TL;DR: We conclude that there is some evidence against ContraPest’s claims that the product is “humane,” “it is not an endocrine disruptor,” and “its effects are reversible.” The literature suggests that the active ingredients in ContraPest may cause bone loss, cancer, organ injury, immunosuppression, and endocrine disruption in rats. Any of these could be a risk factor for decreased well-being in rats. VCD may result in permanent sterility in rats over time or at high doses, and at low doses, it results in irreversible premature reproductive senescence.

Epistemic status: Uncertain. This was about a 40-hour investigation by me, Spencer, a person with ~no biology background. I conclude that more research is needed into every question I pose. This post will be edited if new information comes in.

Quirks: I say “we” because writing “I” in formal writing makes me feel weird. Where I say “We are not aware of studies…” I mean that I searched 3-4 relevant key terms on Google Scholar about that question and came up empty.

Acknowledgements: I am grateful to Constance Li for sponsoring this project. I am grateful to Contance Li, Michael St. Jules, and Holly Elmore for feedback. I am grateful to two interviewees for their help. (None of the acknowledged people have endorsed or rigorously fact-checked my claims herein.)

Introduction

ContraPest is the first and only current EPA-approved contraceptive for Norway rats and roof rats.^[1] It was approved in 2016 and brought to market in 2021.^[2] ContraPest has received increasing attention; for example, it was featured in Time in March 2023.^[3] It is touted as a humane option for rat population control that could replace many use cases for rodenticides. Rodenticides tend to cause prolonged, painful deaths, both for rats and for other wild animals, so ContraPest is thought to be an opportunity to improve wild animal welfare.^[4] Its manufacturer, SenesTech, claims that “ContraPest is a non-lethal rodenticide/pesticide that does not bioaccumulate, it is not an endocrine disruptor, and its effects are reversible.”^[5]

ContraPest contains two chemicals in small amounts, 4-vinylcyclohexene diepoxide (VCD)^[6] and triptolide. VCD reduces fertility in female rats by depleting ovarian follicles, which mature into eggs. Triptolide reduces fertility in male and female rats by interrupting the development of ovarian follicles and sperm.^[1] However, as we will see below, these chemicals might have side effects like permanent reductions in fertility, cancer, bone loss, organ injury, immunosuppression, and hormone disruption at high doses. More research in needed into the one-time and repeated doses where these side effects become apparent in rats, animals that eat rats, other animals that might come into contact with ContraPest, and humans.

We have yet to see a post that thoroughly and critically evaluates SenesTech’s claims about ContraPest. However, we have come to know that “many cities”^[7] and at least one animal sanctuary that ran pilots of ContraPest did not continue to use the product due to their concerns about its effectiveness and side effects. To better understand how this product affects wild animal welfare, we attempt to evaluate SenesTech’s claims below. You can skip to the Conclusion, or read the TL;DRs at the top of each section.

(We wrote this report after reading Holly Elmore et al.’s sequence for Rethink Priorities, “The rodenticide reduction sequence.” You can read our summary of the sequence here.)

Questions

We have the following questions about ContraPest. We will only be able to answer some of them.

• Why did the cities and organizations that tried ContraPest stop using it?
• At what dose is ContraPest toxic?
• Is it true that ContraPest causes no pain or suffering to the animals that ingest it?
• What are the side effects at various doses of VCD and triptolide in rodents, in animals that consume rodents, and in humans?
• Is it true that the reduction in fertility is reversible? Is this true in all animals that might consume ContraPest?
• Is it true that there is a lower risk of secondary ingestion with ContraPest than with rodenticides?
• Do rats ever develop resistance to ContraPest?
• Qualitatively, how do different ecosystems change when ContraPest is introduced?
• How does contraception affect rodent societies?
• How much more total triptolide would be consumed by non-target animals in a solid TwHF bait, compared to liquid ContraPest stored in a secure bait station?

Why did the cities and organizations that tried ContraPest stop using it?

TL;DR: A sanctuary in New York piloted ContraPest, but found that shortly after implementation, rats got sick and died. Washington DC implemented ContraPest in the city, and the pilot is held up as a success story by ContraPest, but the city does not seem to have continued using the product.

Sanctuary in New York^[8]

We interviewed an associate of an animal sanctuary in New York that tried and discontinued ContraPest. She requested for her and the sanctuary not to be named, so we will call her “Dana.”

Dana worked for the sanctuary when they implemented ContraPest in 2018. The sanctuary spans over 100 acres and has several small shelters and one large barn on the property. At the time, the sanctuary had a large rat population who mostly lived in the barn. Their normal behaviour was to quickly scurry away from open areas when a human approached.

The sanctuary had tried trapping and releasing rats away from the barn, but it did not make a significant difference in the population size. Dana did not know if the sanctuary tried any other population control methods.

The sanctuary hired a pest control company to implement ContraPest. The company set up bait stations around the barn. Dana and the staff saw rats enter the bait station. About once a month, the company came to refill the empty bait stations.

After implementing ContraPest, staff at the sanctuary began to find the bodies of dead rats, as well as visibly ill live rats, out in the open spaces of the barn. The live rats moved slowly through the grain room and the aisle of the barn. They would wander around or lie down in view of humans. They appeared to be experiencing laboured breathing.

Dana reported that to her knowledge, the staff did not notice whether the rats had a reduced juvenile population or any changes in shape or size.

Eventually, the population of rats disappeared. They were not seen in the barn, shelters, or field. However, a population of mice soon took over. Mice entered the ContraPest bait stations, but they may have stayed for shelter and not to eat the bait. The mice population did not get lower over time. ContraPest was discontinued. Very few rats were seen again, possibly because mice out-competed them for resources.

The sanctuary sent the body of a dead rat they found to Cornell University College of Veterinary Medicine for a necropsy. The necropsy did not find any known rat poisons in the body. Dana did not remember the cause of death. However, we are trying to obtain a copy of the necropsy report.

None of ContraPest’s resources mention side effects like lethargy or death. They describe the product as humane, and they say that “ContraPest has not been shown to make rats ill or change their behavior.”^[9] So why was there an increase in sightings of dead and sick rats? Possible causes:

• When the barn population of rats started to disappear, rats from another area moved in and brought a disease.
• The rats coincidentally encountered a pathogen or toxin at the same time ContraPest was introduced.
• The bait stations themselves attracted new populations of rats, who brought a disease.
• The bait spoiled over the course of each month, and the rats were accidentally poisoned by bacteria or mould. Some mould was occasionally found at the sanctuary when cleaning stalls.
• ContraPest has unknown side-effects.

Why were mice not affected?

• The mice did not eat any bait.
• The mice ate some bait, but the compound that affected the rats did not affect them in the same way. (ContraPest is not approved for use in mice, but there are studies showing that VCD and triptolide also reduce fertility in mice.^[10][11] Considering mice are much smaller than rats, their population should have dwindled if they were eating the bait. They may not have been large enough to access the bait.)

None of these possible causes are confirmed.

Washington DC

Washington DC completed a trial of ContraPest.^[12] A report of the case study is posted on ContraPest’s website as marketing material.

The Washington DC Department of Health (DOH) administered the product (as part of an integrated pest management plan) to 139 bait stations at 13 locations across the district.^[12] ContraPest marks the start of the pilot as December 2018, but NBC Washington marks the first six months of the pilot as May - October 2019.^[13]

ContraPest’s case study states that two locations (“Site A” and “Site B”), with 11 bait stations in total, were monitored by camera in November 2019, April 2020, and October 2020. Lethal rodenticides were still used, but ContraPest does not state whether the schedule of rodenticide use stayed the same. They state, “Consumption of lethal rodenticides was not monitored.”^[12]

ContraPest claims that the rat population declined 90% overall between Nov 2019 and Oct 2020.^[12]

Site A^[12]

Site A “consists of approximately 1⁄4 mile alley with nearby residential and commercial buildings. Trash, including food refuse, is abundant, allowing rats to flourish.” It contained 3 bait stations. A total of 1.8L of bait was consumed between Nov 2019 - Oct 2020.

In site A, ContraPest reports that total rat activity declined 94% between Nov 2019 - Oct 2020. They do not state how total activity was measured.

Rats were counted using the cameras set up for the pilot. ContraPest reports that the count of adult rats declined from 270 to 44 (84%) and juvenile^[14] rats declined from 121 to 2 (98%). That means total counts declined from 391 to 46 (88%).

Site B^[12]

Site B “consists of approximately 1⁄4 mile long alley that is bordered on both sides entirely by residential properties. There is an abundance of food sources in the form of trash cans and food provided by residents for birds and feral cats.” It contained 8 bait stations. A total of 9.2L of bait was consumed between Nov 2019 - Oct 2020 – significantly more bait per station than at site A.

ContraPest reports that rat activity declined 99% at site B, adults counted declined from 121 to 3 (98%), and juvenile rats declined 100% (were eliminated; from 52 to 0). That means total counts declined from 173 to 3 (98%).

Notes from NBC^[13]

As of December 2019, NBC stated that ContraPest was reporting a reduction in rat activity in the district. This was based on a 77% reduction in the ratio of juveniles to adults in one of the monitored alleys. However, city officials doubted the success.

NBC reports that from May - October 2019, ContraPest was used, but NBC found 16% more rodent reports in this period than before the pilot. Rodent reports across the district were called into a 311 hotline by residents. NBC reports that the aforementioned alley saw 311 calls increase “from 728 in 2018 to 925 in 2019.” That’s an increase of 21%.

As of December 2019, NBC reports that DC had pivoted to using carbon monoxide as an asphyxiant in burrows. But ContraPest’s case study described the pilot as continuing with success until October 2020. We have not reached out to SenesTech for comment on this.

At what dose is ContraPest toxic?

TL;DR: At high doses, VCD and triptolide are toxic to humans and rats, according to Material Safety Data Sheets. However, ContraPest probably contains much less than the LD50 of both chemicals. We would need to know the concentrations of each by weight, not volume, to be sure.

As a principle, all compounds can become toxic if consumed at extreme doses. There is no clear threshold at which VCD or triptolide become toxic, whether to rats or to humans. ContraPest claims that their product is not toxic to humans in their bioaccumulation brochure, saying “Users who deploy ContraPest do not need to worry about exposure to the product as ContraPest does not absorb into the skin; therefore, ContraPest does not affect human fertility.”^[5]

However, the insert label gives a stern warning:^[15]

“FIRST AID

If on skin or clothing:

Take off contaminated clothing.

Rinse skin immediately with plenty of water for 15-20 minutes.

Call a poison control center or doctor for treatment advice.

….

CAUTION. Avoid contact with skin or clothing. Wash thoroughly with soap and water after handling and before eating, drinking, chewing gum, using tobacco or using the toilet.

Personal Protective Equipment: Wear protective nitrile gloves ≥ 14 mils or butyl rubber ≥ 14 mils, long sleeved shirts, and long pants when handling this product.”

This may suggest that some absorption or toxicity in humans is possible at the dose in the product (although multiple exposures may be required to see an effect).

Indeed, Lukefahr et al. report that VCD “is a putative human carcinogen to which latex or PVC disposable gloves are both permeable.”^[16] This would explain why SenesTech recommends nitrile of butyl rubber gloves specifically.

The doses in many of the studies below are much higher doses than a rat or human would reasonably be exposed to by ContraPest in one day. ContraPest tanks are up to 400mL^[17] and contain 0.09604% VCD (0.38416mL) and 0.00118% triptolide (0.00472mL).^[15] We are not sure how many milligrams of each chemical this comes out to, but in one study, VCD could be dissolved in corn oil at a concentration of 128 mg/mL.^[18] This seems like a reasonable benchmark, because ContraPest is a fatty food substance.^[1] Then, we could estimate that there are about 49mg of VCD in one 400mL ContraPest tank.

VCD

The insert label for ContraPest is likely based on Material Safety Data Sheets (MSDS). The MSDS for VCD states that VCD is considered hazardous by the 2012 OSHA Hazard Communication Standard. VCD has the following hazard statements:^[19]

“Highly flammable liquid and vapor

May be fatal if swallowed and enters airways

Causes skin irritation

Causes serious eye irritation

Suspected of causing cancer

Suspected of damaging fertility or the unborn child”

The LD50 (the dose at which 50% of people exposed would die) is given as 2600mg/kg by oral ingestion, 17000 mg/kg by skin contact, and at most 8000 ppm inhaled over 4 hours.^[19]

An adult Norway rat is typically 140 - 500 mg.^[20] If a ContraPest tank can hold 49mg of VCD, then this should be well under the toxic threshold.

Triptolide

The MSDS for triptolide says that it is “Fatal if swallowed or if inhaled” and “Suspected of damaging fertility or the unborn child.” The toxic dosage information for triptolide states that the lowest known non-inhaled lethal dose is 2.4mg/kg as shown in rats, the lowest known toxic dose is 60 ug/kg as shown in mice and 1.2 mg/kg as shown in rats, and the lethal dose for 50% of subjects given an injection into the abdominal cavity is 900 ug/kg as shown in mice.^[21]

We do not know how many milligrams of triptolide are dissolved in a tank of ContraPest. Toxicity might be more of a concern in second-generation birth control products that contain triptolide made from Tripterygium wilfordii Hook F. In such products, the concentration of triptolide would be less consistent, and the dosing would be less controlled due to lack of a required bait station.

Is it true that ContraPest causes no pain or suffering to the animals that ingest it?

TL;DR: The types of side effects that VCD and triptolide can have, as well as Dana’s experience at the sanctuary, suggest that it is possible for ContraPest to cause some suffering. But what’s important is whether it causes less suffering than alternative pest control methods, and we can’t know that without studies focusing on the experience of the rats that consume ContraPest.

To our knowledge, no studies have explicitly monitored rats for signs of pain emotional distress after ingesting ContraPest, VCD, or triptolide. We are also not aware of studies that have specifically looked at differences in mortality rates or causes of death between rats who have consumed ContraPest and a control group. We would need records of this to determine whether ContraPest causes more or less suffering than the alternative, which is usually rodenticide.

What if someone is considering using either ContraPest or a less painful option than rodenticide, such as asphyxiation in burrows? We would need to review more literature to give informed advice on whether ContraPest is the option with the least suffering.

Dana’s observations at the sanctuary indicate that the rats had a likely-unpleasant experience after consuming ContraPest. Furthermore, the following section suggests that cancer is a possible side effect at very high doses, which is a possible cause of suffering. We do not know what the effects of endocrine disruption, bone loss, immunosuppression, or organ injury would be on well-being.

What are the side effects at various doses of VCD and triptolide in rodents, in animals that consume rodents, and in humans?

TL;DR: VCD can cause cancer, endocrine disruption, and bone loss. Triptolide can cause endocrine disruption, organ injury, and immunosuppression. The doses in the studies that show these side-effects vary. We do not know the doses of each chemical in ContraPest by weight, but we expect them to be lower than the doses used in these studies. Still, the doses used in these studies are not necessarily the minimum doses required to see these effects.

Carcinogenicity of VCD

VCD is carcinogenic to some animals and possibly carcinogenic to humans.^[22]

In a paper by Lukefahr et al., the authors state that VCD “is a putative human carcinogen to which latex or PVC disposable gloves are both permeable.”^[16] (Lukefahr et al. were not testing carcinogenicity. They were stating their reasoning for the precautions they took when working with VCD.)

In a segment from the volume “Some Industrial Chemicals” of the series “IARC Monographs on the Evaluation of Carcinogenic Risks to Humans” by a working group of the World Health Organization’s International Agency for Research on Cancer (IARC), VCD was found to have carcinogenic effects.^[23] In repeated skin application of high doses of VCD to Fischer rats,

• “There was a significant increase…in the incidence of squamous-cell carcinoma of the skin in treated males…and females”
• “The incidence of squamous-cell papillomas was increased in male rats”
• “that of basal-cell adenoma or basal-cell carcinoma was increased in males”
• “that of basal-cell carcinoma was increased in females”^[23]

Although rats are often prone to cancer,^[24] the Fischer rats who were dosed with VCD had a significantly higher incidence of cancer than the control group. Out of the female rats given a high dose of VCD, significantly more died than female rats the the control group.^[23]

The IARC concludes, “There is inadequate evidence in humans for the carcinogenicity of 4-vinylcylcohexene diepoxide. There is sufficient evidence in experimental animals for the carcinogenicity of 4-vinylcyclohexene diepoxide. Overall evaluation: 4-Vinylcyclohexene diepoxide is possibly carcinogenic to humans (Group 2B).”^[23]

While VCD is classified as carcinogenic to animals, triptolide has anti-tumorigenic effects that might protect rats when the ingredients are combined in ContraPest.^[25] We are not aware of any studies of ContraPest specifically that assess cancer risk.

Endocrine disruption from VCD and triptolide

ContraPest’s website states, “Although VCD interferes with ovarian function, it’s important to note that it does not affect endocrine function and therefore is not an endocrine disruptor.”^[1]

In 2017, three SenesTech staff co-authored a paper with two USDA staff entitled “Compromised Fertility In Free Feeding Of Wildcaught Norway Rats (Rattus norvegicus) With A Liquid Bait Containing 4-Vinylcyclohexene Diepoxide And Triptolide.”^[26]

In this paper, circulating levels of estrogen and testosterone were not different between groups, supporting SenesTech’s claims that ContraPest is not an endocrine disruptor.^[26] However, this absence of evidence is insufficient evidence to be confident that there are no endocrine effects of ContraPest.

In fact, several studies show the endocrine effects of both VCD and triptolide. Four of the studies below showing endocrine effects were cited in the 2017 USDA/SenesTech paper by Wittmer et al.

VCD

In 2016, Adedara et al. dosed male rats with VCD 28 days in a row. They found that VCD decreased follicle-stimulating hormone, luteinizing hormone, and testosterone in male rats, 24 hours after their last exposure.^[27]

In 2002, Mayer et al. dosed 28-day-old female rats with 80 mg/kg per day of VCD, for 30 days. They found increased follicle-stimulating hormone in the rats several months later. They explain, “These results show that VCD-induced follicular destruction in rats is associated with a sequence of events (loss of preantral follicles, increased plasma FSH, and cyclic disruption) preceding premature ovarian senescence that is similar to events that occur during the onset of menopause in women.”^[28]

In a similar study in 2012, Lukefahr et al. dosed one-month-old female rats with VCD for 25 days. They found that rats treated with VCD had increased follicle-stimulating hormone compared to controls, but similar estradiol levels, 19 months after their first exposure.^[16]

Triptolide

In a study by Zhang et al., triptolide reduced progesterone production by a number of mechanisms. The authors state that “studies have also shown that triptolide is highly disrupt [sic] to the reproductive system by disrupting normal steroid hormone signaling.”^[29]

The authors explain the possible mechanisms for the reduced progesterone production:

“The reproductive toxicity of triptolide may be caused by disruption of cAMP/PKA-mediated expression of a number of progesterone synthesis enzymes or regulatory proteins, leading to reduced progesterone synthesis and reproductive dysfunction.”

In another study by Zhang et al., we see a nearly identical finding but relating to estradiol.^[30] In this study, triptolide reduced estradiol production by a number of mechanisms:

“The reproductive toxicity of triptolide may be mainly caused by disruption of cAMP/PKA-mediated expression of estrogen synthesis enzymes, leading to reduced estradiol synthesis and reproductive dysfunction.”

In a study by Liu et al., triptolide altered the levels of four hormones (estradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone) in female rats, followed by a reduction in the weight of the reproductive organs:^[31]

“The results showed that treatment with 200 and 400 ug/kg of triptolide significantly reduced serum levels of E₂ and P and increased levels of FSH and LH. At these dose levels, relative weights of ovary and uterus were significantly reduced.”

Doses were high in all these studies. Nevertheless, we doubt SenesTech’s claim that ContraPest is not an endocrine disruptor. Clearly, at high doses, the chemicals in ContraPest are capable of disrupting follicle-stimulating hormone, luteinizing hormone, testosterone, progesterone, and estradiol.

Bone loss from VCD

As mentioned above, in 2012, Lukefahr et al. dosed one-month-old female rats with VCD for 25 days. After these 25 days, bone density was normal, as was reproductive cycling. But just over 3 months later, the bone mineral density of the rats given a high dose (160 mg/kg) of VCD was lower than in control-group rats of the same age. Ten months after the last dose, the bone mineral density of the rats given a low dose of VCD (80 mg/kg, a bit lower than our estimate of the dose in one entire tank of ContraPest for an adult Norway rat) was lower than in control-group rats of the same age. Bone mineral density decreases in the high-dose group and the low-dose group “generally coincided with persistent estrus.”^[16]

Bone loss was related to the increase in follicle-stimulating hormone and onset of “persistent estrus.” This is similar to the symptoms we would see in perimenopausal human women.^[16] We do not know whether high doses of VCD would cause early menopause in humans, but it seems to bring on early persistent estrus in rats, along with some of the usual hormone and skeletal symptoms.

Organ injury from triptolide

In a 2017 review paper by Xi et al., the authors find evidence in several papers that triptolide results in injuries to multiple organs, such as “the liver, kidney, testes, ovary, and heart in animals and even in humans,” as well as cell damage such as “membrane damage, mitochondrial disruption, metabolism dysfunction, endoplasmic reticulum stress, oxidative stress, apoptosis and autophagy.”^[32]

Immunosuppression from triptolide

Studies such as a 2003 paper by Qiu and Kao show that triptolide is an immunosuppressive, with applications for treating rheumatoid arthritis and organ transplant patients.^[33] We are not aware of studies that show whether the immunosuppressive action of triptolide makes rats more susceptible to pathogens, but the increased risk of infection in immunosuppressed patients is well-known.

Is it true that the reduction in fertility is reversible? Is this true in all animals that might consume ContraPest?

TL;DR: SenesTech claims repeatedly that ContraPest is not a sterilant in their marketing materials, but their patent and their paper authored with the USDA clearly show that it has permanent effects on the reproductive system of rats, and that an ideal future product would be a sterilant. However, it is more likely for rat populations to become resistant to sterilants than to birth controls.

The reversibility of ContraPest is a key claim made by SenesTech. It is important whether ContraPest is a contraceptive or sterilant because there are different risks for contraceptives vs. sterilants, both to the target animals and to the ecosystem. The pros and cons of contraceptives vs. sterilants are in a table below.

ContraPests’s key claim

ContraPest’s website states, “It’s important to note these ingredients suppress fertility in rats, but they don’t make them sterile. They’re only able to work through repeated consumption, and the effects of ContraPest are reversible over time if the bait is removed. This, in conjunction with the relatively low dose that rats need, minimizes any risk to predators or non-target species.”^[1]

Their bioaccumulation brochure states, “ContraPest is an effective fertility control solution; however, it is not a sterilant….If a rat stops drinking ContraPest, over a period of time they will begin to regain their fertility. Granted, this won’t happen overnight; it could be months before fertility returns. VCD is considered an ovotoxic product, so the confusion that ContraPest is a sterilant is understandable. But the data evidences that ContraPest is a reversible contraceptive/birth control.”^[5] Studies supporting this claim are not cited in-text.

Loss of follicles is not reversible

According to the ContraPest website, the VCD in ContraPest depletes primary and primordial follicles in the ovary, and the triptolide depletes secondary follicles in the ovary, in addition to affecting spermatogenesis in males.^[1][34] Below, we investigate whether these effects on fertility are reversible.

Let’s look at some background on rat reproductive systems. In mammals, primordial follicles are present at birth or form shortly after birth. They develop into primary follicles, secondary follicles, and Graafian follicles, followed by ovulation.^[35][36]  According to Fortune et al., “In rats and mice, follicles form fairly synchronously shortly after birth.”^[37] This suggests that once follicles are gone, they do not continue to form throughout the rat’s life.

This is supported by a paper written collaboratively between SenesTech and the USDA, by Witmer et al. in 2017. The authors state, “Because of the nonregenerating nature of the oocyte, loss of these follicles is irreversible, subsequently resulting in ovarian failure.”^[26] They continue:

“VCD has also been shown to cause ovarian failure in rats, following repeated dosing. Evidence has been provided that daily dosing of mice and rats with VCD, or the parent product 4-vinyl cyclohexene, does not produce generalized toxicity or effects in other tissues. Therefore, use of VCD as a method of sterilization (ovarian failure) in female rat pests might hold promise as a nontoxic method of population control. …

“Future studies are being planned to determine the optimal exposure time and concentration of active ingredients that will be sufficient to cause initial infertility in males and females, with ultimate sterility in females.” 

“Ultimately, continuous longer exposure to active bait would produce subsequent irreversible sterility (VCD effect).”^[26]

This suggests that ContraPest is a multi-dose sterilant for female rats, not a contraceptive, with the potential for future products to be single-dose sterilants.

It is possible that when SenesTech claims that the effects of ContraPest are reversible over time, they mean reversible in the population.^[1] Indeed, if a rat that consumed ContraPest were to successfully mate, there is no reason to believe the fertility of the pups would be impacted, so population-level fertility could be restored if the bait was removed in time for some rats to mate.

But SenesTech also claims that ContraPest does not make rats sterile, and that is a trait of individual rats.^[1]

In SenesTech’s patent on ContraPest, they continue to support the idea that ContraPest may be a multi-dose sterilant: “The combination is used to permanently suppress reproduction in the mammals so treated by the present invention”^[38] (emphasis added).

They repeat the potential for a future single-dose sterilant product: “It is noted that triptolide oral exposure is known to compromise male rat fertility to ultimate sterility. Thus, both male and females can be treated according to the present invention. In a preferred embodiment of the invention, the mammal is sterilized by the treatment in the present invention, i.e., the animal has lost its reproductive capacity. … In a preferred embodiment of the invention, the mammal is sterilized by administration of the composition.”^[38]

More literature

In a paper by Mazaud et al. from 2002, the authors showed that female rat fetuses that lose ovarian follicles by irradiation in utero have an overall shorter reproductive span. Their fertility did not recover from the one-time in-utero irradiation that depleted their original stock of primordial follicles. The authors state, “The primordial follicle stock is not renewable and serves as a reserve for the entire reproductive life span of the adult.”^[39]

Mayer et al. (2002) dosed female rats with 80 mg/kg per day of VCD, for 30 days. The rats experienced “premature ovarian senescence,” (the end of their reproductive span, similar to menopause), as well as increased follicle stimulating hormone and disruptions in their estrus cycles.^[40] This is a somewhat higher dose than we would find in ContraPest. However, since the effects are gradual in either case, we should expect the same effect from ContraPest but slower.

In a 2006 paper by Kanter, et al. VCD induced total ovarian failure within 8 months of daily dosing.^[41]

Effects from triptolide might also be permanent in some cases. In a 2013 paper by Huynh et al, the effects were reversed in most rats after withdrawing triptolide: “By 14 weeks, 4 out of 6 triptolide-treated males were fertile and the females that were impregnated by 3 out of 4 triptolide-treated male rats produced apparently normal litters.”^[42]

However, “The second action presumably is directly on germ cells in testis and causes a variable impairment of spermatogenesis that may not be completely reversible. It is unclear if the earlier effect is a delayed manifestation of subtle testicular injury or post-testicular action.”^[42]

This is an important finding because one of the inventors of ContraPest, Loretta Mayer, is developing a product made from the whole root extract of Tripterygiumwilfordii Hook F (TwHF), which contains triptolide.^[43] This new product would not be regulated as a drug and would not require a bait station, so a rat or non-target animal could ingest a less controlled dose. We recommend more research is done into triptolide’s side effects and reversibility before adopting this product.

Summary of pros and cons of birth control vs. sterilants, adapted from the Rethink Priorities sequence^[4]

Is it true that there is a lower risk of secondary ingestion with ContraPest than with rodenticides?

TL;DR: Probably, yes.

SenesTech alleges that it causes no bioaccumulation or biomagnification because it is absorbed in 15 minutes.^[1][5] Does this mean there is no risk of secondary ingestion after 15 minutes?

The bioaccumulation brochure states, “The plasma half-life of VCD is 14.2 minutes; the average plasma residence time is 15.0 minutes. After 72 hours, less than 1% of VCD remains within all tissues examined (blood, kidney, spleen, liver, lung, ovary, heart, muscle, brain).”^[5]

This suggests that, while bioaccumulation is unlikely, some minor secondary ingestion might be possible for up to 72 hours. A predator will not just eat a rat’s plasma, but many of the tissues.

The bioaccumulation brochure also states that the plasma half-life of triptolide in rats is about 15-71 minutes depending on the method of administration and sex of the rat. They claim that excretion is minimal after 48 hours and that “there is no triptolide accumulation in heart, liver, spleen, lung and kidney of rats.”^[5]

This suggests low risk of secondary ingestion, but we have not fact-checked these statistics.

Do rats ever develop resistance to ContraPest?

TL;DR: Probably not, but unknown.

According to Holly Elmore in “The rodent birth control landscape,” single-dose sterilants are riskier than contraception. She states, “I believe the risk of rodents developing resistance and of non-target consumption would be too great to adopt [a single-dose sterilant] approach.”^[4]

However, if the chemicals used in ContraPest cause sterility at high doses, and the ultimate goal of development is a single-dose sterilant, then ContraPest (or a closely related product) could have this effect in the future. Over generations of use of a single-dose VCD-triptolide sterilant, rats that are exposed and not sterilized would have pups that are also less likely to be sterilized. This could mean the population of rats could never be eliminated with the sterilant.

But with a multi-dose sterilant or birth control (ContraPest is one of these), some of the rats having pups would not be systematically resistant to the treatment – they would just be random rats early on in their dosing – so the pups would be, on average, just as susceptible to the treatment, and could eventually be eradicated.

We are not aware of any studies that currently demonstrate the ability of rats to form resistance to ContraPest, VCD, or triptolide.

Qualitatively, how do different ecosystems change when ContraPest is introduced?

TL;DR: Unknown.

We do not yet know of field studies showing the effects of birth control on ecosystems. However, in Dana’s observation of the sanctuary, the sanctuary ecosystem changed when ContraPest eliminated the entire rat population and a large population of mice permanently took its place. To speculate, perhaps when rat populations are reduced in rural areas, we would generally see fewer of their predators like birds of prey, and more of their competitors, like mice. This might look different in cities vs. rural areas. To continue speculating, perhaps when rat populations are reduced in cities, the populations of other scavengers increase, such as raccoons and cockroaches. It’s hard to say.

How does contraception affect rodent societies?

TL;DR: Unknown.

We do not yet know of field studies showing the effects of birth control on rodent societies, other than reducing or eliminating their populations. If ContraPest’s effects are reversible, then ContraPest can be withdrawn to prevent the collapse of a rodent society, but the rat population at Dana’s sanctuary collapsed. Should the treatment have been withdrawn sooner to prevent mice from taking over, or was the population collapse due to the product?

Assuming ContraPest is withdrawn and a rat population rebounds, will the rats act any differently? Will they relate differently to each other?

We do not know how reduced populations without die-offs affect rats in practice. Holly Elmore suggests that it would reduce stress and competition for resources.^[4]

How much more total triptolide would be consumed by non-target animals in a solid TwHF bait, compared to liquid ContraPest stored in a secure bait station?

TL;DR: Unknown.

We are not currently able to estimate this and we suggest further research.

Conclusion

We conclude that there is some evidence against ContraPest’s claims that the product is “humane,” “it is not an endocrine disruptor,” and “its effects are reversible.” The doses used in all the studies cited were quite high, but we doubt that even at the low dose in ContraPest, the effects we see in the studies would not show up at all.

The experience of our colleague Dana at her former animal sanctuary suggest that rats do suffer after ingesting ContraPest. The fact that many cities have discontinued ContraPest suggests that it may not even be a cost-effective way to reduce rat populations.

The literature suggests that the active ingredients in ContraPest may cause bone loss, cancer, organ injury, immunosuppression, and endocrine disruption in rats. Any of these could be a risk factor for decreased well-being in rats. We recommend that researchers continue to investigate SenesTech’s claims that ContraPest is humane.

Most potential problems with ContraPest seem to come from VCD (carcinogenicity, bone loss, irreversible ovarian cell death, and some part of endocrine disruption). The literature suggests that VCD may result in permanent sterility in rats over time or at high doses, and that at low doses, it results in irreversible premature reproductive senescence. We recommend that researchers continue to investigate SenesTech’s claim that ContraPest is not a multi-dose sterilant, but a reversible contraceptive.

However, if a second-generation birth control for rats is developed without VCD but with triptolide, some of our concerns remain. The literature suggests that triptolide changes the levels of steroid hormones circulating in the body and leads to immunosupporession and organ injury. There is also not enough evidence to be certain that all the reproductive effects of triptolide are reversible.

We suggest that researchers continue to investigate our remaining questions about rat birth control, such as:

• Is it true that ContraPest causes no pain or suffering to the animals that ingest it?
• Is it true that there is a lower risk of secondary ingestion with ContraPest than with rodenticides?
• Do rats ever develop resistance to ContraPest?
• Qualitatively, how do different ecosystems change when ContraPest is introduced?
• How does contraception affect rodent societies?
• How much more total triptolide would be consumed by non-target animals in a solid TwHF bait, compared to liquid ContraPest stored in a secure bait station?

Holly Elmore at Rethink Priorities is conducting excellent research into some of these questions, and we recommend readers to follow the remaining installments in “The rodenticide reduction sequence.”

What can you do?

1. Consider using humane methods for rat population reduction as much as you can before using ContraPest, which has unknown risks. For example, reduce food sources and potential habitats for rats around your property.
2. Avoid rodenticides. If you need to kill rats, consider methods that we suspect are less painful, like the asphyxiation methods and traps described here, after reading the pros and cons of each.
3. Please do let us know if you find any errors in this report or any answers to our remaining questions.

1. ^{^}

    https://contrapeststore.com/pages/resource “What Makes ContraPest® So Effective?”

2. ^{^}

    https://senestech.com/our-story/ 

3. ^{^}

    https://time.com/6264623/rat-birth-control-poison-contrapest/ 

4. ^{^}

    Elmore, H. (2022). The Rodent Birth Control Landscape Paper. https://osf.io/4a2q5 

5. ^{^}

    https://cdn.shopify.com/s/files/1/0255/4986/5032/files/Bioaccumulation_Brochure_2539135e-c3ba-4232-98f2-ce2280d1392f.pdf?v=1653696947 ContraPest Bioaccumulation Brochure

6. ^{^}

    VCD is also known as 1-epoxyethyl-3,4-epoxycyclohexane. https://www.ncbi.nlm.nih.gov/books/NBK507526/ 

7. ^{^}

    Elmore, H., McAuliffe, W., & Mckay, H. (2023). Eradicating rodenticides from pest management is less practical than you think. https://osf.io/458cx 

8. ^{^}

   Anonymized interview.

9. ^{^}

    https://contrapeststore.com/pages/resource “It’s Time for a ContraPest® Deep Dive”

10. ^{^}

     Haas, J. R., Christian, P. J., & Hoyer, P. B. (2007). Effects of impending ovarian failure induced by 4-vinylcyclohexene diepoxide on fertility in C57BL/6 female mice. Comparative medicine, 57(5), 443-449. https://www.ingentaconnect.com/content/aalas/cm/2007/00000057/00000005/art00002 

11. ^{^}

     Xiong, S., Li, Y., Xiang, Y., Peng, N., Shen, C., Cai, Y., ... & Zhang, X. (2019). Dysregulation of lncRNA and circRNA expression in mouse testes after exposure to triptolide. Current Drug Metabolism, 20(8), 665-673. https://www.ingentaconnect.com/content/ben/cdm/2019/00000020/00000008/art00007 

12. ^{^}

     https://cdn.shopify.com/s/files/1/0255/4986/5032/files/DC-CASE-STUDY_NEW-BRAND_WEB2.pdf?v=1653689936 ContraPest report of DC case study

13. ^{^}

     https://www.nbcwashington.com/news/local/is-rat-birth-control-working-district-still-unsure-despite-companys-early-claims/2193250/ 

14. ^{^}

     Juvenile rats were counted as rats that a software, ImageJ, measured as less than 175mm. ImageJ is an image processor in the public domain developed by the NIH. It can identify the size of objects after spatial calibration, according to the ImageJ user guide. The details of ContraPest’s spatial calibration methods are not disclosed. However, an example image is given, and the rat is shown next to the ContraPest bait box. If ImageJ was calibrated appropriately using the standardized size of the bait box, then the measurements of the rats should be reliable. 175mm is a conservative size cut-off, under which we can be fairly sure the rat in the image is a juvenile.

15. ^{^}

     https://cdn.shopify.com/s/files/1/0255/4986/5032/files/ContraPest_Insert_Label_CP-03-10-22.pdf?v=1658265812 ContraPest Insert Label

16. ^{^}

     Lukefahr AL, Frye JB, Wright LE, Marion SL, Hoyer PB, Funk JL. Decreased bone mineral density in rats rendered follicle-deplete by an ovotoxic chemical correlates with changes in follicle-stimulating hormone and inhibin A. Calcif Tissue Int. 2012;90:239–249. https://link.springer.com/article/10.1007/s00223-011-9565-2 

17. ^{^}

     https://contrapeststore.com/pages/shop 

18. ^{^}

     Carolino, R. O., Barros, P. T., Kalil, B., & Anselmo-Franci, J. (2019). Endocrine profile of the VCD-induced perimenopausal model rat. PLoS One, 14(12), e0226874. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936812/ 

19. ^{^}

     https://www.fishersci.com/store/msds?partNumber=AC140885000&productDescription=4-VINYL-1-CYCLOHEXENE%2C+9+500ML&vendorId=VN00032119&countryCode=US&language=en MSDS for VCD

20. ^{^}

     https://en.wikipedia.org/wiki/Brown_rat 

21. ^{^}

     https://cdn.caymanchem.com/cdn/msds/11973m.pdf MSDS for triptolide

22. ^{^}

     In the 2017 paper co-authored by the USDA and SenesTech, carcinogenicity is mentioned in four references. However, we could not access two of these papers. The other two papers were not written to test carcinogencity, but rather to test imaging methods.

23. ^{^}

     https://www.ncbi.nlm.nih.gov/books/NBK507526/ 

24. ^{^}

     https://www.petmd.com/exotic/conditions/cancer/c_ex_rt_cancers_tumors 

25. ^{^}

     Ziaei, S., & Halaby, R. (2016). Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: A mini review. Avicenna journal of phytomedicine, 6(2), 149. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877967/ 

26. ^{^}

     Witmer, G. W., Raymond-Whish, S., Moulton, R. S., Pyzyna, B. R., Calloway, E. M., Dyer, C. A., ... & Hoyer, P. B. (2017). Compromised fertility in free feeding of wild-caught Norway rats (Rattus norvegicus) with a liquid bait containing 4-vinylcyclohexene diepoxide and triptolide. Journal of Zoo and Wildlife Medicine, 48(1), 80-90. https://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=2920&context=icwdm_usdanwrc 

27. ^{^}

     Adedara, I. A., Abolaji, A. O., Ladipo, E. O., Fatunmibi, O. J., Abajingin, A. O., & Farombi, E. O. (2017). 4-Vinylcyclohexene diepoxide disrupts sperm characteristics, endocrine balance and redox status in testes and epididymis of rats. Redox Report, 22(6), 388-398. https://www.tandfonline.com/doi/full/10.1080/13510002.2016.1259718 

28. ^{^}

     Mayer, L. P., Pearsall, N. A., Christian, P. J., Devine, P. J., Payne, C. M., McCuskey, M. K., ... & Hoyer, P. B. (2002). Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene diepoxide. Reproductive Toxicology, 16(6), 775-781. https://www.sciencedirect.com/science/article/pii/S0890623802000485?via%3Dihub 

29. ^{^}

     Zhang, J., Jiang, Z., Mu, X., Wen, J., Su, Y., & Zhang, L. (2012). Effect of triptolide on progesterone production from cultured rat granulosa cells. Arzneimittelforschung, 62(06), 301-306. https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0032-1309041 

30. ^{^}

     Zhang, J., Liu, L., Mu, X., Jiang, Z., & Zhang, L. (2012). Effect of triptolide on estradiol release from cultured rat granulosa cells. Endocrine journal, 59(6), 473-481. https://www.jstage.jst.go.jp/article/endocrj/59/6/59_EJ11-0407/_article/-char/ja/ 

31. ^{^}

     Liu, J., Jiang, Z., Liu, L., Zhang, Y., Zhang, S., Xiao, J., ... & Zhang, L. (2011). Triptolide induces adverse effect on reproductive parameters of female Sprague-Dawley rats. Drug and Chemical Toxicology, 34(1), 1-7. https://www.tandfonline.com/doi/abs/10.3109/01480541003774358 

32. ^{^}

     Xi, C., Peng, S., Wu, Z., Zhou, Q., & Zhou, J. (2017). Toxicity of triptolide and the molecular mechanisms involved. Biomedicine & Pharmacotherapy, 90, 531-541. https://doi.org/10.1016/j.biopha.2017.04.003

33. ^{^}

     Qiu, D., & Kao, P. N. (2003). Immunosuppressive and anti-inflammatory mechanisms of triptolide, the principal active diterpenoid from the Chinese medicinal herb Tripterygium wilfordii Hook. f. Drugs in R & D, 4, 1-18. https://link.springer.com/article/10.2165/00126839-200304010-00001 

34. ^{^}

     This is different from birth control for human women, which uses steroid hormones to prevent ovulation without depleting any ovarian follicles.

35. ^{^}

     https://ivi-fertility.com/blog/difference-primordial-primary-follicles/ 

36. ^{^}

     https://www.sciencedirect.com/topics/medicine-and-dentistry/primordial-follicle 

37. ^{^}

     Fortune, J. E., Yang, M. Y., & Muruvi, W. (2010). The earliest stages of follicular development: follicle formation and activation. Society of Reproduction and Fertility supplement, 67, 203. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316466/ 

38. ^{^}

     Mayer, L. P., & Dyer, C. A. (2020). U.S. Patent No. 10,646,501. Washington, DC: U.S. Patent and Trademark Office. https://patents.google.com/patent/US9956235B2/en 

39. ^{^}

     Mazaud, S., Guigon, C. J., Lozach, A., Coudouel, N., Forest, M. G., Coffigny, H., & Magre, S. (2002). Establishment of the reproductive function and transient fertility of female rats lacking primordial follicle stock after fetal γ-irradiation. Endocrinology, 143(12), 4775-4787. https://academic.oup.com/endo/article/143/12/4775/2880507 

40. ^{^}

     Mayer, L. P., Pearsall, N. A., Christian, P. J., Devine, P. J., Payne, C. M., McCuskey, M. K., ... & Hoyer, P. B. (2002). Long-term effects of ovarian follicular depletion in rats by 4-vinylcyclohexene diepoxide. Reproductive Toxicology, 16(6), 775-781. https://www.sciencedirect.com/science/article/pii/S0890623802000485?via%3Dihub 

41. ^{^}

     Kanter, E. M., Walker, R. M., Marion, S. L., Brewer, M., Hoyer, P. B., & Barton, J. K. (2006). Dual modality imaging of a novel rat model of ovarian carcinogenesis. Journal of biomedical optics, 11(4), 041123-041123. https://www.spiedigitallibrary.org/journals/journal-of-biomedical-optics/volume-11/issue-4/041123/Dual-modality-imaging-of-a-novel-rat-model-of-ovarian/10.1117/1.2236298.full?SSO=1 

42. ^{^}

    Huynh, Phuong N., Amiya P. Sinha Hikim, Christina Wang, Ksenija Stefonovic, Yan He Lue, Andrew Leung, Vince Atienza, Sima Baravarian, Vichai Reutrakul, and Ronald S. Swerdloff. "Long‐term effects of triptolide on spermatogenesis, epididymal sperm function, and fertility in male rats." Journal of Andrology 21, no. 5 (2000): 689-699. https://onlinelibrary.wiley.com/doi/abs/10.1002/j.1939-4640.2000.tb02137.x 

43. ^{^}

     Elmore, H., McAuliffe, W., & Mckay, H. (2023). Paths to reducing rodenticide use in the US Paper. https://osf.io/4ha57/