0, 10, 30, 60, 90 or 120 mg/kg/day from days 6 through 15 of gestation. The animals were examined daily for changes in clinical signs and were weighed on day 0, 6 through of gestation and prior to laparohysterectomy on day 20 of gestation. Food consumption was measured on days 6, 13 and 20 of gestation. At laparohysterectomy, the uterine contents were described and recorded and the foetuses were sexed, weighed and examined for external anomalies. Each foetus was examined for visceral and skeletal anomalies. Approximately one-half of the foetuses from each litter were randonly selected for examination of the intracranial structures.

 

Significant dam mortality (16%) with concomitant pharmacologic signs were observed at 120 mg/kg/day. One dam died at 60 mg/kg, however the death was not considered test material related. Food consumption was significantly reduced from days 6 through 13 of gestation at 120 mg/kg/day. Food consumption was not affected from days 13 through 20 of gestation. No other signs of overt maternal toxicity were seen throughout the study.

 

Measures of prenatal toxicity were not significantly different between the control and treated groups. A few malformations and a variety of developmental variants were observed in control and treated animals with similar frequency, consequently no statistical significant increases were observed.

 

The findings of this study indicated that CGA-15324 Technical was not embryotoxic or teratogenic at dose levels up to 120 mg/kg/day.

Reference 3

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

20 August 1981 to 20 January 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP. Dosing was for 11 consectutive days from 7 - 17 post mating (rather than 5 - 15 as per the guidelines)

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Whilst essentially OECD 414 was followed, exceptions include: dosing was for 11 consectutive days from 7 - 17 post mating (rather than 5 - 15 as per the guidelines)

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

oral: gavage

Vehicle:

olive oil

Analytical verification of doses or concentrations:

no

Details on mating procedure:

After acclimatisation, one female in heat was paired with a male overnight

Duration of treatment / exposure:

11 days, throughout pregnancy from days 7 to 17.

Frequency of treatment:

Once daily (between 9 and 10 am)

Duration of test:

11 days

No. of animals per sex per dose:

23 to 25 pregnant dams/gp

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

ca. 70 mg/kg bw/day (nominal)

Based on:

other:

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

ca. 70 mg/kg bw/day (nominal)

Based on:

other:

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Abnormalities:

not specified

Developmental effects observed:

not specified

MATERNAL TOXICITY:

Mortality and clinical signs:

All animals survived to the scheduled laparohysterectomy. No test material related clinical signs were observed.

 

Bodyweight:

Mean body weight increased in dams treated at dosed of 35 and 70 mg/kg/day on days 20 and/or 21.

 

Food and water consumption:

Dams treated at 70 mg/kg consumed more food than controls on days 14, 20 and 21. Water consumption was increased in the 35 mg/kg/day group (day 17) and in the 70 mg/kg/day group (days 20 and 21).

 

Organ weights:

35 mg/kg/day: group mean right ovary, heart liver, spleen significantly (p<0.05) heavier than control group.

70 mg/kg/day: group mean right kidney significantly (p<0.05) heavier than control group. In comparison these changes were small and not considered biologically relevant.

 

Gross pathology:

No abnormal findings in the internal organ, uterus or ovaries were observed.

 

Caesarean section data:

No significant differences in the mean numbers of implantation sites, corpora lutea, the rat of early or late deaths, sex ratio, body weights, body length, placental weights were observed between the treated groups and the control group. Notable changes in the distribution of foetuses in the uterine horns were observed.

 

DEVELOPMENTAL TOXICITY:

External examinations:

Unremarkable

 

Visceral examinations:

Unremarkable

 

Skeletal examinations:

Increased incidences of progeny with holes in the xiphoid (small cartilaginous extension to the lower part of the sternum) at the mid and high doses and delayed ossification of vertebral arches at the high dose.

 

Table 7.8.2 -1:Skeletal (cartilage) observation of rat foetuses

Dose (mg/kg/day)	0	18	35	70
No. of mothers	5	5	6	6
No. of foetuses examined	34	30	48	45
No. of foetuses with abnormalities	0	0	0	0
No. of foetuses with variations (%)
Hole in the xiphoid	0 (0)	0 (0)	9 (18.8)	7 (15.6)
No. of foetuses with delayed ossification of vertebral arches (%)	3 (8.8)	2 (6.7)	6 (0.5)	12 (26.7)

 

No historical control data were provided and it could not be determined from the data if the findings presented were all from one litter or from multiple litters.

Conclusions:

In conclusion, the NOAEL for maternal and developmental toxicity was 70 mg/kg/day based on the results from this study.

Executive summary:

Groups of 23 -25 pregnant rats were administered Profenofos via oral gavage at dose levels of 0, 18, 35 or 70 mg/kg/day from gestational days (GD) 7 to 17. The doses selected were based upon result from a preliminary range finding study in which 140 mg/kg/day caused death in 5/6 rats durinhd GD 8 to 16.

 

Profenofos administration was associated with increases in body weight in the dams at doses of 35 and 70 mg/kg/day on days 20 and 21, increased water consumption on days 14 to 21. Increases in weights of several organs were reported were seen in the high dose group, these were however small in magnitude. No treatment related changes in mortablity or behaviour were observed and no abnormal findings were observed at gross necropsy.

 

There were no adverse effects on the offspring with respect to resorptions, sex ratios, placental weights, body weights and lengths or distribution of foetuses within the uterine horns. External and visceral examinations of foetuses were unremarkable. Skeletal examination of foetuses showed increased incidences of progeny with holes in the xiphoid at the mid and high doses and delayed ossification of vertebral arches at the high dose. However, no historical control data were provided and it could not be determined if the findings were all from one litter or multiple litters.

 

In conclusion, the NOAEL for maternal and developmental toxicity was 70 mg/kg/day based on the results from this study.

Reference 4

Endpoint:

developmental toxicity

Adequacy of study:

supporting study

Study period:

Started 11 December 1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP

Qualifier:

no guideline followed

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not applicable

GLP compliance:

no

Limit test:

no

Species:

rabbit

Strain:

Chinchilla

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Analytical verification of doses or concentrations:

no

Details on mating procedure:

Rabbits were pair 1:1 for the mating duration. Each doe was bred twice, the second time about about 1hr after the first on the same day. This day was considered day 0 of gestation

Duration of treatment / exposure:

GD 6-18 / oral gavage

Frequency of treatment:

Daily

Duration of test:

12 days

No. of animals per sex per dose:

20 pregnant females

Dose descriptor:

NOAEL

Effect level:

ca. 15 mg/kg bw/day (nominal)

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

ca. 30 mg/kg bw/day (nominal)

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

In conclusion, CGA 15324 technical was devoid of embroyonic or teratogenic activity in Chinchilla rabbits up to a maximum dose of 30 mg/kg/day. The maternal NOAEL was deemed to be 15 mg/kg/day due to reduced food consumption at 30 mg/kg/day.

Executive summary:

CGA 15324 Technical was administered orally by intubation to fertilised Chinchilla rabbits from gestation day 6 to 18. The doses were 0, 5, 15 and 30 mg/kg/day.

 

The dams of the high dose group reacted to the treatment by a slight reduction in food consumption from day 6 of treatment onwards.

 

The progeny of all three treatment groups remained unaffected by treatment.

 

One malformed foetus (omphalocele) found in the 5 mg/kg/day dose group was not considered to be related to test material treatment, with such malformation occuring in 2 control foetuses.

 

In conclusion, CGA 15324 technical was devoid of embroyonic or teratogenic activity in Chinchilla rabbits up to a maximum dose of 30 mg/kg/day. The maternal NOAEL was deemed to be 15 mg/kg/day due to reduced food consumption at 30 mg/kg/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

120 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Additional information

Profenofos did not cause developmental effects in rats or rabbits. In the key study (Kung, 1982) gravid female rats were administered Profenofos orally via gavage at doses up to 120 mg/kg/day during days 6 - 15 of gestation. Whilst an increase in maternal mortality was observed at this dose, no adverse effects on the offspring with respect to resorptions, sex ratios, placental weights, body weights and lengths or distribution of foetuses within the uterine horns. External and visceral examinations of foetuses were unremarkable. The NOAEL for developmental toxicity was 120 mg/kg/day, the maximum dose tested.

 

In rabbits, Profenofos was not prenatally toxic or teratogenic at the maternal toxic dose of 175 mg/kg/day (the highest dose tested).

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008 Prodenofos is not classified for reproductive, or developmental toxicity.